JAK-STAT signaling pathway - Knowledge (XXG)

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receptor. Two STAT proteins then bind to the phosphates, and then the STATs are phosphorylated by JAKs to form a dimer. The dimer enters the nucleus, binds to DNA, and causes transcription of target genes. The JAK-STAT system consists of three main components: (1) a receptor (green), which penetrates the cell membrane; (2) Janus kinase (JAK) (yellow), which is bound to the receptor, and; (3) Signal Transducer and Activator of Transcription (STAT) (blue), which carries the signal into the nucleus and DNA. The red dots are phosphates. After the cytokine binds to the receptor, JAK adds a phosphate to (phosphorylates) the receptor. This attracts the STAT proteins, which are also phosphorylated and bind to each other, forming a pair (dimer). The dimer moves into the nucleus, binds to the DNA, and causes transcription of genes. Enzymes that add phosphate groups are called protein kinases.

812:. SHP-2 has a very similar structure to SHP-1, but unlike SHP-1, SHP-2 is produced in many different cell types - not just blood cells. Humans have two SHP-2 proteins, each made up of 593 and 597 amino acids. The SH2 domains of SHP-2 appear to play an important role in controlling the activity of SHP-2. One of the SH2 domains binds to the catalytic domain of SHP-2, to prevent SHP-2 functioning. Then, when a protein with a phosphorylated tyrosine binds, the SH2 domain changes orientation and SHP-2 is activated. SHP-2 is then able to remove phosphate groups from JAKs, STATs and the receptors themselves - so, like SHP-1, can prevent the phosphorylation needed for the pathway to continue, and therefore inhibit JAK-STAT signalling. Like SHP-1, SHP-2 is able to remove these phosphate groups through the action of the conserved cysteine, arginine, glutamine and WPD loop. 672: 426: 1201: 192: 1035: 507:, can bind to phosphorylated tyrosines on receptors and directly phosphorylate STATs, resulting in STAT dimerization. Therefore, unlike the traditional mechanism, STATs can be phosphorylated not just by JAKs, but by other receptor-bound kinases. So, if one of the kinases (either JAK or the alternative SH2-containing kinase) cannot function, signalling may still occur through activity of the other kinase. This has been shown experimentally. 6608: 409:, and these co-activators increase the rate of transcription of target genes. The coactivators are able to do this by making genes on DNA more accessible to STATs and by recruiting proteins needed for transcription of genes. The interaction between STATs and coactivators occurs through the transactivation domains (TADs) of STATs. The TADs on STATs can also interact with 756:. It contains two SH2 domains and a catalytic domain (the region of a protein that carries out the main function of the protein) - the catalytic domain contains the amino acid sequence VHCSAGIGRTG (a sequence typical of PTPs). As with all PTPs, a number of amino acid structures are essential for their function: conserved 848:. CD45 is mainly produced in blood cells. In humans it has been shown to be able to act on JAK1 and JAK3, whereas in mice, CD45 is capable of acting on all JAKs. One study indicates that CD45 can reduce the amount of time that JAK-STAT signalling is active. The exact details of how CD45 functions is still unknown. 789:(EpoR). Here, SHP-1 binds directly to a tyrosine residue (at position 429) on EpoR and removes phosphate groups from the receptor-associated JAK2. The ability of SHP-1 to negatively regulate the JAK-STAT pathway has also been seen in experiments using mice lacking SHP-1. These mice experience characteristics of 627:

embryos, whilst mutations in the genes coding for JAKs and STATs can cause deformities in the body patterns of flies, particularly defects in forming body segments. One theory as to how interfering with JAK-STAT signalling might cause these defects is that STATs may directly bind to DNA and promote

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However, SHP-1 may also promote JAK-STAT signalling. A study in 1997 found that SHP-1 potentially allows higher amounts of STAT activation, as opposed to reducing STAT activity. A detailed molecular understanding for how SHP-1 can both activate and inhibit the signalling pathway is still unknown.

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Key steps of the JAK-STAT pathway. JAK-STAT signalling is made of three major proteins: cell-surface receptors, Janus kinases (JAKs), and signal transducer and activator of transcription proteins (STATs). Once a ligand (red triangle) binds to the receptor, JAKs add phosphates (red circles) to the

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Remmers, Elaine F.; Plenge, Robert M.; Lee, Annette T.; Graham, Robert R.; Hom, Geoffrey; Behrens, Timothy W.; de Bakker, Paul I.W.; Le, Julie M.; Lee, Hye-Soon; Batliwalla, Franak; Li, Wentian; Masters, Seth L.; Booty, Matthew G.; Carulli, John P.; Padyukov, Leonid; Alfredsson, Lars; Klareskog,

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and a 40-amino-acid region called the SOCS box. The SOCS box can interact with a number of proteins to form a protein complex, and this complex can then cause the breakdown of JAKs and the receptors themselves, therefore inhibiting JAK-STAT signalling. The protein complex does this by allowing a

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Cancer involves abnormal and uncontrollable cell growth in a part of the body. Therefore, since JAK-STAT signalling can allow the transcription of genes involved in cell division, one potential effect of excessive JAK-STAT signalling is cancer formation. High levels of STAT activation have been

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amino acids (WPD loop). When SHP-1 is inactive, the SH2 domains interact with the catalytic domain, and so the phosphatase is unable to function. When SHP-1 is activated however, the SH2 domains move away from the catalytic domain, exposing the catalytic site and therefore allowing phosphatase

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SOCS can also function by binding to proteins involved in JAK-STAT signalling and blocking their activity. For example, the SH2 domain of SOCS1 binds to a tyrosine in the activation loop of JAKs, which prevents JAKs from phosphorylating each other. The SH2 domains of SOCS2, SOCS3 and CIS bind

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by PIAS1 has been shown to prevent activation of genes by STAT1. Other studies have demonstrated that adding a SUMO group to STATs may block phosphorylation of tyrosines on STATs, preventing their dimerization and inhibiting JAK-STAT signalling. PIASγ has also been shown to prevent STAT1 from

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Acetylation. STAT1, STAT2, STAT3, STAT5 and STAT6 have been shown to be acetylated. STAT1 may have an acetyl group attached to lysines at positions 410 and 413, and as a result, STAT1 can promote the transcription of apoptotic genes - triggering cell death. STAT2 acetylation is important for

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12, 13, 14 and 15 of the JAK2 gene are proposed to be a risk factor in developing lymphoma or leukemia. Additionally, mutated STAT3 and STAT5 can increase JAK-STAT signalling in NK and T cells, which promotes very high proliferation of these cells, and increases the likelihood of developing

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Since adding phosphate groups on tyrosines is such an important part of how the JAK-STAT signalling pathway functions, removing these phosphate groups can inhibit signalling. PTPs are tyrosine phosphatases, so are able to remove these phosphates and prevent signalling. Three major PTPs are

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Given the importance of the JAK-STAT signalling pathway, particularly in cytokine signalling, there are a variety of mechanisms that cells possess to regulate the amount of signalling that occurs. Three major groups of proteins that cells use to regulate this signalling pathway are

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directly to receptors themselves. Also, SOCS1 and SOCS3 can prevent JAK-STAT signalling by binding to JAKs, using segments called kinase inhibitory regions (KIRs) and stopping JAKs binding to other proteins. The exact details of how other SOCS function is less understood.

1156:(located within breasts) can promote cell division and reduce cell apoptosis during pregnancy and puberty, and therefore if excessively activated, cancer can form. High STAT3 activity plays a major role in this process, as it can allow the transcription of genes such as 840:

activity, and promote JAK2/STAT5 signalling. It is still unknown how SHP2 can both inhibit and promote JAK-STAT signalling in the JAK2/STAT5 pathway; one theory is that SHP-2 may promote activation of JAK2, but inhibit STAT5 by removing phosphate groups from it.

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Like SHP-1, SHP-2 is also believed to promote JAK-STAT signalling in some instances, as well as inhibit signalling. For example, one study indicates that SHP-2 may promote STAT5 activity instead of reducing it. Also, other studies propose that SHP-2 may increase

468:(mitogen-activated protein kinase), can phosphorylate STATs, which can increase gene transcription by STATs. However, although MAPK can increase transcription induced by STATs, one study indicates that phosphorylation of STAT3 by MAPK can reduce STAT3 activity. 383:

Serine phosphorylation. Most of the seven STATs (except STAT2) undergo serine phosphorylation. Serine phosphorylation of STATs has been shown to reduce gene transcription. It is also required for the transcription of some target genes of the cytokines IL-6 and

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have been proposed as drugs for therapy. For instance, to treat some forms of leukaemia, targeting and inhibiting JAKs could eliminate the effects of EPO signalling and perhaps prevent the development of leukaemia. One example of a JAK inhibitor drug is

1283:, which is used as a JAK2 inhibitor. STAT inhibitors are also being developed, and many of the inhibitors target STAT3. It has been reported that therapies which target STAT3 can improve the survival of patients with cancer. Another drug, called 417:. Adding acetyl groups removes the positive charge on lysine residues, and as a result there are weaker interactions between histones and DNA, making DNA more accessible to STATs and enabling an increase in the transcription of target genes. 464:, has an SH2 domain, and therefore it can bind to receptors phosphorylated by JAKs (in a similar way to PI3K). Grb2 then functions to allow the MAPK/ERK pathway to progress. Secondly, a protein activated by the MAPK/ERK pathway, called 1061:(as well as other cytokines); therefore patients with mutations in the JAK3 gene often experience issues affecting many aspects of the immune system. For example, non-functional JAK3 causes SCID, which results in patients having no 335:. One example of this is tyrosine phosphorylation (which is fundamental for JAK-STAT signalling), but STATs experience other modifications, which may affect STAT behaviour in JAK-STAT signalling. These modifications include: 449:. When JAKs are activated and phosphorylate tyrosine residues on receptors, proteins with SH2 domains (such as STATs) are able bind to the phosphotyrosines, and the proteins can carry out their function. Like STATs, the 1568:

Kisseleva; Bhattacharya, S; Braunstein, J; Schindler, CW; et al. (2002-02-20). "Signaling through the JAK/STAT pathway, recent advances and future challenges". Gene. 285 (1–2): 1–24. doi:10.1016/S0378-1119(02)00398-0.

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associated with cancer; in particular, high amounts of STAT3 and STAT5 activation is mostly linked to more dangerous tumours. For example, too much STAT3 activity has been associated with increasing the likelihood of

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The JAK-STAT pathway in cytokine receptor signalling can activate STATs, which can bind to DNA and allow the transcription of genes involved in immune cell division, survival, activation and recruitment. For example,

228:. STATs then bind to the phosphorylated tyrosines on the receptor using their SH2 domains, and then they are tyrosine-phosphorylated by JAKs, causing the STATs to dissociate from the receptor. At least STAT5 requires 3098:"Cytokine-induced Paracrystals Prolong the Activity of Signal Transducers and Activators of Transcription (STAT) and Provide a Model for the Regulation of Protein Solubility by Small Ubiquitin-like Modifier (SUMO)" 3867:

Irie-Sasaki, Junko; Sasaki, Takehiko; Matsumoto, Wataru; Opavsky, Anne; Cheng, Mary; Welstead, Grant; Griffiths, Emily; Krawczyk, Connie; Richardson, Christopher D.; Aitken, Karen; Iscove, Norman; Koretzky, Gary;

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Johan, M. F.; Bowen, D. T.; Frew, M. E.; Goodeve, A. C.; Reilly, J. T. (2005). "Aberrant methylation of the negative regulators RASSFIA, SHP-1 and SOCS-1 in myelodysplastic syndromes and acute myeloid leukaemia".

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the transcription of genes involved in forming body segments, and therefore by mutating JAKs or STATs, flies experience segmentation defects. STAT binding sites have been identified on one of these genes, called

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Rodig, Scott J; Meraz, Marco A; White, J.Michael; Lampe, Pat A; Riley, Joan K; Arthur, Cora D; King, Kathleen L; Sheehan, Kathleen C.F; Yin, Li; Pennica, Diane; Johnson, Eugene M; Schreiber, Robert D (1998).

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JAK-STAT pathways that use STAT3 require acetylation for transcription of IL-6 response genes. STAT5 acetylation on lysines at positions 694 and 701 is important for effective STAT dimerization in

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are substances produced by immune cells that can alter the activity of neighbouring cells, the effects of JAK-STAT signalling are often more highly seen in cells of the immune system. For example,

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An example of the integration between JAK-STAT, MAPK/ERK and PI3K/AKT/mTOR signalling pathways. JAKs phosphorylate cytokine receptors which can bind a protein called Grb2. Grb2 then activates

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activity. SHP-1 is then able to bind and remove phosphate groups from the JAKs associated with receptors, preventing the transphosphorylation needed for the signalling pathway to progress.

638:), to support this theory. Of all the segment stripes affected by JAK or STAT mutations, the fifth stripe is affected the most, the exact molecular reasons behind this are still unknown. 1649:

Freund, P.; Kerenyi, M. A.; Hager, M.; Wagner, T.; Wingelhofer, B.; Pham, H T T.; Elabd, M.; Han, X.; Valent, P.; Gouilleux, F.; Sexl, V.; Krämer, O. H.; Groner, B.; Moriggl, R. (2017).

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also has an SH2 domain, and therefore it is also able to bind to these phosphorylated receptors. As a result, activating the JAK-STAT pathway can also activate PI3K/AKT/mTOR signalling.

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Paulson, Matthew; Press, Carolyn; Smith, Eric; Tanese, Naoko; Levy, David E. (2002). "IFN-Stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff".

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signalling, where SHP-2 is able to remove phosphate groups from proteins in the pathway, such as STAT1. In a similar manner, SHP-2 has also been shown to reduce signalling involving

5537: 3512:"Positive Effects of SH2 Domain-containing Tyrosine Phosphatase SHP-1 on Epidermal Growth Factor- and Interferon-γ-stimulated Activation of STAT Transcription Factors in HeLa Cells" 2317:"Sustained Src Inhibition Results in Signal Transducer and Activator of Transcription 3 (STAT3) Activation and Cancer Cell Survival via Altered Janus-Activated Kinase-STAT3 Binding" 1813:

Yang, J.; Huang, J.; Dasgupta, M.; Sears, N.; Miyagi, M.; Wang, B.; Chance, M. R.; Chen, X.; Du, Y.; Wang, Y.; An, L.; Wang, Q.; Lu, T.; Zhang, X.; Wang, Z.; Stark, G. R. (2010).

5228: 224:, which increases the activity of their kinase domains. The activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding sites for proteins possessing 307:(IRF9) to enter the nucleus. Not as much is known about nuclear entrance of other STATs, but it has been suggested that a sequence of amino acids in the DNA-binding domain of 1200: 441:, STATs and Akt can then interact with other proteins. The receptor is not shown as a dimer, and only one side of the receptors are shown phosphorylated for simplification 212:, to cell-surface receptors, causes the receptors to dimerize, which brings the receptor-associated JAKs into close proximity. The JAKs then phosphorylate each other on 5769: 3268:"Protein tyrosine phosphatase containing SH2 domains: characterization, preferential expression in hematopoietic cells, and localization to human chromosome 12p12-p13" 6231: 2465:

Grebien, F.; Kerenyi, M. A.; Kovacic, B.; Kolbe, T.; Becker, V.; Dolznig, H.; Pfeffer, K.; Klingmuller, U.; Muller, M.; Beug, H.; Mullner, E. W.; Moriggl, R. (2008).

388:. It has been proposed that phosphorylation of serine can regulate STAT1 dimerization, and that continuous serine phosphorylation on STAT3 influences cell division. 720:

functioning. PIAS proteins may also function by preventing STATs from binding to DNA (and therefore preventing gene activation), and by recruiting proteins called

5697: 1127:, and Th17 cells can induce psoriasis. Also, since many cytokines function through the STAT3 transcription factor, STAT3 plays a significant role in maintaining 5819: 4836: 6251: 4596:

Kim, Jinkoo; Jung, Younghun; Sun, Hongli; Joseph, Jeena; Mishra, Anjali; Shiozawa, Yusuke; Wang, Jingcheng; Krebsbach, Paul H.; Taichman, Russell S. (2012).

1131:. In addition, because patients with JAK3 gene mutations have no functional T cells, B cells or NK cells, they would more likely to develop skin infections. 1111:

Patients with a faulty JAK-STAT signalling pathway may also experience skin disorders. For example, non-functional cytokine receptors, and overexpression of

902:, which signals for a protein to be broken down. The proteins, such as JAKs and the receptors, are then transported to a compartment in the cell called the 433:

which stimulate MAPK signalling. MAPK can also phosphorylate STATs. Phosphorylated cytokine receptors can also be bound by PI3K, which allows activation of

5879: 5530: 595:(the process of a cell becoming more specialised). In some flies with faulty JAK genes, too much blood cell division can occur, potentially resulting in 3923:

Alexander, Warren S.; Hilton, Douglas J. (2004). "The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response".

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and show high levels of cell proliferation, which are typical characteristics of an abnormally high level of JAK-STAT signalling. Additionally, adding

1144:(skin cancer) returning after treatment and abnormally high levels of STAT5 activity have been linked to a greater probability of patient death from 276:

that control the flow of substances in and out of the nucleus. To enable STATs to move into the nucleus, an amino acid sequence on STATs, called the

6222: 6211: 6187: 5677: 5221: 68:(STATs), and receptors (which bind the chemical signals). Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, 3872:; Liu, Peter; Rothstein, David M.; Penninger, Josef M. (2001). "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling". 319:

can both bind to importin α3. In addition, STAT3, STAT5 and STAT6 can enter the nucleus even if they are not phosphorylated at tyrosine residues.

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Groner, Bernd; von Manstein, Viktoria (2017). "Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition".

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Ma, L.; Gao, J.-s.; Guan, Y.; Shi, X.; Zhang, H.; Ayrapetov, M. K.; Zhang, Z.; Xu, L.; Hyun, Y.-M.; Kim, M.; Zhuang, S.; Chin, Y. E. (2010).

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residue, at position 140, and it is suggested that this could reduce STAT3 activity. There is debate as to whether STAT1 is methylated on an

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Ke, Yuehai; Lesperance, Jacqueline; Zhang, Eric E.; Bard-Chapeau, Emilie A.; Oshima, Robert G.; Muller, William J.; Feng, Gen-Sheng (2006).

1119:(an autoimmune disease associated with red, flaky skin). STAT3 plays an important role in psoriasis, as STAT3 can control the production of 5845: 715:(small ubiquitin-like modifier), onto other proteins – such as JAKs and STATs, modifying their function. The addition of a SUMO group onto 704: 648: 3825:"CD45 Controls Interleukin-4-mediated IgE Class Switch Recombination in Human B Cells through Its Function as a Janus Kinase Phosphatase" 5371: 5214: 5083: 1212: 1018:, dysfunctional proteins in the pathway may lead to a number of diseases. For example, alterations in JAK-STAT signalling can result in 983: 2658:

Yan, Riqiang; Small, Stephen; Desplan, Claude; Dearolf, Charles R; Darnell, James E; Roberts, T M; D'Andrea, A D; Dearolf, C R (1996).

5577: 5319: 5051: 1310: 967: 866: 656: 3551:

Neel, Benjamin G.; Gu, Haihua; Pao, Lily (2003). "The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling".

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Lars; Chen, Wei V.; Amos, Christopher I.; Criswell, Lindsey A.; Seldin, Michael F.; Kastner, Daniel L.; Gregersen, Peter K. (2007).

959: 858: 4800: 244:, where the SH2 domain of each STAT binds the phosphorylated tyrosine of the opposite STAT, and the dimer then translocates to the 1023: 465: 3965:"Suppressors of Cytokine Signaling (SOCS) Proteins and JAK/STAT Pathways: Regulation of T-Cell Inflammation by SOCS1 and SOCS3" 3733:"Conditional Deletion of Shp2 in the Mammary Gland Leads to Impaired Lobulo-alveolar Outgrowth and Attenuated Stat5 Activation" 2418:"Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses" 483:, which then phosphorylates key tyrosines on the tail of the receptor. Phosphorylation then recruits an adaptor protein called 332: 288:(associated with GTP) binds to the importins, releasing them from the STAT dimer. The STAT dimer is then free in the nucleus. 6638: 6242: 5944: 3869: 3383:"SHP1 and SHP2 Protein-tyrosine Phosphatases Associate with βc after Interleukin-3-induced Receptor Tyrosine Phosphorylation" 367:

Acetylation of STAT3 has been suggested to be important for its dimerization, DNA-binding and gene-transcribing ability, and

3592:"SHP-2 Is a Dual-specificity Phosphatase Involved in Stat1 Dephosphorylation at Both Tyrosine and Serine Residues in Nuclei" 591:

JAK-STAT signalling plays an important role in animal development. The pathway can promote blood cell division, as well as

5457: 612:). When mutations occur in genes coding for JAKs, some cells in the eye may be unable to divide, and other cells, such as 277: 155:. STAT proteins contain many different domains, each with a different function, of which the most conserved region is the 6598: 3631:

Chen, Yuhong; Wen, Renren; Yang, Shoua; Schuman, James; Zhang, Eric E.; Yi, Taolin; Feng, Gen-Sheng; Wang, Demin (2003).

6628: 6546: 5078: 4822: 1651:"O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies" 927: 652: 2043:"Essential Role of STAT3 in Postnatal Survival and Growth Revealed by Mice Lacking STAT3 Serine 727 Phosphorylation" 6536: 6178: 4880: 4863: 4648:

Razaghi, Ali; Szakos, Attila; Alouda, Marwa; Bozóky, Béla; Björnstedt, Mikael; Szekely, Laszlo (14 November 2022).

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Lyons, Bonnie L; Lynes, Michael A; Burzenski, Lisa; Joliat, Melissa J; Hadjout, Nacima; Shultz, Leonard D (2003).

6137: 5607: 5276: 5093: 5088: 4902: 2619:"Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila" 1204: 450: 410: 4107:

Pesu, Marko; Candotti, Fabio; Husa, Matthew; Hofmann, Sigrun R.; Notarangelo, Luigi D.; O'Shea, John J. (2005).

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Negative regulation by SHP-2 has been reported in a number of experiments - one example has been when exploring

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signalling. Adding acetyl groups to STAT6 is suggested to be essential for gene transcription in some forms of

249: 2946:"Dynamic Regulation of JAK-STAT Signaling Through the Prolactin Receptor Predicted by Computational Modeling" 1602:"JAK/STAT Pathways in Cytokine Signaling and Myeloproliferative Disorders: Approaches for Targeted Therapies" 5890: 5586: 5013: 4985: 4912: 4892: 1120: 786: 608: 57: 5602: 6275: 5025: 4998: 1304: 1275: 1192:(EPO), which usually allows the development of red blood cells, may be altered in patients with leukemia. 398: 229: 168: 2748:

Henenstreit, D.; Horeks-Hoeck, J.; Duschl, A. (2005). "JAK/STAT-dependent gene regulation by cytokines".

1287:, has been used for psoriasis and rheumatoid arthritis treatment, and has been approved for treatment of 6087: 6082: 6033: 5245: 5151: 5113: 4993: 4939: 4917: 4870: 4650:"Proteomic Analysis of Pleural Effusions from COVID-19 Deceased Patients: Enhanced Inflammatory Markers" 663:

have elucidated the importance of these different regulatory mechanisms on JAK-STAT signaling dynamics.

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Messina, Jane L.; Yu, Hua; Riker, Adam I.; Munster, Pamela N.; Jove, Richard L.; Daud, Adil I. (2008).

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Kershaw, Nadia J.; Murphy, James M.; Lucet, Isabelle S.; Nicola, Nicos A.; Babon, Jeffrey J. (2013).

3881: 3784:"Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling" 3685: 3160: 2566:

Luo, H; Rose, P; Barber, D; Hanratty, W P; Lee, S; Roberts, T M; D'Andrea, A D; Dearolf, C R (1997).

1995: 1826: 1767: 1348: 1097: 402: 328: 221: 6445: 252:- but since most receptors lack built-in kinase activity, JAKs are usually required for signalling. 6153: 6043: 5935: 5652: 5647: 5642: 5632: 5180: 5163: 4849: 1247: 1062: 996: 721: 680: 560: 336: 120:(approximately 300 residues). The kinase domain is vital for JAK activity, since it allows JAKs to 117: 5906: 5764: 5733: 978:, SOCS3 and CIS can bind receptors. SOCS1 and SOCS3 can signal JAKs and receptor for degradation. 6067: 6062: 6028: 6023: 5969: 5784: 5557: 5549: 4773: 4575: 4395:

Ghoreschi, Kamran; Laurence, Arian; Yang, Xiang-Ping; Hirahara, Kiyoshi; O'Shea, John J. (2011).

4377: 4136: 3905: 3587: 3492: 3328:

M. Scott, Latanya; R. Lawrence, Harshani; M. Sebti, Said; J. Lawrence, Nicholas; Wu, Jie (2010).

3037: 2926: 2871: 2814: 2689: 2568:"Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian JAK-STAT pathways" 2548: 2447: 2156: 2041:

Shen, Y.; Schlessinger, K.; Zhu, X.; Meffre, E.; Quimby, F.; Levy, D. E.; Darnell, J. E. (2003).

1372: 1292: 1078: 790: 613: 180: 37: 6556: 5860: 5850: 5840: 5774: 5723: 1288: 6485: 6475: 6465: 6402: 6127: 5830: 4451:"The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours" 3096:

Droescher, Mathias; Begitt, Andreas; Marg, Andreas; Zacharias, Martin; Vinkemeier, Uwe (2011).

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group to STATs can block their phosphorylation, which prevents STATs entering the nucleus. (B)

425: 413:(HATs); these HATs add acetyl groups to lysine residues on proteins associated with DNA called 248:

to induce transcription of target genes. STATs may also be tyrosine-phosphorylated directly by

6495: 6480: 6397: 6362: 6107: 5612: 5546: 5309: 5263: 5030: 4765: 4734: 4689: 4671: 4627: 4567: 4523: 4482: 4426: 4369: 4334: 4284: 4235: 4184: 4128: 4089: 4035: 3986: 3940: 3897: 3846: 3805: 3764: 3713: 3654: 3613: 3568: 3533: 3484: 3448: 3427:"Mechanisms of anemia in SHP-1 protein tyrosine phosphatase-deficient "viable motheaten" mice" 3404: 3359: 3299: 3248: 3188: 3129: 3078: 3029: 2983: 2965: 2918: 2910: 2863: 2855: 2806: 2765: 2730: 2681: 2640: 2599: 2540: 2496: 2439: 2397: 2348: 2297: 2245: 2204: 2148: 2113: 2072: 2023: 1964: 1908: 1854: 1795: 1736: 1680: 1631: 1570: 1551: 1485: 1434: 1364: 660: 516: 105: 6422: 5597: 3936: 1756:"STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin- 3" 445:

JAK-STAT signalling is able to interconnect with other cell-signalling pathways, such as the

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proteins can enter the nucleus by binding to importin α3 and importin α6. On the other hand,

6148: 6077: 6072: 5960: 5617: 5156: 5127: 5056: 4952: 4885: 4755: 4724: 4679: 4661: 4617: 4609: 4559: 4513: 4472: 4462: 4416: 4408: 4361: 4324: 4316: 4274: 4266: 4225: 4215: 4174: 4163:"Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors" 4120: 4079: 4069: 4025: 4017: 3976: 3932: 3889: 3836: 3795: 3754: 3744: 3703: 3693: 3644: 3603: 3586:

Wu, Tong R.; Hong, Y. Kate; Wang, Xu-Dong; Ling, Mike Y.; Dragoi, Ana M.; Chung, Alicia S.;

3560: 3523: 3476: 3438: 3394: 3349: 3341: 3289: 3279: 3238: 3230: 3178: 3168: 3119: 3109: 3068: 3019: 2973: 2957: 2902: 2890: 2845: 2796: 2757: 2720: 2671: 2630: 2589: 2579: 2532: 2486: 2478: 2429: 2387: 2379: 2338: 2328: 2287: 2279: 2235: 2194: 2140: 2103: 2062: 2054: 2013: 2003: 1954: 1946: 1898: 1890: 1844: 1834: 1785: 1775: 1726: 1718: 1670: 1662: 1621: 1613: 1541: 1533: 1475: 1465: 1424: 1356: 1124: 600: 580: 519:, the JAK-STAT signalling pathway plays a major role in cytokine receptor signalling. Since 457: 434: 430: 385: 273: 36:

is a chain of interactions between proteins in a cell, and is involved in processes such as

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Since excessive JAK-STAT signalling is responsible for some cancers and immune disorders,

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Luo, Hong; Dearolf, Charles R. (2001). "The JAK/STAT pathway andDrosophila development".

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triggers hyperinflammation through the JAK/STAT pathway, resulting in the recruitment of

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groups to the SHP-1 gene (which reduces the amount of SHP-1 produced) has been linked to

499:

An alternative mechanism for JAK-STAT signalling has also been suggested. In this model,

4797: 3885: 3689: 3164: 1999: 1830: 1771: 1352: 571:. In response to cytokines, such as IL-4, JAK-STAT signalling is also able to stimulate 6612: 6387: 6377: 6304: 5921: 5911: 5835: 5667: 5304: 5299: 5294: 5168: 4975: 4845: 4814: 4684: 4649: 4622: 4597: 4477: 4450: 4421: 4396: 4329: 4304: 4279: 4254: 4230: 4203: 4084: 4057: 4030: 4005: 3759: 3732: 3378: 3354: 3329: 3243: 3218: 3124: 3097: 2978: 2491: 2466: 2392: 2367: 2343: 2316: 2292: 2267: 2224:"Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK)" 2018: 1983: 1959: 1934: 1903: 1878: 1849: 1814: 1790: 1755: 1731: 1706: 1675: 1650: 1626: 1601: 1546: 1521: 1480: 1453: 1263: 1239: 1189: 1172: 1058: 1054: 1042: 1034: 899: 837: 817: 630: 540: 536: 524: 480: 101: 97: 93: 4760: 4747: 3708: 3673: 3564: 3443: 3426: 3294: 3267: 2850: 2833: 2676: 2659: 2594: 2567: 2434: 2417: 2067: 2042: 539:

is needed to carry out signalling for receptors of the cytokines IFNγ, IL-2, IL-4 and

52:. The pathway communicates information from chemical signals outside of a cell to the 6622: 5955: 5738: 5657: 4970: 4792: 4124: 3480: 3183: 3148: 1153: 1149: 1128: 1050: 1046: 1010:

Since the JAK-STAT pathway plays a major role in many fundamental processes, such as

568: 528: 472: 376: 368: 4381: 4352:

Vercelli, Donata (2008). "Discovering susceptibility genes for asthma and allergy".

4140: 4109:"Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs" 3496: 2930: 2875: 2832:

Yamada, Satoshi; Shiono, Satoru; Joo, Akiko; Yoshimura, Akihiko (23 December 2002).

2818: 2693: 2552: 2451: 2160: 1376: 112:(approximately 400 residues), an SH2-related domain (approximately 100 residues), a 6561: 6541: 6460: 6450: 6392: 6339: 6269: 6168: 6112: 5799: 5789: 5779: 5682: 5662: 5627: 5622: 5328: 5286: 5195: 4960: 4956: 4777: 4579: 3909: 3041: 2268:"Interleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity" 1015: 992: 712: 684: 676: 552: 269: 265: 245: 86: 82: 65: 61: 53: 4255:"Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway" 4056:

Villarino, Alejandro V.; Kanno, Yuka; Ferdinand, John R.; O’Shea, John J. (2015).

3055:

Ungureanu, D.; Vanhatupa, S.; Grönholm, J.; Palvimo, J.; Silvennoinen, O. (2005).

2333: 2058: 1950: 1454:"Phosphotyrosine recognition domains: the typical, the atypical and the versatile" 1073:, and this would make SCID individuals susceptible to infection. Mutations of the 4220: 2761: 2482: 2283: 1894: 1537: 1223:

The Janus kinase (JAK)/signal transducer and the activator of the transcription (

379:

signalling, but not all the amino acids which are acetylated on STAT6 are known.

6571: 6566: 6470: 6455: 6427: 6417: 6412: 6367: 6334: 6329: 6324: 6319: 6314: 6299: 6294: 6117: 6102: 6097: 5916: 5901: 5718: 5447: 5190: 5003: 4666: 3149:"A transcriptional corepressor of Stat1 with an essential LXXLL signature motif" 2368:"Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling" 1339:

Aaronson DS, Horvath CM (2002). "A road map for those who don't know JAK-STAT".

1284: 1280: 862: 551:

can enable the transcription of genes which inhibit cell division and stimulate

487:, which activates the MAPK/ERK pathway, and this facilitates gene regulation by 340: 284:. Once the STAT dimer (bound to importins) enters the nucleus, a protein called 237: 209: 176: 175:. In addition, STATs also contain: tyrosine activation, amino-terminal, linker, 160: 109: 49: 41: 17: 6607: 5515: 4518: 4501: 4161:

Welsch, Katharina; Holstein, Julia; Laurence, Arian; Ghoreschi, Kamran (2017).

3981: 3964: 3345: 3073: 3056: 2961: 2801: 2784: 2222:

Jain, Neeraj; Zhang, Tong; Fong, Siok Lyn; Lim, Cheh Peng; Cao, Xinmin (1998).

785:

One example of this is seen in the JAK-STAT signalling pathway mediated by the

6407: 6309: 6163: 5708: 5143: 4563: 3963:

Tamiya, T.; Kashiwagi, I.; Takahashi, R.; Yasukawa, H.; Yoshimura, A. (2011).

3008:"Regulation of gene-activation pathways by PIAS proteins in the immune system" 1243: 1232: 1208: 903: 894: 769: 753: 579:

proliferation, immune cell survival, and the production of an antibody called

532: 500: 285: 225: 205: 191: 172: 164: 156: 5206: 4675: 4412: 4305:"STAT4 and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus" 4074: 3528: 3511: 3399: 3382: 2969: 2945: 2944:

Mortlock, Ryland D.; Georgia, Senta K.; Finley, Stacey D. (1 February 2021).

2914: 2859: 1815:"Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes" 1617: 1092:

are often more likely to develop infections from bacteria and viruses. Also,

606:

The signalling pathway is also crucial for eye development in the fruit fly (

363:

interactions with other STATs, and for the transcription of anti-viral genes.

359:

residue (at position 31), and what the function of this methylation could be.

6581: 6576: 6357: 5804: 5173: 4907: 3698: 3114: 3006:

Shuai, Ke; Liu, Bin; Zhang, Di; Cui, Yan; Zhou, Jinlian; Cui, Sheng (2005).

2008: 1839: 1780: 1470: 1360: 1235: 1116: 1011: 777: 765: 520: 372: 241: 233: 45: 4769: 4738: 4693: 4631: 4571: 4527: 4486: 4430: 4373: 4338: 4288: 4239: 4188: 4132: 4093: 4039: 3990: 3944: 3901: 3850: 3841: 3824: 3809: 3800: 3783: 3768: 3749: 3717: 3674:"Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism" 3658: 3649: 3632: 3617: 3608: 3591: 3572: 3488: 3452: 3363: 3252: 3192: 3173: 3133: 3082: 3033: 2987: 2922: 2891:"Modeling regulatory mechanisms in IL-6 signal transduction in hepatocytes" 2867: 2810: 2769: 2734: 2544: 2500: 2401: 2352: 2301: 2240: 2223: 2208: 2152: 2117: 2108: 2091: 2076: 2027: 1968: 1912: 1858: 1799: 1740: 1684: 1635: 1574: 1555: 1489: 1438: 1429: 1412: 1368: 1227:) pathway were at the centre of attention for driving hyperinflammation in 303:

bind to importin α5. Studies indicate that STAT2 requires a protein called

4202:

Casanova, Jean-Laurent; Holland, Steven M.; Notarangelo, Luigi D. (2012).

4179: 4162: 3537: 3408: 3303: 2725: 2708: 2685: 2644: 2603: 2584: 2443: 2383: 2249: 691:, lowering gene expression. (C) PIAS can also prevent STATs binding to DNA 291:

Specific STATs appear to bind to specific importin proteins. For example,

236:

92 for strong STAT5 tyrosine phosphorylation. These activated STATs form

5809: 5253: 4965: 4922: 4810:

Web Site of Austrian Special Research Program (SFB) on Jak STAT signaling

4467: 4320: 3284: 2467:"Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2" 1452:

Kaneko, Tomonori; Joshi, Rakesh; Feller, Stephan M; Li, Shawn SC (2012).

1228: 1216: 1180: 1176: 1141: 798: 761: 757: 596: 356: 281: 213: 4729: 4712: 4397:"T helper 17 cell heterogeneity and pathogenicity in autoimmune disease" 4021: 3057:"SUMO-1 conjugation selectively modulates STAT1-mediated gene responses" 2660:"Identification of a Stat Gene That Functions in Drosophila Development" 2635: 2618: 659:(SOCS). Computational models of JAK-STAT signaling based on the laws of 4947: 4598:"Erythropoietin mediated bone formation is regulated by mTOR signaling" 4270: 3782:

Yu, Wen-Mei; Hawley, Teresa S; Hawley, Robert G; Qu, Cheng-Kui (2003).

3330:"Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery" 2536: 2366:

Smith, Geoffrey A; Uchida, Kenji; Weiss, Arthur; Taunton, Jack (2016).

1722: 1666: 773: 688: 414: 397:

Like many other transcription factors, STATs are capable of recruiting

261: 201: 4613: 2906: 2199: 2182: 675:

Three ways PIAS proteins can inhibit JAK-STAT signaling. (A) Adding a

471:

One example of JAK-STAT signalling integrating with other pathways is

6382: 6372: 6017: 6013: 6009: 6005: 6001: 5997: 3893: 2315:

Sen, B.; Saigal, B.; Parikh, N.; Gallick, G.; Johnson, F. M. (2009).

2181:

Rawlings, Jason S.; Rosler, Kristin M.; Harrison, Douglas A. (2004).

1600:

Jatiani, S. S.; Baker, S. J.; Silverman, L. R.; Reddy, E. P. (2011).

1259: 1255: 1105: 1070: 1066: 1019: 936: 898:

marker called ubiquitin to be added to proteins, in a process called

809: 794: 576: 504: 476: 352: 351:

Methylation. STAT3 can be dimethylated (have two methyl groups) on a

344: 148: 144: 69: 4713:"Interferon-gamma: an overview of signals, mechanisms and functions" 4365: 4108: 3024: 3007: 4748:"Cytokine signaling in 2002: new surprises in the Jak/Stat pathway" 3823:

Yamada, Takechiyo; Zhu, Daocheng; Saxon, Andrew; Zhang, Ke (2002).

2144: 1148:. Altered JAK-STAT signalling can also be involved in developing 1038:

Psoriasis on the hands can be caused by faulty JAK-STAT signalling.

167:

and is formed approximately from residues 575–680. STATs also have

6052: 5993: 5989: 5985: 5981: 5977: 5973: 5870: 5442: 5437: 5432: 5427: 5422: 5417: 5412: 5394: 5389: 5384: 5379: 5361: 5356: 5351: 5346: 5341: 5336: 1224: 1158: 1112: 1101: 1093: 1089: 1085: 1074: 975: 971: 948: 944: 940: 932: 890: 886: 882: 878: 874: 870: 845: 829: 825: 821: 749: 738: 734: 716: 708: 700: 696: 572: 564: 556: 548: 488: 479:. IL-2 receptors have γ (gamma) chains, which are associated with 406: 316: 312: 308: 300: 296: 292: 152: 140: 136: 132: 128: 3234: 1313:, a helper protein used by major proteins in signalling pathways. 1307:, a type of Janus kinases-blocking drugs used for cancer therapy. 1077:

protein, which can signal with JAK3, has been shown to result in

6437: 6349: 6286: 5500: 5495: 5490: 5485: 5480: 5475: 5470: 5465: 1184: 742: 484: 461: 304: 5519: 5210: 4818: 460:. Firstly, a protein important for MAPK/ERK signalling, called 4793:

JAK-STAT, peer-reviewed journal published by Landes Bioscience

3377:

Bone, Heather; Dechert, Ute; Jirik, Frank; Schrader, John W.;

1522:"Biology and significance of the JAK/STAT signalling pathways" 1164: 599:. JAK-STAT signalling has also been associated with excessive 56:, resulting in the activation of genes through the process of 4449:

Thomas, S J; Snowden, J A; Zeidler, M P; Danson, S J (2015).

3672:

Zhang, E. E.; Chapeau, E.; Hagihara, K.; Feng, G.-S. (2004).

1411:

Schindler, Christian; Levy, David E.; Decker, Thomas (2007).

2709:"Regulation of cytokine signaling pathways by PIAS proteins" 4711:

Schroder K, Hertzog PJ, Ravasi T, Hume DA (February 2004).

2834:"Control mechanism of JAK/STAT signal transduction pathway" 1188:

leukaemia. Also, a JAK-STAT signalling pathway mediated by

331:, they have non-protein molecules attached to them, called 4058:"Mechanisms of Jak/STAT Signaling in Immunity and Disease" 3590:; Han, Zhi-Yong; Feng, Gen-Sheng; Chin, Y. Eugene (2002). 2785:"SOCS proteins: negative regulators of cytokine signaling" 4253:

Au-Yeung, Nancy; Mandhana, Roli; Horvath, Curt M (2014).

535:

development and function. Also, one study indicates that

66:

signal transducer and activator of transcription proteins

1207:

via activation of JAK/STAT signalling pathway following

999:

to lower gene expression. Prevent STATs binding to DNA.

954:

Removes phosphate groups from receptors, JAKs and STATs

5678:

Methoxy polyethylene glycol-epoetin beta (CERA/Mircera)

4809: 3219:"Protein tyrosine phosphatases in the JAK/STAT pathway" 1984:"Acetylation modulates prolactin receptor dimerization" 171:(TAD), which are less conserved and are located at the 1084:

It has been suggested that patients with mutations in

272:(NPCs), which are protein complexes present along the 6596: 3147:

Liu, B.; Gross, M.; ten Hoeve, J.; Shuai, K. (2001).

2889:

Singh, Abhay; Jayaraman, Arul; Hahn, Juergen (2006).

60:. There are three key parts of JAK-STAT signalling: 6516: 6494: 6436: 6348: 6285: 6268: 6261: 6241: 6221: 6201: 6177: 6136: 5943: 5934: 5889: 5869: 5818: 5752: 5696: 5585: 5576: 5556: 5456: 5403: 5370: 5327: 5318: 5285: 5262: 5244: 5136: 5106: 5069: 5044: 5012: 4984: 4938: 4931: 4856: 3862: 3860: 1413:"JAK-STAT Signaling: From Interferons to Cytokines" 724:(HDACs), which lower the level of gene expression. 3969:Arteriosclerosis, Thrombosis, and Vascular Biology 1022:and diseases affecting the immune system, such as 4051: 4049: 3633:"Identification of Shp-2 as a Stat5A Phosphatase" 1406: 995:group to STATs to inhibit STAT activity. Recruit 256:Movement of STATs from the cytosol to the nucleus 5770:Granulocyte macrophage colony-stimulating factor 4746:O'Shea JJ, Gadina M, Schreiber RD (April 2002). 2176: 2174: 2172: 2170: 1404: 1402: 1400: 1398: 1396: 1394: 1392: 1390: 1388: 1386: 863:cytokine-inducible SH2 domain-containing protein 456:JAK-STAT signalling can also integrate with the 3678:Proceedings of the National Academy of Sciences 3153:Proceedings of the National Academy of Sciences 1988:Proceedings of the National Academy of Sciences 1819:Proceedings of the National Academy of Sciences 1760:Proceedings of the National Academy of Sciences 1334: 1332: 1330: 1328: 1326: 695:PIAS are a four-member protein family made of: 4545: 4543: 4541: 4539: 4537: 4444: 4442: 4440: 4156: 4154: 4152: 4150: 4006:"Regulation of Janus kinases by SOCS proteins" 3958: 3956: 3954: 3420: 3418: 3323: 3321: 3319: 3317: 3315: 3313: 1928: 1926: 1924: 1922: 1754:Liu, L.; McBride, K. M.; Reich, N. C. (2005). 1595: 1593: 1591: 1589: 1587: 1585: 1583: 5531: 5222: 4830: 4643: 4641: 3001: 2999: 2997: 2261: 2259: 1935:"Regulation of STAT signaling by acetylation" 1872: 1870: 1868: 683:(histone deacetylase) recruitment can remove 72:, and disorders affecting the immune system. 8: 1877:Stark, George R.; Darnell, James E. (2012). 1700: 1698: 1696: 1694: 667:Protein inhibitors of activated STATs (PIAS) 616:, have been shown not to develop correctly. 4591: 4589: 3266:Yi, T L; Cleveland, J L; Ihle, J N (1992). 2518: 2516: 2514: 2512: 2510: 974:block JAKs active sites using KIR domains. 6537:Leukemia/leukocyte inhibitory factor (LIF) 6282: 6265: 5940: 5582: 5538: 5524: 5516: 5324: 5229: 5215: 5207: 5018: 4935: 4837: 4823: 4815: 3212: 3210: 3208: 3206: 3204: 3202: 1515: 1513: 1511: 1509: 1507: 1505: 1503: 1501: 1499: 619:The entire removal of a JAK and a STAT in 421:Integration with other signalling pathways 6532:FMS-like tyrosine kinase 3 ligand (FLT3L) 5961:Interferon alpha (interferon alfa, IFN-α) 4759: 4728: 4683: 4665: 4621: 4517: 4476: 4466: 4420: 4328: 4278: 4229: 4219: 4178: 4083: 4073: 4029: 3980: 3840: 3799: 3758: 3748: 3707: 3697: 3648: 3607: 3527: 3442: 3398: 3353: 3293: 3283: 3242: 3182: 3172: 3123: 3113: 3072: 3023: 2977: 2849: 2800: 2724: 2675: 2634: 2593: 2583: 2490: 2433: 2391: 2342: 2332: 2291: 2239: 2198: 2107: 2066: 2017: 2007: 1958: 1902: 1848: 1838: 1789: 1779: 1730: 1674: 1625: 1545: 1479: 1469: 1428: 1024:severe combined immunodeficiency disorder 853:Suppressors of cytokine signalling (SOCS) 515:Given that many JAKs are associated with 6554:Additional cytokine receptor modulators: 4798:Jak/Stat pathway (human) on wikipathways 3937:10.1146/annurev.immunol.22.091003.090312 1199: 1123:, and IL-23 can help the development of 1033: 939:: Negative, but could also be positive. 912: 832:proteins, by removing phosphate groups. 670: 424: 323:Role of post-translational modifications 190: 6603: 4204:"Inborn Errors of Human JAKs and STATs" 2266:Malek, Thomas R.; Castro, Iris (2010). 2090:Decker, Thomas; Kovarik, Pavel (2000). 1520:Kiu, Hiu; Nicholson, Sandra E. (2012). 1322: 1168:, which are involved in cell division. 906:, which carries out protein breakdown. 857:There are eight protein members of the 6378:Cucurbitacin I (elatericin B, JSI-124) 5714:Granulocyte colony-stimulating factor 2950:Cellular and Molecular Bioengineering 7: 6073:Interferon kappa (IFN-ε/κ/τ/ζ, IFNK) 5846:Macrophage colony-stimulating factor 4552:Molecular and Cellular Endocrinology 1705:Reich, Nancy C; Rout, M. P. (2014). 1096:mutations have been associated with 728:Protein tyrosine phosphatases (PTPs) 711:. The proteins add a marker, called 649:protein inhibitors of activated STAT 511:Role in cytokine receptor signalling 124:(add phosphate groups to) proteins. 6547:Thymic stromal lymphopoietin (TSLP) 5084:Transcription preinitiation complex 280:(NLS), is bound by proteins called 268:, STAT dimers have to pass through 216:residues located in regions called 116:(approximately 250 residues) and a 5052:Signal transducing adaptor protein 3510:You, Min; Zhao, Zhizhuang (1997). 1311:Signal transducing adaptor protein 1045:can be used for the signalling of 657:suppressors of cytokine signalling 311:might allow nuclear import; also, 169:transcriptional activation domains 25: 2092:"Serine phosphorylation of STATs" 6606: 4602:Journal of Cellular Biochemistry 4125:10.1111/j.0105-2896.2005.00220.x 4010:Biochemical Society Transactions 3481:10.1111/j.1365-2141.2005.05412.x 2895:Biotechnology and Bioengineering 2183:"The JAK/STAT signaling pathway" 1879:"The JAK-STAT Pathway at Twenty" 1458:Cell Communication and Signaling 768:amino acids, and a loop made of 333:post-translational modifications 159:. The SH2 domain is formed of 2 6078:Interferon omega (IFN-ω, IFNW1) 4309:New England Journal of Medicine 3829:Journal of Biological Chemistry 3737:Journal of Biological Chemistry 3637:Journal of Biological Chemistry 3596:Journal of Biological Chemistry 3516:Journal of Biological Chemistry 3387:Journal of Biological Chemistry 3217:Xu, Dan; Qu, Cheng-Kui (2008). 3102:Journal of Biological Chemistry 2617:Binari, R; Perrimon, N (1994). 1417:Journal of Biological Chemistry 1115:have both been associated with 919:Positive or Negative regulation 752:. SHP-1 is mainly expressed in 127:There are seven STAT proteins: 4754:. 109 Suppl (Suppl): S121-31. 4502:"Activated Stat-3 in Melanoma" 4167:European Journal of Immunology 3553:Trends in Biochemical Sciences 3469:British Journal of Haematology 3272:Molecular and Cellular Biology 2572:Molecular and Cellular Biology 2047:Molecular and Cellular Biology 1030:Immune system-related diseases 569:formation of white blood cells 495:Alternative signalling pathway 305:interferon regulatory factor 9 27:Biological signaling pathway h 1: 4761:10.1016/S0092-8674(02)00701-8 3565:10.1016/S0968-0004(03)00091-4 3444:10.1016/S0301-472X(02)01031-7 3334:Current Pharmaceutical Design 2851:10.1016/s0014-5793(02)03842-5 2677:10.1016/S0092-8674(00)81287-8 2435:10.1016/S0092-8674(00)81166-6 2334:10.1158/0008-5472.CAN-08-2944 2059:10.1128/MCB.24.1.407-419.2004 1951:10.1016/j.cellsig.2013.05.007 1183:. Specifically, mutations in 653:protein tyrosine phosphatases 603:division in humans and mice. 475:(IL-2) receptor signaling in 204:, usually cytokines, such as 92:There are four JAK proteins: 4717:Journal of Leukocyte Biology 4221:10.1016/j.immuni.2012.03.016 2783:Krebs DL, Hilton DJ (2001). 2762:10.1358/dnp.2005.18.4.908658 2750:Drug News & Perspectives 2483:10.1182/blood-2007-07-102848 2284:10.1016/j.immuni.2010.08.004 1895:10.1016/j.immuni.2012.03.013 1538:10.3109/08977194.2012.660936 563:(natural killer cells), and 393:Recruitment of co-activators 5922:Thrombopoietin (THPO, MGDF) 5688:Pegol sihematide (EPO-018B) 5608:Carbamylated erythropoietin 4667:10.3390/diagnostics12112789 3925:Annual Review of Immunology 801:(a type of blood cancer) . 278:nuclear localization signal 220:, through a process called 76:Structure of JAKs and STATs 6655: 5238:JAK-STAT signaling pathway 4519:10.1177/107327480801500302 3982:10.1161/ATVBAHA.110.207464 3346:10.2174/138161210791209027 3074:10.1182/blood-2004-11-4514 2962:10.1007/s12195-020-00647-8 2802:10.1634/stemcells.19-5-378 527:activation in response to 411:histone acetyltransferases 34:JAK-STAT signaling pathway 6471:Tofacitinib (tasocitinib) 6428:Tofacitinib (tasocitinib) 6335:Tofacitinib (tasocitinib) 5277:Type II cytokine receptor 5021: 4564:10.1016/j.mce.2017.05.033 4455:British Journal of Cancer 4354:Nature Reviews Immunology 4062:The Journal of Immunology 3012:Nature Reviews Immunology 1933:Zhuang, Shougang (2013). 1707:"STATs get their move on" 1152:. JAK-STAT signalling in 250:receptor tyrosine kinases 6149:Interferon gamma (IFN-γ) 5272:Type I cytokine receptor 5164:Neuroendocrine signaling 4413:10.1016/j.it.2011.06.007 4075:10.4049/jimmunol.1401867 3529:10.1074/jbc.272.37.23376 3400:10.1074/jbc.272.22.14470 1618:10.1177/1947601910397187 1104:mutations are linked to 327:After STATs are made by 6049:Interferon beta (IFN-β) 4803:6 February 2018 at the 3699:10.1073/pnas.0405041101 3431:Experimental Hematology 3223:Frontiers in Bioscience 3115:10.1074/jbc.M111.235978 2623:Genes & Development 2372:Nature Chemical Biology 2187:Journal of Cell Science 2009:10.1073/pnas.1010253107 1840:10.1073/pnas.1016147107 1781:10.1073/pnas.0501643102 1471:10.1186/1478-811X-10-32 1361:10.1126/science.1071545 1250:(NK) cells, as well as 1211:infection resulting in 787:erythropoietin receptor 609:Drosophila melanogaster 200:The binding of various 6527:Cardiotrophin 1 (CT-1) 5026:cAMP-dependent pathway 3842:10.1074/jbc.M201781200 3801:10.1038/sj.onc.1206846 3750:10.1074/jbc.M607325200 3650:10.1074/jbc.M210572200 3609:10.1074/jbc.M207536200 3174:10.1073/pnas.051489598 2241:10.1038/sj.onc.1202238 2109:10.1038/sj.onc.1203481 1430:10.1074/jbc.R700016200 1305:Janus kinase inhibitor 1220: 1039: 893:, each protein has an 692: 442: 270:nuclear pore complexes 197: 6639:Transcription factors 6524:Additional cytokines: 6451:Decernotinib (VX-509) 6088:Peginterferon alfa-2b 6083:Peginterferon alfa-2a 5603:Asialo erythropoietin 5152:Synaptic transmission 5148:Neurocrine signaling 5071:Transcription factors 4918:PI3K/AKT/mTOR pathway 4180:10.1002/eji.201646680 4113:Immunological Reviews 2726:10.1038/sj.cr.7310027 2585:10.1128/MCB.17.3.1562 2384:10.1038/nchembio.2056 1203: 1037: 1006:Clinical significance 674: 447:PI3K/AKT/mTOR pathway 428: 194: 6039:Interferon alfacon-1 5668:Erythropoietin (EPO) 4468:10.1038/bjc.2015.233 4401:Trends in Immunology 4321:10.1056/NEJMoa073003 3285:10.1128/MCB.12.2.836 1262:progressing towards 1098:rheumatoid arthritis 1079:autoimmune disorders 997:histone deacetylases 722:histone deacetylases 575:, which can promote 559:is able to activate 329:protein biosynthesis 222:transphosphorylation 6629:Signal transduction 6186:See IL-28R (IFNLR) 6154:Interferon gamma 1b 6044:Interferon alpha-n3 5181:Mechanotransduction 5169:Exocrine signalling 4976:Signaling molecules 4850:Signal transduction 4730:10.1189/jlb.0603252 4022:10.1042/BST20130077 3886:2001Natur.409..349I 3835:(32): 28830–28835. 3743:(45): 34374–34380. 3690:2004PNAS..10116064Z 3684:(45): 16064–16069. 3643:(19): 16520–16527. 3602:(49): 47572–47580. 3588:Campbell, Andrew G. 3522:(37): 23376–23381. 3393:(22): 14470–14476. 3165:2001PNAS...98.3203L 3108:(21): 18731–18746. 2636:10.1101/gad.8.3.300 2133:Nature Cell Biology 2000:2010PNAS..10719314M 1994:(45): 19314–19319. 1939:Cellular Signalling 1831:2010PNAS..10721499Y 1825:(50): 21499–21504. 1772:2005PNAS..102.8150L 1423:(28): 20059–20063. 1353:2002Sci...296.1653A 791:autoimmune diseases 614:photoreceptor cells 587:Role in development 181:DNA-binding domains 118:pseudokinase domain 6542:Oncostatin M (OSM) 6068:Interferon beta 1b 6063:Interferon beta 1a 6034:Interferon alfa n1 6029:Interferon alfa 2b 6024:Interferon alfa 2a 5858:Kinase inhibitors: 5191:Ion channel gating 4923:Integrin receptors 4857:Signaling pathways 4271:10.4161/jkst.23931 3379:Welham, Melanie J. 2537:10.1002/bies.10016 1723:10.4161/jkst.27080 1667:10.1038/leu.2017.4 1606:Genes & Cancer 1293:ulcerative colitis 1221: 1040: 693: 517:cytokine receptors 443: 347:phosphorylation. 198: 108:. JAKs contains a 6594: 6593: 6590: 6589: 6512: 6511: 6279: 6197: 6196: 5930: 5929: 5673:Erythropoietin-Fc 5547:Cytokine receptor 5513: 5512: 5509: 5508: 5264:Cytokine receptor 5204: 5203: 5186:Phototransduction 5144:Intracrine action 5102: 5101: 5065: 5064: 4953:Neurotransmitters 4614:10.1002/jcb.23347 3880:(6818): 349–354. 3794:(38): 5995–6004. 3340:(16): 1843–1862. 2907:10.1002/bit.21026 2531:(12): 1138–1147. 2234:(24): 3157–3167. 2200:10.1242/jcs.00963 2102:(21): 2628–2637. 1766:(23): 8150–8155. 1661:(10): 2132–2142. 1003: 1002: 687:modifications on 661:chemical kinetics 260:To move from the 16:(Redirected from 6646: 6611: 6610: 6602: 6283: 6273: 6266: 6125:Decoy receptors: 5941: 5618:Darbepoetin alfa 5583: 5540: 5533: 5526: 5517: 5325: 5320:Adaptor proteins 5231: 5224: 5217: 5208: 5157:Chemical synapse 5057:Scaffold protein 5019: 5014:Second messenger 4940:Receptor ligands 4936: 4839: 4832: 4825: 4816: 4781: 4763: 4742: 4732: 4698: 4697: 4687: 4669: 4645: 4636: 4635: 4625: 4593: 4584: 4583: 4547: 4532: 4531: 4521: 4497: 4491: 4490: 4480: 4470: 4446: 4435: 4434: 4424: 4392: 4386: 4385: 4349: 4343: 4342: 4332: 4299: 4293: 4292: 4282: 4250: 4244: 4243: 4233: 4223: 4199: 4193: 4192: 4182: 4173:(7): 1096–1107. 4158: 4145: 4144: 4104: 4098: 4097: 4087: 4077: 4053: 4044: 4043: 4033: 4016:(4): 1042–1047. 4001: 3995: 3994: 3984: 3960: 3949: 3948: 3920: 3914: 3913: 3894:10.1038/35053086 3870:Johnson, Pauline 3864: 3855: 3854: 3844: 3820: 3814: 3813: 3803: 3779: 3773: 3772: 3762: 3752: 3728: 3722: 3721: 3711: 3701: 3669: 3663: 3662: 3652: 3628: 3622: 3621: 3611: 3583: 3577: 3576: 3548: 3542: 3541: 3531: 3507: 3501: 3500: 3463: 3457: 3456: 3446: 3422: 3413: 3412: 3402: 3374: 3368: 3367: 3357: 3325: 3308: 3307: 3297: 3287: 3263: 3257: 3256: 3246: 3229:(1): 4925–4932. 3214: 3197: 3196: 3186: 3176: 3159:(6): 3203–3207. 3144: 3138: 3137: 3127: 3117: 3093: 3087: 3086: 3076: 3052: 3046: 3045: 3027: 3003: 2992: 2991: 2981: 2941: 2935: 2934: 2886: 2880: 2879: 2853: 2844:(1–3): 190–196. 2829: 2823: 2822: 2804: 2780: 2774: 2773: 2745: 2739: 2738: 2728: 2707:Shuai K (2006). 2704: 2698: 2697: 2679: 2655: 2649: 2648: 2638: 2614: 2608: 2607: 2597: 2587: 2578:(3): 1562–1571. 2563: 2557: 2556: 2520: 2505: 2504: 2494: 2477:(9): 4511–4522. 2462: 2456: 2455: 2437: 2412: 2406: 2405: 2395: 2363: 2357: 2356: 2346: 2336: 2327:(5): 1958–1965. 2312: 2306: 2305: 2295: 2263: 2254: 2253: 2243: 2219: 2213: 2212: 2202: 2193:(8): 1281–1283. 2178: 2165: 2164: 2128: 2122: 2121: 2111: 2087: 2081: 2080: 2070: 2038: 2032: 2031: 2021: 2011: 1979: 1973: 1972: 1962: 1945:(9): 1924–1931. 1930: 1917: 1916: 1906: 1874: 1863: 1862: 1852: 1842: 1810: 1804: 1803: 1793: 1783: 1751: 1745: 1744: 1734: 1702: 1689: 1688: 1678: 1646: 1640: 1639: 1629: 1597: 1578: 1566: 1560: 1559: 1549: 1517: 1494: 1493: 1483: 1473: 1449: 1443: 1442: 1432: 1408: 1381: 1380: 1347:(5573): 1653–5. 1336: 1205:Cytokine release 913: 623:causes death of 601:white blood cell 458:MAPK/ERK pathway 274:nuclear envelope 218:activation loops 50:tumour formation 21: 18:JAK/STAT pathway 6654: 6653: 6649: 6648: 6647: 6645: 6644: 6643: 6634:Gene expression 6619: 6618: 6617: 6605: 6597: 6595: 6586: 6508: 6504:Deucravacitinib 6490: 6432: 6344: 6272: 6257: 6237: 6217: 6193: 6173: 6132: 5966:Interferon alfa 5926: 5885: 5865: 5814: 5748: 5744:Pegnartograstim 5729:Lipegfilgrastim 5692: 5638:Epoetin epsilon 5572: 5552: 5544: 5514: 5505: 5452: 5399: 5366: 5314: 5281: 5258: 5240: 5235: 5205: 5200: 5132: 5098: 5061: 5040: 5036:Lipid signaling 5008: 4980: 4927: 4852: 4843: 4805:Wayback Machine 4789: 4784: 4745: 4710: 4706: 4704:Further reading 4701: 4647: 4646: 4639: 4595: 4594: 4587: 4549: 4548: 4535: 4499: 4498: 4494: 4448: 4447: 4438: 4394: 4393: 4389: 4366:10.1038/nri2257 4351: 4350: 4346: 4315:(10): 977–986. 4301: 4300: 4296: 4252: 4251: 4247: 4201: 4200: 4196: 4160: 4159: 4148: 4106: 4105: 4101: 4055: 4054: 4047: 4003: 4002: 3998: 3962: 3961: 3952: 3922: 3921: 3917: 3866: 3865: 3858: 3822: 3821: 3817: 3781: 3780: 3776: 3730: 3729: 3725: 3671: 3670: 3666: 3630: 3629: 3625: 3585: 3584: 3580: 3550: 3549: 3545: 3509: 3508: 3504: 3465: 3464: 3460: 3424: 3423: 3416: 3376: 3375: 3371: 3327: 3326: 3311: 3265: 3264: 3260: 3216: 3215: 3200: 3146: 3145: 3141: 3095: 3094: 3090: 3054: 3053: 3049: 3025:10.1038/nri1667 3005: 3004: 2995: 2943: 2942: 2938: 2888: 2887: 2883: 2831: 2830: 2826: 2782: 2781: 2777: 2747: 2746: 2742: 2706: 2705: 2701: 2657: 2656: 2652: 2616: 2615: 2611: 2565: 2564: 2560: 2522: 2521: 2508: 2464: 2463: 2459: 2414: 2413: 2409: 2365: 2364: 2360: 2321:Cancer Research 2314: 2313: 2309: 2265: 2264: 2257: 2221: 2220: 2216: 2180: 2179: 2168: 2130: 2129: 2125: 2089: 2088: 2084: 2040: 2039: 2035: 1981: 1980: 1976: 1932: 1931: 1920: 1876: 1875: 1866: 1812: 1811: 1807: 1753: 1752: 1748: 1704: 1703: 1692: 1648: 1647: 1643: 1612:(10): 979–993. 1599: 1598: 1581: 1577:. November 2020 1567: 1563: 1519: 1518: 1497: 1451: 1450: 1446: 1410: 1409: 1384: 1338: 1337: 1324: 1320: 1301: 1289:Crohn's disease 1272: 1252:differentiation 1240:dendritic cells 1198: 1146:prostate cancer 1137: 1121:IL-23 receptors 1032: 1008: 855: 730: 669: 644: 593:differentiation 589: 513: 497: 423: 395: 325: 258: 189: 81:Main articles: 78: 28: 23: 22: 15: 12: 11: 5: 6652: 6650: 6642: 6641: 6636: 6631: 6621: 6620: 6616: 6615: 6592: 6591: 6588: 6587: 6585: 6584: 6579: 6574: 6569: 6564: 6559: 6550: 6549: 6544: 6539: 6534: 6529: 6520: 6518: 6514: 6513: 6510: 6509: 6507: 6506: 6500: 6498: 6492: 6491: 6489: 6488: 6483: 6478: 6473: 6468: 6463: 6458: 6453: 6448: 6446:Cercosporamide 6442: 6440: 6434: 6433: 6431: 6430: 6425: 6420: 6415: 6410: 6405: 6400: 6395: 6390: 6388:Deuruxolitinib 6385: 6380: 6375: 6370: 6365: 6360: 6354: 6352: 6346: 6345: 6343: 6342: 6337: 6332: 6327: 6322: 6317: 6312: 6307: 6305:Deuruxolitinib 6302: 6297: 6291: 6289: 6280: 6263: 6259: 6258: 6256: 6255: 6247: 6245: 6239: 6238: 6236: 6235: 6227: 6225: 6219: 6218: 6216: 6215: 6207: 6205: 6199: 6198: 6195: 6194: 6192: 6191: 6183: 6181: 6179:IFNLR (λ, III) 6175: 6174: 6172: 6171: 6166: 6157: 6156: 6151: 6142: 6140: 6134: 6133: 6131: 6130: 6121: 6120: 6115: 6110: 6105: 6100: 6091: 6090: 6085: 6080: 6075: 6070: 6065: 6060: 6046: 6041: 6036: 6031: 6026: 6021: 5963: 5958: 5949: 5947: 5945:IFNAR (α/β, I) 5938: 5932: 5931: 5928: 5927: 5925: 5924: 5919: 5914: 5912:Promegapoietin 5909: 5904: 5895: 5893: 5891:Thrombopoietin 5887: 5886: 5884: 5883: 5875: 5873: 5867: 5866: 5864: 5863: 5854: 5853: 5848: 5843: 5838: 5836:Interleukin-34 5833: 5824: 5822: 5816: 5815: 5813: 5812: 5807: 5802: 5793: 5792: 5787: 5782: 5777: 5772: 5767: 5758: 5756: 5750: 5749: 5747: 5746: 5741: 5736: 5731: 5726: 5721: 5716: 5711: 5702: 5700: 5694: 5693: 5691: 5690: 5685: 5680: 5675: 5670: 5665: 5660: 5655: 5650: 5645: 5640: 5635: 5630: 5625: 5620: 5615: 5610: 5605: 5600: 5591: 5589: 5587:Erythropoietin 5580: 5574: 5573: 5571: 5570: 5562: 5560: 5554: 5553: 5545: 5543: 5542: 5535: 5528: 5520: 5511: 5510: 5507: 5506: 5504: 5503: 5498: 5493: 5488: 5483: 5478: 5473: 5468: 5462: 5460: 5454: 5453: 5451: 5450: 5445: 5440: 5435: 5430: 5425: 5420: 5415: 5409: 5407: 5401: 5400: 5398: 5397: 5392: 5387: 5382: 5376: 5374: 5368: 5367: 5365: 5364: 5359: 5354: 5349: 5344: 5339: 5333: 5331: 5322: 5316: 5315: 5313: 5312: 5307: 5302: 5297: 5291: 5289: 5283: 5282: 5280: 5279: 5274: 5268: 5266: 5260: 5259: 5257: 5256: 5250: 5248: 5242: 5241: 5236: 5234: 5233: 5226: 5219: 5211: 5202: 5201: 5199: 5198: 5193: 5188: 5183: 5178: 5177: 5176: 5166: 5161: 5160: 5159: 5154: 5146: 5140: 5138: 5137:Other concepts 5134: 5133: 5131: 5130: 5125: 5116: 5110: 5108: 5104: 5103: 5100: 5099: 5097: 5096: 5091: 5086: 5081: 5075: 5073: 5067: 5066: 5063: 5062: 5060: 5059: 5054: 5048: 5046: 5042: 5041: 5039: 5038: 5033: 5028: 5022: 5016: 5010: 5009: 5007: 5006: 5001: 4996: 4990: 4988: 4982: 4981: 4979: 4978: 4973: 4971:Growth factors 4968: 4963: 4950: 4944: 4942: 4933: 4929: 4928: 4926: 4925: 4920: 4915: 4910: 4905: 4900: 4895: 4890: 4889: 4888: 4883: 4873: 4868: 4866: 4860: 4858: 4854: 4853: 4846:Cell signaling 4844: 4842: 4841: 4834: 4827: 4819: 4813: 4812: 4807: 4795: 4788: 4787:External links 4785: 4783: 4782: 4743: 4707: 4705: 4702: 4700: 4699: 4637: 4608:(1): 220–228. 4585: 4533: 4512:(3): 196–201. 4506:Cancer Control 4492: 4461:(3): 365–371. 4436: 4407:(9): 395–401. 4387: 4360:(3): 169–182. 4344: 4294: 4245: 4214:(4): 515–528. 4194: 4146: 4119:(1): 127–142. 4099: 4045: 3996: 3975:(5): 980–985. 3950: 3931:(1): 503–529. 3915: 3856: 3815: 3774: 3723: 3664: 3623: 3578: 3559:(6): 284–293. 3543: 3502: 3458: 3437:(3): 234–243. 3414: 3369: 3309: 3278:(2): 836–846. 3258: 3198: 3139: 3088: 3067:(1): 224–226. 3047: 3018:(8): 593–605. 2993: 2936: 2901:(5): 850–862. 2881: 2824: 2775: 2740: 2719:(2): 196–202. 2699: 2670:(3): 421–430. 2650: 2629:(3): 300–312. 2609: 2558: 2506: 2457: 2428:(3): 373–383. 2407: 2378:(5): 373–379. 2358: 2307: 2278:(2): 153–165. 2255: 2214: 2166: 2145:10.1038/ncb747 2139:(2): 140–147. 2123: 2082: 2053:(1): 407–419. 2033: 1974: 1918: 1889:(4): 503–514. 1864: 1805: 1746: 1690: 1641: 1579: 1561: 1526:Growth Factors 1495: 1444: 1382: 1321: 1319: 1316: 1315: 1314: 1308: 1300: 1297: 1276:JAK inhibitors 1271: 1268: 1264:cytokine storm 1248:natural killer 1197: 1194: 1190:erythropoietin 1154:mammary glands 1136: 1133: 1031: 1028: 1007: 1004: 1001: 1000: 989: 986: 980: 979: 965: 962: 956: 955: 952: 930: 924: 923: 920: 917: 900:ubiquitination 854: 851: 850: 849: 814: 813: 783: 782: 729: 726: 668: 665: 643: 640: 588: 585: 567:can drive the 512: 509: 496: 493: 422: 419: 394: 391: 390: 389: 365: 364: 360: 324: 321: 257: 254: 188: 185: 77: 74: 26: 24: 14: 13: 10: 9: 6: 4: 3: 2: 6651: 6640: 6637: 6635: 6632: 6630: 6627: 6626: 6624: 6614: 6609: 6604: 6600: 6583: 6580: 6578: 6575: 6573: 6570: 6568: 6565: 6563: 6560: 6558: 6555: 6552: 6551: 6548: 6545: 6543: 6540: 6538: 6535: 6533: 6530: 6528: 6525: 6522: 6521: 6519: 6515: 6505: 6502: 6501: 6499: 6497: 6493: 6487: 6484: 6482: 6479: 6477: 6474: 6472: 6469: 6467: 6464: 6462: 6459: 6457: 6454: 6452: 6449: 6447: 6444: 6443: 6441: 6439: 6435: 6429: 6426: 6424: 6421: 6419: 6416: 6414: 6411: 6409: 6406: 6404: 6401: 6399: 6396: 6394: 6391: 6389: 6386: 6384: 6381: 6379: 6376: 6374: 6371: 6369: 6366: 6364: 6361: 6359: 6356: 6355: 6353: 6351: 6347: 6341: 6338: 6336: 6333: 6331: 6328: 6326: 6323: 6321: 6318: 6316: 6313: 6311: 6308: 6306: 6303: 6301: 6298: 6296: 6293: 6292: 6290: 6288: 6284: 6281: 6277: 6271: 6267: 6264: 6260: 6253: 6249: 6248: 6246: 6244: 6240: 6233: 6229: 6228: 6226: 6224: 6220: 6213: 6209: 6208: 6206: 6204: 6200: 6189: 6185: 6184: 6182: 6180: 6176: 6170: 6167: 6165: 6162: 6159: 6158: 6155: 6152: 6150: 6147: 6144: 6143: 6141: 6139: 6138:IFNGR (γ, II) 6135: 6129: 6126: 6123: 6122: 6119: 6116: 6114: 6111: 6109: 6106: 6104: 6101: 6099: 6096: 6093: 6092: 6089: 6086: 6084: 6081: 6079: 6076: 6074: 6071: 6069: 6066: 6064: 6061: 6058: 6054: 6050: 6047: 6045: 6042: 6040: 6037: 6035: 6032: 6030: 6027: 6025: 6022: 6019: 6015: 6011: 6007: 6003: 5999: 5995: 5991: 5987: 5983: 5979: 5975: 5971: 5967: 5964: 5962: 5959: 5957: 5956:Albinterferon 5954: 5951: 5950: 5948: 5946: 5942: 5939: 5937: 5933: 5923: 5920: 5918: 5915: 5913: 5910: 5908: 5905: 5903: 5900: 5897: 5896: 5894: 5892: 5888: 5881: 5877: 5876: 5874: 5872: 5868: 5862: 5859: 5856: 5855: 5852: 5849: 5847: 5844: 5842: 5839: 5837: 5834: 5832: 5829: 5826: 5825: 5823: 5821: 5817: 5811: 5808: 5806: 5803: 5801: 5798: 5795: 5794: 5791: 5788: 5786: 5783: 5781: 5778: 5776: 5773: 5771: 5768: 5766: 5763: 5760: 5759: 5757: 5755: 5754:GM-CSF (CSF2) 5751: 5745: 5742: 5740: 5739:Pegfilgrastim 5737: 5735: 5732: 5730: 5727: 5725: 5722: 5720: 5717: 5715: 5712: 5710: 5707: 5704: 5703: 5701: 5699: 5695: 5689: 5686: 5684: 5681: 5679: 5676: 5674: 5671: 5669: 5666: 5664: 5661: 5659: 5658:Epoetin theta 5656: 5654: 5653:Epoetin omega 5651: 5649: 5648:Epoetin kappa 5646: 5644: 5643:Epoetin gamma 5641: 5639: 5636: 5634: 5633:Epoetin delta 5631: 5629: 5626: 5624: 5621: 5619: 5616: 5614: 5611: 5609: 5606: 5604: 5601: 5599: 5596: 5593: 5592: 5590: 5588: 5584: 5581: 5579: 5575: 5568: 5564: 5563: 5561: 5559: 5555: 5551: 5548: 5541: 5536: 5534: 5529: 5527: 5522: 5521: 5518: 5502: 5499: 5497: 5494: 5492: 5489: 5487: 5484: 5482: 5479: 5477: 5474: 5472: 5469: 5467: 5464: 5463: 5461: 5459: 5455: 5449: 5446: 5444: 5441: 5439: 5436: 5434: 5431: 5429: 5426: 5424: 5421: 5419: 5416: 5414: 5411: 5410: 5408: 5406: 5402: 5396: 5393: 5391: 5388: 5386: 5383: 5381: 5378: 5377: 5375: 5373: 5369: 5363: 5360: 5358: 5355: 5353: 5350: 5348: 5345: 5343: 5340: 5338: 5335: 5334: 5332: 5330: 5326: 5323: 5321: 5317: 5311: 5308: 5306: 5303: 5301: 5298: 5296: 5293: 5292: 5290: 5288: 5284: 5278: 5275: 5273: 5270: 5269: 5267: 5265: 5261: 5255: 5252: 5251: 5249: 5247: 5243: 5239: 5232: 5227: 5225: 5220: 5218: 5213: 5212: 5209: 5197: 5194: 5192: 5189: 5187: 5184: 5182: 5179: 5175: 5172: 5171: 5170: 5167: 5165: 5162: 5158: 5155: 5153: 5150: 5149: 5147: 5145: 5142: 5141: 5139: 5135: 5129: 5126: 5124: 5120: 5117: 5115: 5112: 5111: 5109: 5105: 5095: 5092: 5090: 5087: 5085: 5082: 5080: 5077: 5076: 5074: 5072: 5068: 5058: 5055: 5053: 5050: 5049: 5047: 5043: 5037: 5034: 5032: 5029: 5027: 5024: 5023: 5020: 5017: 5015: 5011: 5005: 5002: 5000: 4999:Intracellular 4997: 4995: 4992: 4991: 4989: 4987: 4983: 4977: 4974: 4972: 4969: 4967: 4964: 4962: 4961:Neurohormones 4958: 4957:Neuropeptides 4954: 4951: 4949: 4946: 4945: 4943: 4941: 4937: 4934: 4930: 4924: 4921: 4919: 4916: 4914: 4911: 4909: 4908:Fas apoptosis 4906: 4904: 4901: 4899: 4896: 4894: 4891: 4887: 4884: 4882: 4879: 4878: 4877: 4874: 4872: 4869: 4867: 4865: 4862: 4861: 4859: 4855: 4851: 4847: 4840: 4835: 4833: 4828: 4826: 4821: 4820: 4817: 4811: 4808: 4806: 4802: 4799: 4796: 4794: 4791: 4790: 4786: 4779: 4775: 4771: 4767: 4762: 4757: 4753: 4749: 4744: 4740: 4736: 4731: 4726: 4723:(2): 163–89. 4722: 4718: 4714: 4709: 4708: 4703: 4695: 4691: 4686: 4681: 4677: 4673: 4668: 4663: 4659: 4655: 4651: 4644: 4642: 4638: 4633: 4629: 4624: 4619: 4615: 4611: 4607: 4603: 4599: 4592: 4590: 4586: 4581: 4577: 4573: 4569: 4565: 4561: 4557: 4553: 4546: 4544: 4542: 4540: 4538: 4534: 4529: 4525: 4520: 4515: 4511: 4507: 4503: 4496: 4493: 4488: 4484: 4479: 4474: 4469: 4464: 4460: 4456: 4452: 4445: 4443: 4441: 4437: 4432: 4428: 4423: 4418: 4414: 4410: 4406: 4402: 4398: 4391: 4388: 4383: 4379: 4375: 4371: 4367: 4363: 4359: 4355: 4348: 4345: 4340: 4336: 4331: 4326: 4322: 4318: 4314: 4310: 4306: 4298: 4295: 4290: 4286: 4281: 4276: 4272: 4268: 4264: 4260: 4256: 4249: 4246: 4241: 4237: 4232: 4227: 4222: 4217: 4213: 4209: 4205: 4198: 4195: 4190: 4186: 4181: 4176: 4172: 4168: 4164: 4157: 4155: 4153: 4151: 4147: 4142: 4138: 4134: 4130: 4126: 4122: 4118: 4114: 4110: 4103: 4100: 4095: 4091: 4086: 4081: 4076: 4071: 4067: 4063: 4059: 4052: 4050: 4046: 4041: 4037: 4032: 4027: 4023: 4019: 4015: 4011: 4007: 4000: 3997: 3992: 3988: 3983: 3978: 3974: 3970: 3966: 3959: 3957: 3955: 3951: 3946: 3942: 3938: 3934: 3930: 3926: 3919: 3916: 3911: 3907: 3903: 3899: 3895: 3891: 3887: 3883: 3879: 3875: 3871: 3863: 3861: 3857: 3852: 3848: 3843: 3838: 3834: 3830: 3826: 3819: 3816: 3811: 3807: 3802: 3797: 3793: 3789: 3785: 3778: 3775: 3770: 3766: 3761: 3756: 3751: 3746: 3742: 3738: 3734: 3727: 3724: 3719: 3715: 3710: 3705: 3700: 3695: 3691: 3687: 3683: 3679: 3675: 3668: 3665: 3660: 3656: 3651: 3646: 3642: 3638: 3634: 3627: 3624: 3619: 3615: 3610: 3605: 3601: 3597: 3593: 3589: 3582: 3579: 3574: 3570: 3566: 3562: 3558: 3554: 3547: 3544: 3539: 3535: 3530: 3525: 3521: 3517: 3513: 3506: 3503: 3498: 3494: 3490: 3486: 3482: 3478: 3474: 3470: 3462: 3459: 3454: 3450: 3445: 3440: 3436: 3432: 3428: 3421: 3419: 3415: 3410: 3406: 3401: 3396: 3392: 3388: 3384: 3380: 3373: 3370: 3365: 3361: 3356: 3351: 3347: 3343: 3339: 3335: 3331: 3324: 3322: 3320: 3318: 3316: 3314: 3310: 3305: 3301: 3296: 3291: 3286: 3281: 3277: 3273: 3269: 3262: 3259: 3254: 3250: 3245: 3240: 3236: 3232: 3228: 3224: 3220: 3213: 3211: 3209: 3207: 3205: 3203: 3199: 3194: 3190: 3185: 3180: 3175: 3170: 3166: 3162: 3158: 3154: 3150: 3143: 3140: 3135: 3131: 3126: 3121: 3116: 3111: 3107: 3103: 3099: 3092: 3089: 3084: 3080: 3075: 3070: 3066: 3062: 3058: 3051: 3048: 3043: 3039: 3035: 3031: 3026: 3021: 3017: 3013: 3009: 3002: 3000: 2998: 2994: 2989: 2985: 2980: 2975: 2971: 2967: 2963: 2959: 2955: 2951: 2947: 2940: 2937: 2932: 2928: 2924: 2920: 2916: 2912: 2908: 2904: 2900: 2896: 2892: 2885: 2882: 2877: 2873: 2869: 2865: 2861: 2857: 2852: 2847: 2843: 2839: 2835: 2828: 2825: 2820: 2816: 2812: 2808: 2803: 2798: 2795:(5): 378–87. 2794: 2790: 2786: 2779: 2776: 2771: 2767: 2763: 2759: 2755: 2751: 2744: 2741: 2736: 2732: 2727: 2722: 2718: 2714: 2713:Cell Research 2710: 2703: 2700: 2695: 2691: 2687: 2683: 2678: 2673: 2669: 2665: 2661: 2654: 2651: 2646: 2642: 2637: 2632: 2628: 2624: 2620: 2613: 2610: 2605: 2601: 2596: 2591: 2586: 2581: 2577: 2573: 2569: 2562: 2559: 2554: 2550: 2546: 2542: 2538: 2534: 2530: 2526: 2519: 2517: 2515: 2513: 2511: 2507: 2502: 2498: 2493: 2488: 2484: 2480: 2476: 2472: 2468: 2461: 2458: 2453: 2449: 2445: 2441: 2436: 2431: 2427: 2423: 2419: 2411: 2408: 2403: 2399: 2394: 2389: 2385: 2381: 2377: 2373: 2369: 2362: 2359: 2354: 2350: 2345: 2340: 2335: 2330: 2326: 2322: 2318: 2311: 2308: 2303: 2299: 2294: 2289: 2285: 2281: 2277: 2273: 2269: 2262: 2260: 2256: 2251: 2247: 2242: 2237: 2233: 2229: 2225: 2218: 2215: 2210: 2206: 2201: 2196: 2192: 2188: 2184: 2177: 2175: 2173: 2171: 2167: 2162: 2158: 2154: 2150: 2146: 2142: 2138: 2134: 2127: 2124: 2119: 2115: 2110: 2105: 2101: 2097: 2093: 2086: 2083: 2078: 2074: 2069: 2064: 2060: 2056: 2052: 2048: 2044: 2037: 2034: 2029: 2025: 2020: 2015: 2010: 2005: 2001: 1997: 1993: 1989: 1985: 1978: 1975: 1970: 1966: 1961: 1956: 1952: 1948: 1944: 1940: 1936: 1929: 1927: 1925: 1923: 1919: 1914: 1910: 1905: 1900: 1896: 1892: 1888: 1884: 1880: 1873: 1871: 1869: 1865: 1860: 1856: 1851: 1846: 1841: 1836: 1832: 1828: 1824: 1820: 1816: 1809: 1806: 1801: 1797: 1792: 1787: 1782: 1777: 1773: 1769: 1765: 1761: 1757: 1750: 1747: 1742: 1738: 1733: 1728: 1724: 1720: 1716: 1712: 1708: 1701: 1699: 1697: 1695: 1691: 1686: 1682: 1677: 1672: 1668: 1664: 1660: 1656: 1652: 1645: 1642: 1637: 1633: 1628: 1623: 1619: 1615: 1611: 1607: 1603: 1596: 1594: 1592: 1590: 1588: 1586: 1584: 1580: 1576: 1572: 1565: 1562: 1557: 1553: 1548: 1543: 1539: 1535: 1532:(2): 88–106. 1531: 1527: 1523: 1516: 1514: 1512: 1510: 1508: 1506: 1504: 1502: 1500: 1496: 1491: 1487: 1482: 1477: 1472: 1467: 1463: 1459: 1455: 1448: 1445: 1440: 1436: 1431: 1426: 1422: 1418: 1414: 1407: 1405: 1403: 1401: 1399: 1397: 1395: 1393: 1391: 1389: 1387: 1383: 1378: 1374: 1370: 1366: 1362: 1358: 1354: 1350: 1346: 1342: 1335: 1333: 1331: 1329: 1327: 1323: 1317: 1312: 1309: 1306: 1303: 1302: 1298: 1296: 1294: 1290: 1286: 1282: 1277: 1269: 1267: 1265: 1261: 1257: 1253: 1249: 1245: 1241: 1237: 1234: 1230: 1226: 1218: 1214: 1210: 1206: 1202: 1195: 1193: 1191: 1186: 1182: 1178: 1174: 1171:Mutations in 1169: 1167: 1166: 1161: 1160: 1155: 1151: 1150:breast cancer 1147: 1143: 1134: 1132: 1130: 1129:skin immunity 1126: 1122: 1118: 1114: 1109: 1107: 1103: 1099: 1095: 1091: 1087: 1082: 1080: 1076: 1072: 1068: 1064: 1060: 1056: 1052: 1048: 1044: 1036: 1029: 1027: 1025: 1021: 1017: 1013: 1005: 998: 994: 990: 987: 985: 982: 981: 977: 973: 969: 966: 963: 961: 958: 957: 953: 950: 946: 942: 938: 934: 931: 929: 926: 925: 921: 918: 915: 914: 911: 907: 905: 901: 896: 892: 888: 884: 880: 876: 872: 868: 864: 860: 852: 847: 844: 843: 842: 839: 833: 831: 827: 823: 819: 811: 808: 807: 806: 802: 800: 796: 792: 788: 779: 775: 771: 767: 763: 759: 755: 751: 748: 747: 746: 744: 740: 736: 727: 725: 723: 718: 714: 710: 706: 702: 698: 690: 686: 682: 678: 673: 666: 664: 662: 658: 654: 650: 641: 639: 637: 633: 632: 626: 622: 617: 615: 611: 610: 604: 602: 598: 594: 586: 584: 582: 578: 574: 570: 566: 562: 558: 554: 550: 544: 542: 538: 534: 531:is vital for 530: 526: 522: 518: 510: 508: 506: 502: 494: 492: 490: 486: 482: 478: 474: 473:Interleukin-2 469: 467: 463: 459: 454: 452: 448: 440: 436: 432: 427: 420: 418: 416: 412: 408: 404: 400: 399:co-activators 392: 387: 382: 381: 380: 378: 374: 370: 361: 358: 354: 350: 349: 348: 346: 342: 338: 334: 330: 322: 320: 318: 314: 310: 306: 302: 298: 294: 289: 287: 283: 279: 275: 271: 267: 263: 255: 253: 251: 247: 243: 239: 235: 231: 230:glycosylation 227: 223: 219: 215: 211: 207: 203: 193: 186: 184: 182: 178: 174: 170: 166: 162: 158: 154: 150: 146: 142: 138: 134: 130: 125: 123: 122:phosphorylate 119: 115: 114:kinase domain 111: 107: 103: 99: 95: 90: 89: 88: 84: 75: 73: 71: 67: 63: 62:Janus kinases 59: 58:transcription 55: 51: 47: 43: 42:cell division 39: 35: 30: 19: 6562:Lestaurtinib 6553: 6523: 6461:Ritlecitinib 6393:Lestaurtinib 6340:Upadacitinib 6169:Fontolizumab 6160: 6145: 6124: 6113:Rontalizumab 6094: 5952: 5907:Pegacaristim 5898: 5857: 5827: 5820:M-CSF (CSF1) 5800:Mavrilimumab 5796: 5790:Sargramostim 5780:Molgramostim 5765:Ecogramostim 5761: 5734:Nartograstim 5705: 5698:G-CSF (CSF3) 5683:Peginesatide 5663:Epoetin zeta 5628:Epoetin beta 5623:Epoetin alfa 5594: 5287:Janus kinase 5237: 5196:Gap junction 5031:Ca signaling 4994:Cell surface 4897: 4751: 4720: 4716: 4660:(11): 2789. 4657: 4653: 4605: 4601: 4555: 4551: 4509: 4505: 4495: 4458: 4454: 4404: 4400: 4390: 4357: 4353: 4347: 4312: 4308: 4297: 4265:(3): 23931. 4262: 4258: 4248: 4211: 4207: 4197: 4170: 4166: 4116: 4112: 4102: 4068:(1): 21–27. 4065: 4061: 4013: 4009: 3999: 3972: 3968: 3928: 3924: 3918: 3877: 3873: 3832: 3828: 3818: 3791: 3787: 3777: 3740: 3736: 3726: 3681: 3677: 3667: 3640: 3636: 3626: 3599: 3595: 3581: 3556: 3552: 3546: 3519: 3515: 3505: 3475:(1): 60–65. 3472: 3468: 3461: 3434: 3430: 3390: 3386: 3372: 3337: 3333: 3275: 3271: 3261: 3235:10.2741/3051 3226: 3222: 3156: 3152: 3142: 3105: 3101: 3091: 3064: 3060: 3050: 3015: 3011: 2956:(1): 15–30. 2953: 2949: 2939: 2898: 2894: 2884: 2841: 2838:FEBS Letters 2837: 2827: 2792: 2788: 2778: 2756:(4): 243–9. 2753: 2749: 2743: 2716: 2712: 2702: 2667: 2663: 2653: 2626: 2622: 2612: 2575: 2571: 2561: 2528: 2524: 2474: 2470: 2460: 2425: 2421: 2410: 2375: 2371: 2361: 2324: 2320: 2310: 2275: 2271: 2231: 2227: 2217: 2190: 2186: 2136: 2132: 2126: 2099: 2095: 2085: 2050: 2046: 2036: 1991: 1987: 1977: 1942: 1938: 1886: 1882: 1822: 1818: 1808: 1763: 1759: 1749: 1717:(4): 27080. 1714: 1710: 1658: 1654: 1644: 1609: 1605: 1564: 1529: 1525: 1461: 1457: 1447: 1420: 1416: 1344: 1340: 1273: 1231:, i.e., the 1222: 1175:can lead to 1170: 1163: 1157: 1138: 1110: 1083: 1041: 1016:inflammation 1009: 908: 856: 834: 815: 803: 784: 731: 694: 655:(PTPs) and 645: 635: 631:even-skipped 629: 624: 620: 618: 607: 605: 590: 553:inflammation 545: 514: 503:-containing 498: 470: 455: 451:PI3K protein 444: 431:SOS proteins 396: 366: 326: 290: 259: 246:cell nucleus 210:interleukins 199: 126: 91: 80: 79: 54:cell nucleus 33: 31: 29: 6572:Quizartinib 6567:Midostaurin 6456:Peficitinib 6418:Ruxolitinib 6413:Peficitinib 6368:Baricitinib 6330:Ruxolitinib 6325:Peficitinib 6320:Oclacitinib 6315:Momelotinib 6300:Baricitinib 6295:Abrocitinib 6203:Interleukin 6161:Antibodies: 6118:Sifalimumab 6103:Faralimomab 6098:Anifrolumab 6095:Antibodies: 5917:Romiplostim 5902:Eltrombopag 5871:SCF (c-Kit) 5797:Antibodies: 5785:Regramostim 5719:Lenograstim 5107:By distance 5045:Assistants: 5004:Co-receptor 4654:Diagnostics 2737:. 16474434. 1285:Tofacitinib 1281:ruxolitinib 1244:macrophages 1215:related to 754:blood cells 341:acetylation 337:methylation 226:SH2 domains 206:interferons 177:coiled-coil 110:FERM domain 6623:Categories 6557:Emfilermin 6408:Pacritinib 6310:Filgotinib 6276:inhibitors 6164:Emapalumab 5936:Interferon 5861:Agerafenib 5851:Mirimostim 5841:Lanimostim 5775:Milodistim 5724:Leridistim 5709:Filgrastim 5550:modulators 5174:Pheromones 5114:Juxtacrine 2789:Stem Cells 1318:References 1270:Treatments 1233:SARS-CoV-2 1209:SARS-Cov-2 1125:Th17 cells 951:: Negative 904:proteasome 895:SH2 domain 770:tryptophan 642:Regulation 625:Drosophila 621:Drosophila 533:lymphocyte 501:SH2 domain 242:homodimers 173:C-terminus 157:SH2 domain 46:cell death 6582:Sunitinib 6577:Sorafenib 6486:ZM-449829 6476:WHI-P 154 6466:TCS-21311 6403:NSC-33994 6358:Atiprimod 6146:Agonists: 6128:Bifarcept 5953:Agonists: 5899:Agonists: 5831:Cilmostim 5828:Agonists: 5805:Namilumab 5762:Agonists: 5706:Agonists: 5595:Agonists: 5558:Chemokine 5128:Endocrine 5123:Paracrine 5119:Autocrine 4986:Receptors 4966:Cytokines 4676:2075-4418 2970:1865-5033 2915:1097-0290 2860:0014-5793 2525:BioEssays 1464:(1): 32. 1236:infection 1177:leukaemia 1117:psoriasis 1012:apoptosis 922:Function 916:Regulator 778:aspartate 766:glutamine 651:(PIAS), 597:leukaemia 521:cytokines 373:prolactin 282:importins 234:threonine 187:Mechanism 161:α-helices 6481:ZM-39923 6398:NSC-7908 6363:AZD-1480 6254:instead. 6234:instead. 6214:instead. 6190:instead. 6108:MEDI-545 5882:instead. 5810:Otilimab 5613:CNTO-530 5569:instead. 5254:Cytokine 4948:Hormones 4898:JAK-STAT 4886:MAPK/ERK 4881:TGF beta 4801:Archived 4770:11983158 4739:14525967 4694:36428847 4632:21898543 4572:28576744 4558:: 1–14. 4528:18596671 4487:26151455 4431:21782512 4382:27558099 4374:18301422 4339:17804842 4289:24069549 4259:JAK-STAT 4240:22520845 4208:Immunity 4189:28555727 4141:20684919 4133:15661026 4094:25527793 4040:23863176 3991:21508344 3945:15032587 3902:11201744 3851:11994288 3810:12955078 3788:Oncogene 3769:16959766 3718:15520383 3659:12615921 3618:12270932 3573:12826400 3497:25021813 3489:15801956 3453:12644021 3381:(1997). 3364:20337577 3253:18508557 3193:11248056 3134:21460228 3083:15761017 3034:16056253 2988:33633812 2931:20924311 2923:16752369 2876:38090088 2868:12527385 2819:20847942 2811:11553846 2770:16034480 2735:16474434 2694:15765894 2553:41826277 2545:11746233 2501:18239084 2452:18684846 2402:27018889 2353:19223541 2302:20732639 2272:Immunity 2228:Oncogene 2209:15020666 2161:20623715 2153:11802163 2118:10851062 2096:Oncogene 2077:14673173 2028:20962278 1969:23707527 1913:22520844 1883:Immunity 1859:21098664 1800:15919823 1741:24470978 1711:JAK-STAT 1685:28074064 1655:Leukemia 1636:21442038 1575:12039028 1556:22339650 1490:23134684 1439:17502367 1377:20857536 1369:12040185 1299:See also 1229:COVID-19 1217:COVID-19 1196:Covid-19 1181:lymphoma 1142:melanoma 1063:NK cells 1026:(SCID). 988:Negative 964:Negative 865:(CISH), 861:family: 799:lymphoma 762:arginine 758:cysteine 689:histones 561:NK cells 555:. Also, 415:histones 401:such as 357:arginine 214:tyrosine 64:(JAKs), 38:immunity 6613:Biology 6423:SD-1008 5598:ARA-290 5079:General 4903:Akt/PKB 4778:8251837 4685:9689825 4623:3237787 4580:3833538 4478:4522639 4422:3163735 4330:2630215 4280:3772101 4231:3334867 4085:4524500 4031:3773493 3910:4423377 3882:Bibcode 3760:1761121 3686:Bibcode 3538:9287352 3409:9162089 3355:3076191 3304:1732748 3244:2599796 3161:Bibcode 3125:3099690 3042:7466028 2979:7878662 2686:8608596 2645:8314084 2604:9032284 2492:2976848 2444:9590172 2393:4837022 2344:2929826 2293:2946796 2250:9872331 2019:2984224 1996:Bibcode 1960:4550442 1904:3909993 1850:3003019 1827:Bibcode 1791:1149424 1768:Bibcode 1732:3891633 1676:5629373 1627:3063998 1547:3762697 1481:3507883 1349:Bibcode 1341:Science 1260:T cells 1256:B cells 1071:T cells 1067:B cells 774:proline 505:kinases 477:T cells 266:nucleus 264:to the 262:cytosol 238:hetero- 202:ligands 165:β-sheet 70:cancers 6599:Portal 6517:Others 6383:CYT387 6373:CHZ868 6262:Others 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