240:. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:
535:
437:, through activation of MEK1(MAP2K1) and MEK2(MAP2K2). The JNKs are regulated by the MEKK 1/4, MLK 2/3, and ASK 1 MAPKKKs. The p38 MAPK is regulated by MEKK 1-4 and TAO 1/2 families of MAPKKKs and is responsible for inflammation, apoptosis, cell differentiation, and cell cycle regulation. The determination for what cascade is followed is based upon the type of signal, the strength of binding, and the length of binding.
3763:
236:. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and
493:
specific for a tumor necrosis factor. Since MAPKKK are activated through the addition of a phosphates group on a serine/threonine residue, they are deactivated by a phosphatase. A common phosphatase used in ASK-1 regulation is PP5. MAPKKKs contain a docking domain which is different from their active
432:
of MAP kinases. There are three main classes of MAP Kinases and are regulated by their respective MAPKKKs. These MAP kinases include the extracellular regulated kinases (ERKs), the c-Jun N-terminal
Kinases (JNKs), and the p38 MAP kinase. The ERKs are regulated by the Raf family of MAPKKKs and are
494:
site that allows them to contact another substrate. Additionally, several scaffolds are used in the MAPKKK cascade in order to ensure that a specific cascade is used. These scaffolds have a binding site for the MAPKKK, MAPKK, and MAPK, ensuring that the signal occurs rapidly.
502:
Because MAPKKKs are involved in a wide range of cell responses occurring both in the cytoplasm and the nucleus, a mutation in these genes can cause several diseases. Over-expression of the MAPKKK upstream of the ERK 1/2 MAPK and an increase in
433:
responsible for cell growth, differentiation, and meiosis. Perhaps the best characterized MAP3K are the members of the oncogenic RAF family (RAF1, BRAF, ARAF), which are effectors of mitogenic ras signaling and which activate the
484:
The most upstream stimuli that activate MAPKKK is either stress or growth factors. This includes mitogens, inflammatory cytokines, ER stress, oxidative stress, UV radiation, and DNA damage. Most MAPKKKs are activated through
1000:
Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K (December 1995). "Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction".
961:"Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative"
489:'s where the signal from the stimuli binds to the GPCR and the GTPase activity of the g-protein activates the downstream MAPKKK. Other mechanisms for MAPKKK do exist. For instance, the MAPKKK ASK-1 is activated by a
1626:
1911:
511:. This is also seen when there is too much oxidative stress in the brain, causing these MAPKs to undergo more apoptosis and destroy brain cells. MLK, a type of MAPKKK, are associated with
515:
and inhibitors to the MLK proteins have been shown to treat
Parkinson's disease. The MAPKKK pathways and specifically the over-expression of cascades of JNK and p38 are also involved in
1619:
587:"Global Identification, Classification, and Expression Analysis of MAPKKK genes: Functional Characterization of MdRaf5 Reveals Evolution and Drought-Responsive Profile in Apple"
908:
Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ (1994). "Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1".
1612:
1819:
507:(EGFR) can lead to tumor formation, such as triple negative breast cancer. A mutation in the JNK or p38 family of MAPK or their MAPKKK upstream precursors can result in
173:
534:
659:
192:
2367:
3206:
1670:
1410:
1250:
3315:
2053:
1940:
2328:
3301:
2766:
1657:
1639:
229:
3403:
3284:
1420:
2990:
1859:
1477:
429:
3054:
2029:
1516:
463:
3310:
1844:
3367:
3042:
3482:
2299:
2289:
1974:
660:"MAP3Kinase-dependent SnRK2-kinase activation is required for abscisic acid signal transduction and rapid osmotic stress response"
628:"MAPK kinase kinases (MKKKs) as a target class for small-molecule inhibition to modulate signaling networks and gene expression".
185:
2981:
1469:
1243:
566:
504:
1555:
3250:
2922:
2284:
2275:
561:
152:
128:
3638:
2665:
2162:
2153:
1810:
1756:
3753:
1853:
1236:
1604:
2877:
2695:
2191:
486:
3623:
3739:
3726:
3713:
3700:
3687:
3674:
3661:
2867:
2862:
2857:
2847:
2842:
2837:
2827:
2622:
2397:
1993:
520:
146:
3633:
3783:
3587:
3530:
3032:
1798:
1643:
1494:
1220:
1214:
490:
455:
441:
39:
133:
3535:
3390:
2813:
512:
508:
197:
121:
3556:
3475:
2089:
20:
3628:
56:
2656:
1210:
1010:
917:
149:
3592:
73:
51:
3164:
1368:
3788:
3525:
3267:
3221:
1034:
941:
833:"TAOK3 - Serine/threonine-protein kinase TAO3 - Homo sapiens (Human) - TAOK3 gene & protein"
516:
2527:
2236:
1189:
1181:
1140:
1122:
1083:
1075:
1026:
982:
933:
890:
882:
766:
748:
641:
556:
233:
140:
380:
366:
3571:
3566:
3540:
3468:
3120:
2362:
2352:
2347:
2265:
2256:
2186:
2177:
2123:
2114:
1771:
1593:
1320:
1171:
1130:
1114:
1065:
1018:
972:
925:
872:
756:
740:
706:
681:
671:
633:
608:
598:
459:
434:
282:
109:
808:
3618:
3602:
3515:
2946:
2017:
2012:
2007:
416:
384:
370:
314:
300:
286:
85:
1052:
Takeda, Kohsuke; Matsuzawa, Atsushi; Nishitoh, Hideki; Ichijo, Hidenori (February 2003).
44:
1103:"Expression and clinical significance of MAPK and EGFR in triple-negative breast cancer"
1014:
921:
3767:
3656:
3597:
1135:
1102:
761:
728:
686:
613:
586:
472:(TAK1) participates in regulation of transcription by transforming growth factor-beta (
168:
1101:
Jiang, Weihua; Wang, Xiaowen; Zhang, Chenguang; Xue, Laiti; Yang, Liang (March 2020).
3777:
3561:
3520:
2070:
2002:
1038:
3510:
2941:
1766:
945:
710:
1022:
1176:
1159:
860:
3734:
3669:
3505:
3147:
2779:
2719:
2602:
2522:
2246:
1350:
744:
402:
3762:
676:
637:
603:
540:
MAPK pathway. Many of the MAP3K's here are labelled by their alternative names.
3235:
1709:
1340:
551:
523:. Inhibitors of these pathways help in treating the symptoms of the diseases.
1185:
1126:
1079:
886:
752:
3708:
3682:
2196:
237:
1193:
1144:
1087:
977:
960:
894:
770:
701:
Bruce D. Cuevas (2014). "Mitogen-Activated
Protein Kinase Kinase Kinases".
645:
1118:
1030:
986:
937:
784:
2552:
2447:
2442:
2437:
1223:
832:
473:
97:
1228:
3211:
3189:
3184:
3174:
3169:
2971:
2966:
2961:
2956:
2951:
2936:
2931:
2582:
2547:
1786:
1781:
1776:
1393:
1388:
1378:
1373:
1271:
959:
Ellinger-Ziegelbauer H, Brown K, Kelly K, Siebenlist U (January 1997).
361:
356:
350:
346:
340:
334:
330:
325:
116:
1070:
1053:
877:
3721:
3491:
3441:
3436:
3431:
3426:
3421:
3416:
3411:
3362:
3357:
3352:
3347:
3342:
3325:
3320:
3194:
3179:
3130:
3125:
3110:
3105:
3100:
3095:
3069:
3064:
3059:
3047:
3025:
3020:
2912:
2887:
2562:
2387:
2382:
2377:
2372:
2357:
2201:
2138:
2133:
2128:
2104:
1930:
1925:
1899:
1894:
1889:
1879:
1874:
1864:
1704:
1635:
1570:
1536:
1531:
1526:
1521:
1509:
1459:
1454:
1449:
1444:
1439:
1434:
1429:
1398:
1383:
1330:
1325:
1310:
1305:
1300:
1295:
929:
469:
451:
445:
320:
306:
296:
292:
272:
266:
260:
256:
250:
244:
180:
92:
80:
68:
462:
by activating SEK and MEK1/2 respectively; it does not regulate the
809:"TAOK3 Gene - GeneCards | TAOK3 Protein | TAOK3 Antibody"
3695:
3337:
3330:
3240:
3137:
3037:
3015:
3010:
3005:
3000:
2995:
2907:
2902:
2897:
2892:
2882:
2852:
2832:
2709:
2704:
2685:
2680:
2670:
2646:
2641:
2636:
2612:
2607:
2597:
2592:
2587:
2577:
2557:
2542:
2537:
2532:
2512:
2507:
2497:
2492:
2487:
2482:
2477:
2467:
2462:
2457:
2452:
2432:
2427:
2422:
2417:
2412:
2407:
2392:
2342:
2337:
2231:
2226:
2221:
2216:
2211:
2206:
2167:
2099:
2094:
2043:
2038:
1964:
1959:
1954:
1920:
1912:
3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring) kinase
1714:
1699:
1694:
1689:
1684:
1679:
1565:
1560:
1548:
1543:
1504:
1499:
1487:
1482:
388:
374:
1160:"Pathological roles of MAPK signaling pathways in human diseases"
785:"TAOK3 TAO kinase 3 [Homo sapiens (human)] - Gene - NCBI"
3230:
3157:
3152:
3142:
3115:
2872:
2822:
2803:
2798:
2793:
2788:
2743:
2738:
2733:
2728:
2675:
2631:
2572:
2567:
2517:
2502:
2472:
2402:
2318:
2313:
2308:
2241:
2143:
2084:
2079:
1983:
1949:
1834:
1829:
1824:
1793:
1761:
1749:
1744:
1739:
1729:
1724:
1360:
1355:
1345:
1315:
1164:
Biochimica et
Biophysica Acta (BBA) - Molecular Basis of Disease
407:
397:
310:
276:
104:
3464:
3388:
2764:
1655:
1608:
1232:
3199:
1734:
1719:
1575:
1403:
412:
460:
extracellular signal-regulated protein kinase (ERK) pathways
3460:
3751:
428:
Several classes of MAPKKK exist, and all of them are
210:
Mitogen
Activated Protein (MAP) kinase kinase kinase
3647:
3611:
3580:
3549:
3498:
3402:
3300:
3283:
3266:
3249:
3220:
3080:
2980:
2921:
2812:
2778:
2718:
2694:
2655:
2621:
2327:
2298:
2274:
2255:
2176:
2152:
2113:
2069:
2052:
2028:
1992:
1973:
1939:
1910:
1843:
1809:
1669:
1586:
1468:
1419:
1280:
1264:
1054:"Roles of MAPKKK ASK1 in stress-induced cell death"
191:
179:
167:
162:
139:
127:
115:
103:
91:
79:
67:
62:
50:
38:
33:
28:
29:Mitogen-activated protein kinase kinase kinase
3476:
1671:Non-specific serine/threonine protein kinases
1620:
1244:
8:
859:Qi, Maosong; Elion, Elaine A. (2005-08-15).
1158:Kim, Eun Kyung; Choi, Eui-Ju (2010-04-01).
19:"mkkk" redirects here. For other uses, see
3483:
3469:
3461:
3399:
3385:
2775:
2761:
2054:Goodpasture-antigen-binding protein kinase
1666:
1652:
1627:
1613:
1605:
1251:
1237:
1229:
733:Cold Spring Harbor Perspectives in Biology
159:
2767:Serine/threonine-specific protein kinases
1941:(isocitrate dehydrogenase (NADP+)) kinase
1658:Serine/threonine-specific protein kinases
1640:Serine/threonine-specific protein kinases
1213:at the U.S. National Library of Medicine
1175:
1134:
1069:
976:
876:
760:
685:
675:
612:
602:
444:by phosphorylation of its activator SEK1(
3302:Receptor protein serine/threonine kinase
230:serine/threonine-specific protein kinase
3758:
3285:Low-density-lipoprotein receptor kinase
578:
530:
1478:Extracellular signal-regulated kinases
25:
2030:Fas-activated serine/threonine kinase
1517:P38 mitogen-activated protein kinases
480:Activation and deactivation of MAPKKK
424:Classes of MAPKKK and their functions
7:
3311:Bone morphogenetic protein receptors
854:
852:
722:
720:
1845:Dephospho-(reductase kinase) kinase
965:The Journal of Biological Chemistry
727:Morrison, Deborah K. (2012-11-01).
630:Current Opinion in Chemical Biology
2300:G-protein coupled receptor kinases
14:
2290:Beta adrenergic receptor kinase-2
1975:(tyrosine 3-monooxygenase) kinase
3761:
2982:Mitogen-activated protein kinase
567:List of unusual biological names
533:
505:epidermal growth factor receptor
3368:Anti-MĂĽllerian hormone receptor
3251:(acetyl-CoA carboxylase) kinase
2923:(RNA-polymerase)-subunit kinase
2285:Beta adrenergic receptor kinase
2276:Beta adrenergic receptor kinase
562:MAP kinase kinase kinase kinase
2991:Extracellular signal-regulated
711:10.1007/978-3-662-46875-3_7192
1:
3055:P38 mitogen-activated protein
2154:cGMP-dependent protein kinase
2115:cAMP-dependent protein kinase
1811:Pyruvate dehydrogenase kinase
1757:Ataxia telangiectasia mutated
1023:10.1126/science.270.5244.2008
1854:AMP-activated protein kinase
1177:10.1016/j.bbadis.2009.12.009
435:ERK1/2 (MAPK3/MAPK1) pathway
2769:(EC 2.7.11.21-EC 2.7.11.30)
1058:Cell Structure and Function
745:10.1101/cshperspect.a011254
394:MAP3K18 (aka TAO3 or TAOK3)
3805:
2696:Elongation factor 2 kinase
1660:(EC 2.7.11.1-EC 2.7.11.20)
677:10.1038/s41467-019-13875-y
638:10.1016/j.cbpa.2005.04.004
604:10.1038/s41598-017-13627-2
18:
3639:Michaelis–Menten kinetics
3398:
3384:
3091:MAP kinase kinase kinases
2774:
2760:
2623:Myosin light-chain kinase
2329:Ca2+/calmodulin-dependent
1994:Myosin-heavy-chain kinase
1665:
1651:
1291:MAP kinase kinase kinases
1211:MAP+Kinase+Kinase+Kinases
521:polycystic kidney disease
158:
3531:Diffusion-limited enzyme
3391:Dual-specificity kinases
1495:C-Jun N-terminal kinases
1282:MAP kinase kinase kinase
1215:Medical Subject Headings
491:receptor-tyrosine kinase
2814:Cyclin-dependent kinase
865:Journal of Cell Science
454:directly regulates the
978:10.1074/jbc.272.5.2668
703:Encyclopedia of Cancer
3624:Eadie–Hofstee diagram
3557:Allosteric regulation
1259:MAP kinase activation
1119:10.3892/ol.2020.11274
861:"MAP kinase pathways"
729:"MAP Kinase Pathways"
664:Nature Communications
498:Clinical significance
3634:Lineweaver–Burk plot
2657:Phosphorylase kinase
789:www.ncbi.nlm.nih.gov
1015:1995Sci...270.2008Y
922:1994Natur.372..798Y
513:Parkinson's disease
509:Alzheimer's disease
3593:Enzyme superfamily
3526:Enzyme promiscuity
3268:Tropomyosin kinase
3222:Tau-protein kinase
591:Scientific Reports
3749:
3748:
3458:
3457:
3454:
3453:
3450:
3449:
3380:
3379:
3376:
3375:
2756:
2755:
2752:
2751:
2237:Protein kinase N1
2192:Protein kinase Cζ
1602:
1601:
1421:MAP kinase kinase
1071:10.1247/csf.28.23
1009:(5244): 2008–11.
916:(6508): 798–800.
878:10.1242/jcs.02470
871:(16): 3569–3572.
813:www.genecards.org
557:MAP kinase kinase
234:MAP kinase kinase
207:
206:
203:
202:
122:metabolic pathway
3796:
3766:
3765:
3757:
3629:Hanes–Woolf plot
3572:Enzyme activator
3567:Enzyme inhibitor
3541:Enzyme catalysis
3485:
3478:
3471:
3462:
3400:
3386:
3033:C-Jun N-terminal
2776:
2762:
2266:Rhodopsin kinase
2257:Rhodopsin kinase
2187:Protein kinase C
2178:Protein kinase C
2163:Protein kinase G
2124:Protein kinase A
1735:Protein kinase B
1667:
1653:
1629:
1622:
1615:
1606:
1594:MAPK phosphatase
1253:
1246:
1239:
1230:
1198:
1197:
1179:
1155:
1149:
1148:
1138:
1113:(3): 1842–1848.
1107:Oncology Letters
1098:
1092:
1091:
1073:
1049:
1043:
1042:
997:
991:
990:
980:
956:
950:
949:
930:10.1038/372798a0
905:
899:
898:
880:
856:
847:
846:
844:
843:
829:
823:
822:
820:
819:
805:
799:
798:
796:
795:
781:
775:
774:
764:
724:
715:
714:
698:
692:
691:
689:
679:
656:
650:
649:
625:
619:
618:
616:
606:
583:
537:
440:MEKK1 activates
232:which acts upon
160:
26:
16:Class of enzymes
3804:
3803:
3799:
3798:
3797:
3795:
3794:
3793:
3784:Protein kinases
3774:
3773:
3772:
3760:
3752:
3750:
3745:
3657:Oxidoreductases
3643:
3619:Enzyme kinetics
3607:
3603:List of enzymes
3576:
3545:
3516:Catalytic triad
3494:
3489:
3459:
3446:
3394:
3372:
3296:
3279:
3262:
3245:
3216:
3076:
2976:
2947:P70-S6 Kinase 1
2917:
2808:
2770:
2748:
2714:
2690:
2651:
2617:
2323:
2294:
2270:
2251:
2172:
2148:
2109:
2065:
2048:
2024:
2018:Aurora C kinase
2013:Aurora B kinase
2008:Aurora A kinase
1988:
1969:
1935:
1906:
1839:
1805:
1661:
1647:
1633:
1603:
1598:
1582:
1464:
1415:
1284:(MAP3K or MKKK)
1276:
1260:
1257:
1207:
1202:
1201:
1157:
1156:
1152:
1100:
1099:
1095:
1051:
1050:
1046:
999:
998:
994:
958:
957:
953:
907:
906:
902:
858:
857:
850:
841:
839:
837:www.uniprot.org
831:
830:
826:
817:
815:
807:
806:
802:
793:
791:
783:
782:
778:
739:(11): a011254.
726:
725:
718:
700:
699:
695:
658:
657:
653:
627:
626:
622:
585:
584:
580:
575:
548:
541:
538:
529:
517:Crohn's disease
500:
482:
426:
24:
17:
12:
11:
5:
3802:
3800:
3792:
3791:
3786:
3776:
3775:
3771:
3770:
3747:
3746:
3744:
3743:
3730:
3717:
3704:
3691:
3678:
3665:
3651:
3649:
3645:
3644:
3642:
3641:
3636:
3631:
3626:
3621:
3615:
3613:
3609:
3608:
3606:
3605:
3600:
3595:
3590:
3584:
3582:
3581:Classification
3578:
3577:
3575:
3574:
3569:
3564:
3559:
3553:
3551:
3547:
3546:
3544:
3543:
3538:
3533:
3528:
3523:
3518:
3513:
3508:
3502:
3500:
3496:
3495:
3490:
3488:
3487:
3480:
3473:
3465:
3456:
3455:
3452:
3451:
3448:
3447:
3445:
3444:
3439:
3434:
3429:
3424:
3419:
3414:
3408:
3406:
3396:
3395:
3389:
3382:
3381:
3378:
3377:
3374:
3373:
3371:
3370:
3365:
3360:
3355:
3350:
3345:
3340:
3335:
3334:
3333:
3328:
3323:
3318:
3307:
3305:
3304:(EC 2.7.11.30)
3298:
3297:
3295:
3294:
3290:
3288:
3287:(EC 2.7.11.29)
3281:
3280:
3278:
3277:
3273:
3271:
3270:(EC 2.7.11.28)
3264:
3263:
3261:
3260:
3256:
3254:
3253:(EC 2.7.11.27)
3247:
3246:
3244:
3243:
3238:
3233:
3227:
3225:
3224:(EC 2.7.11.26)
3218:
3217:
3215:
3214:
3209:
3204:
3203:
3202:
3197:
3192:
3187:
3182:
3177:
3172:
3162:
3161:
3160:
3155:
3150:
3145:
3135:
3134:
3133:
3128:
3123:
3118:
3113:
3108:
3103:
3098:
3087:
3085:
3084:(EC 2.7.11.25)
3078:
3077:
3075:
3074:
3073:
3072:
3067:
3062:
3052:
3051:
3050:
3045:
3040:
3030:
3029:
3028:
3023:
3018:
3013:
3008:
3003:
2998:
2987:
2985:
2984:(EC 2.7.11.24)
2978:
2977:
2975:
2974:
2969:
2964:
2959:
2954:
2949:
2944:
2939:
2934:
2928:
2926:
2925:(EC 2.7.11.23)
2919:
2918:
2916:
2915:
2910:
2905:
2900:
2895:
2890:
2885:
2880:
2875:
2870:
2865:
2860:
2855:
2850:
2845:
2840:
2835:
2830:
2825:
2819:
2817:
2816:(EC 2.7.11.22)
2810:
2809:
2807:
2806:
2801:
2796:
2791:
2785:
2783:
2782:(EC 2.7.11.21)
2772:
2771:
2765:
2758:
2757:
2754:
2753:
2750:
2749:
2747:
2746:
2741:
2736:
2731:
2725:
2723:
2722:(EC 2.7.11.21)
2716:
2715:
2713:
2712:
2707:
2701:
2699:
2698:(EC 2.7.11.20)
2692:
2691:
2689:
2688:
2683:
2678:
2673:
2668:
2662:
2660:
2659:(EC 2.7.11.19)
2653:
2652:
2650:
2649:
2644:
2639:
2634:
2628:
2626:
2625:(EC 2.7.11.18)
2619:
2618:
2616:
2615:
2610:
2605:
2600:
2595:
2590:
2585:
2580:
2575:
2570:
2565:
2560:
2555:
2550:
2545:
2540:
2535:
2530:
2525:
2520:
2515:
2510:
2505:
2500:
2495:
2490:
2485:
2480:
2475:
2470:
2465:
2460:
2455:
2450:
2445:
2440:
2435:
2430:
2425:
2420:
2415:
2410:
2405:
2400:
2395:
2390:
2385:
2380:
2375:
2370:
2365:
2360:
2355:
2350:
2345:
2340:
2334:
2332:
2331:(EC 2.7.11.17)
2325:
2324:
2322:
2321:
2316:
2311:
2305:
2303:
2302:(EC 2.7.11.16)
2296:
2295:
2293:
2292:
2287:
2281:
2279:
2278:(EC 2.7.11.15)
2272:
2271:
2269:
2268:
2262:
2260:
2259:(EC 2.7.11.14)
2253:
2252:
2250:
2249:
2244:
2239:
2234:
2229:
2224:
2219:
2214:
2209:
2204:
2199:
2194:
2189:
2183:
2181:
2180:(EC 2.7.11.13)
2174:
2173:
2171:
2170:
2165:
2159:
2157:
2156:(EC 2.7.11.12)
2150:
2149:
2147:
2146:
2141:
2136:
2131:
2126:
2120:
2118:
2117:(EC 2.7.11.11)
2111:
2110:
2108:
2107:
2102:
2097:
2092:
2087:
2082:
2076:
2074:
2073:(EC 2.7.11.10)
2067:
2066:
2064:
2063:
2059:
2057:
2050:
2049:
2047:
2046:
2041:
2035:
2033:
2026:
2025:
2023:
2022:
2021:
2020:
2015:
2010:
1999:
1997:
1990:
1989:
1987:
1986:
1980:
1978:
1971:
1970:
1968:
1967:
1962:
1957:
1952:
1946:
1944:
1937:
1936:
1934:
1933:
1928:
1923:
1917:
1915:
1908:
1907:
1905:
1904:
1903:
1902:
1897:
1892:
1884:
1883:
1882:
1877:
1869:
1868:
1867:
1862:
1850:
1848:
1841:
1840:
1838:
1837:
1832:
1827:
1822:
1816:
1814:
1807:
1806:
1804:
1803:
1802:
1801:
1791:
1790:
1789:
1784:
1779:
1774:
1764:
1759:
1754:
1753:
1752:
1747:
1742:
1732:
1727:
1722:
1717:
1712:
1707:
1702:
1697:
1692:
1687:
1682:
1676:
1674:
1663:
1662:
1656:
1649:
1648:
1634:
1632:
1631:
1624:
1617:
1609:
1600:
1599:
1597:
1596:
1590:
1588:
1584:
1583:
1581:
1580:
1579:
1578:
1573:
1568:
1563:
1556:Atypical MAPKs
1553:
1552:
1551:
1541:
1540:
1539:
1534:
1529:
1524:
1514:
1513:
1512:
1507:
1502:
1492:
1491:
1490:
1485:
1474:
1472:
1466:
1465:
1463:
1462:
1457:
1452:
1447:
1442:
1437:
1432:
1426:
1424:
1423:(MAP2K or MKK)
1417:
1416:
1414:
1413:
1408:
1407:
1406:
1401:
1396:
1391:
1386:
1381:
1376:
1366:
1365:
1364:
1358:
1353:
1348:
1343:
1335:
1334:
1333:
1328:
1323:
1318:
1313:
1308:
1303:
1298:
1287:
1285:
1278:
1277:
1275:
1274:
1268:
1266:
1262:
1261:
1258:
1256:
1255:
1248:
1241:
1233:
1227:
1226:
1218:
1206:
1205:External links
1203:
1200:
1199:
1170:(4): 396–405.
1150:
1093:
1044:
992:
971:(5): 2668–74.
951:
900:
848:
824:
800:
776:
716:
693:
651:
620:
577:
576:
574:
571:
570:
569:
564:
559:
554:
547:
544:
543:
542:
539:
532:
528:
525:
499:
496:
481:
478:
425:
422:
421:
420:
410:
405:
400:
395:
392:
378:
364:
359:
354:
344:
338:
328:
323:
318:
304:
290:
280:
270:
264:
254:
248:
205:
204:
201:
200:
195:
189:
188:
183:
177:
176:
171:
165:
164:
156:
155:
144:
137:
136:
131:
125:
124:
119:
113:
112:
107:
101:
100:
95:
89:
88:
83:
77:
76:
71:
65:
64:
60:
59:
54:
48:
47:
42:
36:
35:
31:
30:
15:
13:
10:
9:
6:
4:
3:
2:
3801:
3790:
3787:
3785:
3782:
3781:
3779:
3769:
3764:
3759:
3755:
3741:
3737:
3736:
3731:
3728:
3724:
3723:
3718:
3715:
3711:
3710:
3705:
3702:
3698:
3697:
3692:
3689:
3685:
3684:
3679:
3676:
3672:
3671:
3666:
3663:
3659:
3658:
3653:
3652:
3650:
3646:
3640:
3637:
3635:
3632:
3630:
3627:
3625:
3622:
3620:
3617:
3616:
3614:
3610:
3604:
3601:
3599:
3598:Enzyme family
3596:
3594:
3591:
3589:
3586:
3585:
3583:
3579:
3573:
3570:
3568:
3565:
3563:
3562:Cooperativity
3560:
3558:
3555:
3554:
3552:
3548:
3542:
3539:
3537:
3534:
3532:
3529:
3527:
3524:
3522:
3521:Oxyanion hole
3519:
3517:
3514:
3512:
3509:
3507:
3504:
3503:
3501:
3497:
3493:
3486:
3481:
3479:
3474:
3472:
3467:
3466:
3463:
3443:
3440:
3438:
3435:
3433:
3430:
3428:
3425:
3423:
3420:
3418:
3415:
3413:
3410:
3409:
3407:
3405:
3401:
3397:
3392:
3387:
3383:
3369:
3366:
3364:
3361:
3359:
3356:
3354:
3351:
3349:
3346:
3344:
3341:
3339:
3336:
3332:
3329:
3327:
3324:
3322:
3319:
3317:
3314:
3313:
3312:
3309:
3308:
3306:
3303:
3299:
3292:
3291:
3289:
3286:
3282:
3275:
3274:
3272:
3269:
3265:
3258:
3257:
3255:
3252:
3248:
3242:
3239:
3237:
3234:
3232:
3229:
3228:
3226:
3223:
3219:
3213:
3210:
3208:
3205:
3201:
3198:
3196:
3193:
3191:
3188:
3186:
3183:
3181:
3178:
3176:
3173:
3171:
3168:
3167:
3166:
3163:
3159:
3156:
3154:
3151:
3149:
3146:
3144:
3141:
3140:
3139:
3136:
3132:
3129:
3127:
3124:
3122:
3119:
3117:
3114:
3112:
3109:
3107:
3104:
3102:
3099:
3097:
3094:
3093:
3092:
3089:
3088:
3086:
3083:
3079:
3071:
3068:
3066:
3063:
3061:
3058:
3057:
3056:
3053:
3049:
3046:
3044:
3041:
3039:
3036:
3035:
3034:
3031:
3027:
3024:
3022:
3019:
3017:
3014:
3012:
3009:
3007:
3004:
3002:
2999:
2997:
2994:
2993:
2992:
2989:
2988:
2986:
2983:
2979:
2973:
2970:
2968:
2965:
2963:
2960:
2958:
2955:
2953:
2950:
2948:
2945:
2943:
2940:
2938:
2935:
2933:
2930:
2929:
2927:
2924:
2920:
2914:
2911:
2909:
2906:
2904:
2901:
2899:
2896:
2894:
2891:
2889:
2886:
2884:
2881:
2879:
2876:
2874:
2871:
2869:
2866:
2864:
2861:
2859:
2856:
2854:
2851:
2849:
2846:
2844:
2841:
2839:
2836:
2834:
2831:
2829:
2826:
2824:
2821:
2820:
2818:
2815:
2811:
2805:
2802:
2800:
2797:
2795:
2792:
2790:
2787:
2786:
2784:
2781:
2777:
2773:
2768:
2763:
2759:
2745:
2742:
2740:
2737:
2735:
2732:
2730:
2727:
2726:
2724:
2721:
2717:
2711:
2708:
2706:
2703:
2702:
2700:
2697:
2693:
2687:
2684:
2682:
2679:
2677:
2674:
2672:
2669:
2667:
2664:
2663:
2661:
2658:
2654:
2648:
2645:
2643:
2640:
2638:
2635:
2633:
2630:
2629:
2627:
2624:
2620:
2614:
2611:
2609:
2606:
2604:
2601:
2599:
2596:
2594:
2591:
2589:
2586:
2584:
2581:
2579:
2576:
2574:
2571:
2569:
2566:
2564:
2561:
2559:
2556:
2554:
2551:
2549:
2546:
2544:
2541:
2539:
2536:
2534:
2531:
2529:
2526:
2524:
2521:
2519:
2516:
2514:
2511:
2509:
2506:
2504:
2501:
2499:
2496:
2494:
2491:
2489:
2486:
2484:
2481:
2479:
2476:
2474:
2471:
2469:
2466:
2464:
2461:
2459:
2456:
2454:
2451:
2449:
2446:
2444:
2441:
2439:
2436:
2434:
2431:
2429:
2426:
2424:
2421:
2419:
2416:
2414:
2411:
2409:
2406:
2404:
2401:
2399:
2396:
2394:
2391:
2389:
2386:
2384:
2381:
2379:
2376:
2374:
2371:
2369:
2366:
2364:
2361:
2359:
2356:
2354:
2351:
2349:
2346:
2344:
2341:
2339:
2336:
2335:
2333:
2330:
2326:
2320:
2317:
2315:
2312:
2310:
2307:
2306:
2304:
2301:
2297:
2291:
2288:
2286:
2283:
2282:
2280:
2277:
2273:
2267:
2264:
2263:
2261:
2258:
2254:
2248:
2245:
2243:
2240:
2238:
2235:
2233:
2230:
2228:
2225:
2223:
2220:
2218:
2215:
2213:
2210:
2208:
2205:
2203:
2200:
2198:
2195:
2193:
2190:
2188:
2185:
2184:
2182:
2179:
2175:
2169:
2166:
2164:
2161:
2160:
2158:
2155:
2151:
2145:
2142:
2140:
2137:
2135:
2132:
2130:
2127:
2125:
2122:
2121:
2119:
2116:
2112:
2106:
2103:
2101:
2098:
2096:
2093:
2091:
2088:
2086:
2083:
2081:
2078:
2077:
2075:
2072:
2068:
2061:
2060:
2058:
2056:(EC 2.7.11.9)
2055:
2051:
2045:
2042:
2040:
2037:
2036:
2034:
2032:(EC 2.7.11.8)
2031:
2027:
2019:
2016:
2014:
2011:
2009:
2006:
2005:
2004:
2003:Aurora kinase
2001:
2000:
1998:
1996:(EC 2.7.11.7)
1995:
1991:
1985:
1982:
1981:
1979:
1977:(EC 2.7.11.6)
1976:
1972:
1966:
1963:
1961:
1958:
1956:
1953:
1951:
1948:
1947:
1945:
1943:(EC 2.7.11.5)
1942:
1938:
1932:
1929:
1927:
1924:
1922:
1919:
1918:
1916:
1914:(EC 2.7.11.4)
1913:
1909:
1901:
1898:
1896:
1893:
1891:
1888:
1887:
1885:
1881:
1878:
1876:
1873:
1872:
1870:
1866:
1863:
1861:
1858:
1857:
1855:
1852:
1851:
1849:
1847:(EC 2.7.11.3)
1846:
1842:
1836:
1833:
1831:
1828:
1826:
1823:
1821:
1818:
1817:
1815:
1813:(EC 2.7.11.2)
1812:
1808:
1800:
1797:
1796:
1795:
1792:
1788:
1785:
1783:
1780:
1778:
1775:
1773:
1770:
1769:
1768:
1767:EIF-2 kinases
1765:
1763:
1760:
1758:
1755:
1751:
1748:
1746:
1743:
1741:
1738:
1737:
1736:
1733:
1731:
1728:
1726:
1723:
1721:
1718:
1716:
1713:
1711:
1708:
1706:
1703:
1701:
1698:
1696:
1693:
1691:
1688:
1686:
1683:
1681:
1678:
1677:
1675:
1673:(EC 2.7.11.1)
1672:
1668:
1664:
1659:
1654:
1650:
1645:
1641:
1637:
1630:
1625:
1623:
1618:
1616:
1611:
1610:
1607:
1595:
1592:
1591:
1589:
1585:
1577:
1574:
1572:
1569:
1567:
1564:
1562:
1559:
1558:
1557:
1554:
1550:
1547:
1546:
1545:
1542:
1538:
1535:
1533:
1530:
1528:
1525:
1523:
1520:
1519:
1518:
1515:
1511:
1508:
1506:
1503:
1501:
1498:
1497:
1496:
1493:
1489:
1486:
1484:
1481:
1480:
1479:
1476:
1475:
1473:
1471:
1467:
1461:
1458:
1456:
1453:
1451:
1448:
1446:
1443:
1441:
1438:
1436:
1433:
1431:
1428:
1427:
1425:
1422:
1418:
1412:
1409:
1405:
1402:
1400:
1397:
1395:
1392:
1390:
1387:
1385:
1382:
1380:
1377:
1375:
1372:
1371:
1370:
1367:
1362:
1359:
1357:
1354:
1352:
1349:
1347:
1344:
1342:
1339:
1338:
1336:
1332:
1329:
1327:
1324:
1322:
1319:
1317:
1314:
1312:
1309:
1307:
1304:
1302:
1299:
1297:
1294:
1293:
1292:
1289:
1288:
1286:
1283:
1279:
1273:
1270:
1269:
1267:
1263:
1254:
1249:
1247:
1242:
1240:
1235:
1234:
1231:
1225:
1222:
1219:
1216:
1212:
1209:
1208:
1204:
1195:
1191:
1187:
1183:
1178:
1173:
1169:
1165:
1161:
1154:
1151:
1146:
1142:
1137:
1132:
1128:
1124:
1120:
1116:
1112:
1108:
1104:
1097:
1094:
1089:
1085:
1081:
1077:
1072:
1067:
1063:
1059:
1055:
1048:
1045:
1040:
1036:
1032:
1028:
1024:
1020:
1016:
1012:
1008:
1004:
996:
993:
988:
984:
979:
974:
970:
966:
962:
955:
952:
947:
943:
939:
935:
931:
927:
923:
919:
915:
911:
904:
901:
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888:
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879:
874:
870:
866:
862:
855:
853:
849:
838:
834:
828:
825:
814:
810:
804:
801:
790:
786:
780:
777:
772:
768:
763:
758:
754:
750:
746:
742:
738:
734:
730:
723:
721:
717:
712:
708:
704:
697:
694:
688:
683:
678:
673:
669:
665:
661:
655:
652:
647:
643:
639:
635:
632:. June 2005.
631:
624:
621:
615:
610:
605:
600:
596:
592:
588:
582:
579:
572:
568:
565:
563:
560:
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555:
553:
550:
549:
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536:
531:
526:
524:
522:
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488:
479:
477:
475:
471:
467:
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436:
431:
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401:
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336:
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329:
327:
324:
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312:
308:
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281:
278:
274:
271:
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265:
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258:
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241:
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227:
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196:
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178:
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142:
138:
135:
132:
130:
126:
123:
120:
118:
114:
111:
108:
106:
102:
99:
98:NiceZyme view
96:
94:
90:
87:
84:
82:
78:
75:
72:
70:
66:
61:
58:
55:
53:
49:
46:
43:
41:
37:
32:
27:
22:
3735:Translocases
3732:
3719:
3706:
3693:
3680:
3670:Transferases
3667:
3654:
3511:Binding site
3090:
3081:
2942:P70S6 kinase
1290:
1281:
1167:
1163:
1153:
1110:
1106:
1096:
1064:(1): 23–29.
1061:
1057:
1047:
1006:
1002:
995:
968:
964:
954:
913:
909:
903:
868:
864:
840:. Retrieved
836:
827:
816:. Retrieved
812:
803:
792:. Retrieved
788:
779:
736:
732:
702:
696:
667:
663:
654:
629:
623:
594:
590:
581:
501:
483:
468:
450:
439:
427:
337:) (aka MLK3)
225:
221:
217:
213:
209:
208:
86:BRENDA entry
57:146702-84-3
3506:Active site
3393:(EC 2.7.12)
2780:Polo kinase
2720:Polo kinase
1587:Phosphatase
1544:ERK5 kinase
269:(aka MEKK4)
253:(aka MEKK2)
247:(aka MEKK1)
74:IntEnz view
34:Identifiers
3778:Categories
3709:Isomerases
3683:Hydrolases
3550:Regulation
2071:IÎşB kinase
1646:2.7.11-12)
1470:MAP kinase
1265:Initiation
842:2022-01-04
818:2022-01-04
794:2022-01-04
573:References
552:MAP kinase
143:structures
110:KEGG entry
3789:EC 2.7.11
3588:EC number
2197:PKC alpha
1224:2.7.11.25
1186:0925-4439
1127:1792-1074
1080:0386-7196
887:0021-9533
753:1943-0264
466:pathway.
456:MAPK8/JNK
442:MAPK8/JNK
343:(aka MUK)
238:apoptosis
63:Databases
45:2.7.11.25
3612:Kinetics
3536:Cofactor
3499:Activity
2553:KIAA0999
2448:MAPKAPK5
2443:MAPKAPK3
2438:MAPKAPK2
1194:20079433
1145:32194678
1088:12655147
1039:46600809
895:16105880
771:23125017
670:. 2020.
646:15939336
617:. 13511.
597:. 2017.
546:See also
474:TGF-beta
430:upstream
198:proteins
186:articles
174:articles
147:RCSB PDB
3768:Biology
3722:Ligases
3492:Enzymes
3212:MAP3K14
3190:MAP3K11
3185:MAP3K10
3175:MAP3K13
3170:MAP3K12
2972:RPS6KC1
2967:RPS6KA1
2962:RPS6KA3
2957:RPS6KA2
2952:RPS6KB2
2937:RPS6KA4
2932:RPS6KA5
2583:Kalirin
2548:SNF1LK2
1787:EIF2AK4
1782:EIF2AK3
1636:Kinases
1394:MAP3K11
1389:MAP3K10
1379:MAP3K13
1374:MAP3K12
1272:Mitogen
1136:7038935
1031:8533096
1011:Bibcode
1003:Science
987:9006902
946:4369739
938:7997270
918:Bibcode
762:3536342
687:6940395
614:5647345
381:MAP3K17
367:MAP3K16
362:MAP3K15
357:MAP3K14
347:MAP3K13
341:MAP3K12
331:MAP3K11
326:MAP3K10
299:) (aka
228:) is a
134:profile
117:MetaCyc
52:CAS no.
3754:Portal
3696:Lyases
3442:MAP2K7
3437:MAP2K6
3432:MAP2K5
3427:MAP2K4
3422:MAP2K3
3417:MAP2K2
3412:MAP2K1
3363:ACVRL1
3358:ACVR2B
3353:ACVR2A
3348:ACVR1C
3343:ACVR1B
3326:BMPR1B
3321:BMPR1A
3195:MAP3K7
3180:MAP3K9
3131:MAP3K8
3126:MAP3K7
3121:MAP3K6
3116:MAP3K5
3111:MAP3K4
3106:MAP3K3
3101:MAP3K2
3096:MAP3K1
3070:MAPK14
3065:MAPK13
3060:MAPK11
3048:MAPK10
3026:MAPK15
3021:MAPK12
2913:CDC2L1
2888:CDC2L5
2563:SNF1LK
2388:CAMK2G
2383:CAMK2D
2378:CAMK2B
2373:CAMK2A
2363:CAMK1G
2358:CAMK1D
2353:CAMK1B
2348:CAMK1A
2202:PRKCB1
2139:PRKACA
2134:PRKACB
2129:PRKACG
2105:IKBKAP
1931:BCKDHB
1926:BCKDHA
1900:PRKAG3
1895:PRKAG2
1890:PRKAG1
1880:PRKAB2
1875:PRKAB1
1865:PRKAA2
1860:PRKAA1
1705:STK38L
1571:MAPK15
1537:MAPK14
1532:MAPK13
1527:MAPK12
1522:MAPK11
1510:MAPK10
1460:MAP2K7
1455:MAP2K6
1450:MAP2K5
1445:MAP2K4
1440:MAP2K3
1435:MAP2K2
1430:MAP2K1
1399:MAP3K7
1384:MAP3K9
1331:MAP3K8
1326:MAP3K7
1321:MAP3K6
1316:MAP3K5
1311:MAP3K4
1306:MAP3K3
1301:MAP3K2
1296:MAP3K1
1217:(MeSH)
1192:
1184:
1143:
1133:
1125:
1086:
1078:
1037:
1029:
985:
944:
936:
910:Nature
893:
885:
769:
759:
751:
684:
644:
611:
527:Images
470:MAP3K7
452:MAP3K3
446:MAP2K4
335:MEKK11
321:MAP3K9
307:MAP3K8
293:MAP3K7
283:MAP3K6
273:MAP3K5
267:MAP3K4
257:MAP3K3
251:MAP3K2
245:MAP3K1
224:, or,
214:MAPKKK
181:PubMed
163:Search
153:PDBsum
93:ExPASy
81:BRENDA
69:IntEnz
40:EC no.
3648:Types
3404:MAP2K
3338:ACVR1
3331:BMPR2
3316:BMPR1
3241:GSK-3
3082:MAP3K
3043:MAPK9
3038:MAPK8
3016:MAPK7
3011:MAPK6
3006:MAPK4
3001:MAPK3
2996:MAPK1
2908:PFTK1
2903:PCTK3
2898:PCTK2
2893:PCTK1
2883:CDK12
2878:CDK10
2853:CDKL5
2833:CDKL2
2710:STK19
2705:EEF2K
2686:PHKG2
2681:PHKG1
2671:PHKA2
2666:PHKA1
2647:MYLK4
2642:MYLK3
2637:MYLK2
2613:DCLK1
2608:Titin
2598:TRIB3
2593:TRIB2
2588:TRIB1
2578:TSSK2
2558:STK40
2543:PSKH1
2538:PRKD3
2533:PRKD2
2513:PHKG2
2508:PHKG1
2498:OBSCN
2493:NUAK2
2488:NUAK1
2483:MKNK2
2478:MKNK1
2468:MARK4
2463:MARK3
2458:MARK2
2453:MARK1
2433:STK11
2428:DAPK3
2423:DAPK2
2418:DAPK1
2413:CHEK2
2408:CHEK1
2393:CAMK4
2368:CAMK2
2343:CAMK1
2338:BRSK2
2232:PRKCQ
2227:PRKCI
2222:PRKCG
2217:PRKCH
2212:PRKCE
2207:PRKCD
2168:PRKG1
2100:IKBKG
2095:IKBKE
2044:STK10
2039:FASTK
1965:IDH3G
1960:IDH3B
1955:IDH3A
1921:BCKDK
1715:ROCK1
1700:STK38
1695:MAST2
1690:MAST1
1685:LATS2
1680:LATS1
1566:MAPK6
1561:MAPK4
1549:MAPK7
1505:MAPK9
1500:MAPK8
1488:MAPK3
1483:MAPK1
1337:RAFs
1035:S2CID
942:S2CID
690:. 12.
415:(aka
389:TAOK2
383:(aka
375:TAOK1
369:(aka
349:(aka
333:(aka
309:(aka
297:MEKK7
295:(aka
285:(aka
275:(aka
261:MEKK3
259:(aka
226:MAP3K
129:PRIAM
3740:list
3733:EC7
3727:list
3720:EC6
3714:list
3707:EC5
3701:list
3694:EC4
3688:list
3681:EC3
3675:list
3668:EC2
3662:list
3655:EC1
3231:TPK1
3207:CDC7
3165:MLKs
3158:KSR2
3153:KSR1
3148:BRAF
3143:ARAF
3138:RAFs
2873:CDK9
2868:CDK8
2863:CDK7
2858:CDK6
2848:CDK5
2843:CDK4
2838:CDK3
2828:CDK2
2823:CDK1
2804:PLK4
2799:PLK3
2794:PLK2
2789:PLK1
2744:PLK4
2739:PLK3
2734:PLK2
2729:PLK1
2676:PHKB
2632:MYLK
2603:TRIO
2573:SPEG
2568:SNRK
2528:PKD1
2523:PIM2
2518:PIM1
2503:PASK
2473:MELK
2403:CASK
2398:MLCK
2319:GRK6
2314:GRK5
2309:GRK4
2247:PKN3
2242:PKN2
2144:PRKY
2090:TBK1
2085:IKK2
2080:CHUK
1984:STK4
1950:IDH2
1835:PDK4
1830:PDK3
1825:PDK2
1820:PDK1
1799:WEE1
1794:Wee1
1762:mTOR
1750:AKT3
1745:AKT2
1740:AKT1
1730:SGK3
1725:SGK2
1411:CDC7
1369:MLKs
1361:KSR2
1356:KSR1
1351:BRAF
1346:ARAF
1341:RAF1
1190:PMID
1182:ISSN
1168:1802
1141:PMID
1123:ISSN
1084:PMID
1076:ISSN
1027:PMID
983:PMID
934:PMID
891:PMID
883:ISSN
767:PMID
749:ISSN
642:PMID
519:and
487:GPCR
458:and
417:MLTK
408:ARAF
403:BRAF
398:RAF1
385:TAO2
371:TAO1
315:Tpl2
311:TPL2
301:TAK1
287:ASK2
277:ASK1
218:MKKK
193:NCBI
150:PDBe
105:KEGG
21:MKKK
3236:TTK
3200:ZAK
1777:HRI
1772:PKR
1720:SGK
1710:CIT
1576:NLK
1404:ZAK
1172:doi
1131:PMC
1115:doi
1066:doi
1019:doi
1007:270
973:doi
969:272
926:doi
914:372
873:doi
869:118
757:PMC
741:doi
707:doi
682:PMC
672:doi
634:doi
609:PMC
599:doi
476:).
464:p38
448:).
413:ZAK
387:or
373:or
351:LZK
313:or
222:M3K
169:PMC
141:PDB
3780::
1886:Îł
1871:β
1856:α
1644:EC
1638::
1221:EC
1188:.
1180:.
1166:.
1162:.
1139:.
1129:.
1121:.
1111:19
1109:.
1105:.
1082:.
1074:.
1062:28
1060:.
1056:.
1033:.
1025:.
1017:.
1005:.
981:.
967:.
963:.
940:.
932:.
924:.
912:.
889:.
881:.
867:.
863:.
851:^
835:.
811:.
787:.
765:.
755:.
747:.
735:.
731:.
719:^
705:.
680:.
668:11
666:.
662:.
640:.
607:.
593:.
589:.
220:,
216:,
3756::
3742:)
3738:(
3729:)
3725:(
3716:)
3712:(
3703:)
3699:(
3690:)
3686:(
3677:)
3673:(
3664:)
3660:(
3484:e
3477:t
3470:v
3293:-
3276:-
3259:-
2062:-
1642:(
1628:e
1621:t
1614:v
1363:)
1252:e
1245:t
1238:v
1196:.
1174::
1147:.
1117::
1090:.
1068::
1041:.
1021::
1013::
989:.
975::
948:.
928::
920::
897:.
875::
845:.
821:.
797:.
773:.
743::
737:4
713:.
709::
674::
648:.
636::
601::
595:7
419:)
391:)
377:)
353:)
317:)
303:)
289:)
279:)
263:)
212:(
23:.
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