93:
place, as the cytosolic ratio of GTP is much higher than GDP at 10:1. The binding of GTP to the GTPase results in the release of the GEF, which can then activate a new GTPase. Thus, GEFs both destabilize the GTPase interaction with GDP and stabilize the nucleotide-free GTPase until a GTP molecule binds to it. GAPs (GTPase-activating protein) act antagonistically to inactivate GTPases by increasing their intrinsic rate of GTP hydrolysis. GDP remains bound to the inactive GTPase until a GEF binds and stimulates its release.
20:
69:
122:
phosphate-binding region, while the base-binding region remains accessible. When the GEF binds the GTPase, the phosphate groups are released first and the GEF is displaced upon binding of the entering GTP molecule. Though this general scheme is common among GEFs, the specific interactions between the regions of the GTPase and GEF vary among individual proteins.
166:. The human genome encodes 71 members, distributed into 20 subfamilies. All 71 members were already present in early Vertebrates, and most of the 20 subfamilies were already present in early Metazoans. Many of the mammalian Dbl family proteins are tissue-specific and their number in Metazoa varies in proportion of cell signaling complexity.
203:. DOCK family members are involved in cell migration, morphogenesis and phagocytosis. The DHR2 domain is approximately 400 amino acids. These proteins also contain a second conserved domain, DHR1, which is approximately 250 amino acids. The DHR1 domain been shown to be involved in the membrane localization of some GEFs.
104:, is present in the nucleus while the Ran GAP is present in the cytosol, modulating nuclear import and export of proteins. RCC1 converts RanGDP to RanGTP in the nucleus, activating Ran for the export of proteins. When the Ran GAP catalyzes conversion of RanGTP to RanGDP in the cytosol, the protein cargo is released.
130:
Some GEFs are specific to a single GTPase while others have multiple GTPase substrates. While different subfamilies of Ras superfamily GTPases have a conserved GTP binding domain, this is not the case for GEFs. Different families of GEFs correspond to different Ras subfamilies. The functional domains
178:
in 64 of the 71 Dbl family members. The PH domain is located immediately adjacent to the C terminus of the DH domain. Together, these two domains constitute the minimum structural unit necessary for the activity of most Dbl family proteins. The PH domain is involved in intracellular targeting of the
112:
The mechanism of GTPase activation varies among different GEFs. However, there are some similarities in how different GEFs alter the conformation of the G protein nucleotide-binding site. GTPases contain two loops called switch 1 and switch 2 that are situated on either side of the bound nucleotide.
92:
GDP dissociates from inactive GTPases very slowly. The binding of GEFs to their GTPase substrates catalyzes the dissociation of GDP, allowing a GTP molecule to bind in its place. GEFs function to promote the dissociation of GDP. After GDP has disassociated from the GTPase, GTP generally binds in its
84:
and are involved in essential cell processes such as cell differentiation and proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport. GTPases are active when bound to GTP and inactive when bound to GDP, allowing their activity to be regulated by GEFs and the opposing
121:
ion to maintain high affinity binding of the nucleotide. GEF binding induces conformational changes in the P loop and switch regions of the GTPase while the rest of the structure is largely unchanged. The binding of the GEF sterically hinders the magnesium-binding site and interferes with the
195:, DHR2 was already present at the origin of eukaryotes. The DOCK family is a separate subset of GEFs from the Dbl family and bears no structural or sequence relation to the DH domain. There are 11 identified DOCK family members divided into subfamilies based on their activation of
315:, which can be activated by the GEF receptor, has been shown to promote tumor proliferation in pancreatic cancer. GEFs represent possible therapeutic targets as they can potentially play a role in regulating these pathways through their activation of GTPases.
235:
in response to upstream signals. GEFs are multi-domain proteins and interact with other proteins inside the cell through these domains. Adaptor proteins can modulate GEF activity by interacting with other domains besides the catalytic domain. For example,
179:
DH domain. It is generally thought to modulate membrane binding through interactions with phospholipids, but its function has been shown to vary in different proteins. This PH domain is also present in other proteins beyond RhoGEFs.
275:
Crosstalk has also been shown between GEFs and multiple GTPase signaling pathways. For example, SOS contains a Dbl homology domain in addition to its CDC25 catalytic domain. SOS can act as a GEF to activate
333:
is a eukaryotic initiation factor necessary to initiate protein translation. eIF-2b regenerates the GTP-bound form of eIF-2 for an additional cycle in protein synthesis initiation, i.e., its binding to the
340:
are trans-membrane receptors that act as GEFs for their cognate G proteins upon binding of a ligand. Ligand binding induces a conformational change that allows the GPCR to activate an associated GTPase.
143:, is the catalytic domain of many Ras GEFs, which activate Ras GTPases. The CDC25 domain comprises approximately 500 amino acids and was first identified in the CDC25 protein in budding yeast (
158:
Dbl-like RhoGEFs were present at the origin of eukaryotes and evolved as highly adaptive cell signaling mediators. Dbl-like RhoGEFs are characterized by the presence of a Dbl
Homology domain (
1346:
327:(SOS1) is an important GEF in the cell growth-regulatory MAPK/ERK pathway. SOS1 binds GRB2 at the plasma membrane after EGF receptor activation. SOS1 activates the small G protein Ras.
131:
of these GEF families are not structurally related and do not share sequence homology. These GEF domains appear to be evolutionarily unrelated despite similar function and substrates.
223:
trafficking. Though ARF GEFs are divergent in their overall sequences, they contain a conserved Sec 7 domain. This 200 amino acid region is homologous to the yeast Sec7p protein.
1077:
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D (May 1993). "Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2".
1232:
Margolis SS, Salogiannis J, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho HY, Soskis MJ, Sahin M, Greenberg ME (October 2010).
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is the guanine nucleotide exchange factor for Ran GTPase. It localizes to the nucleus and catalyzes the activation of Ran to allow nuclear export of proteins.
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1339:
996:
Yang J, Zhang Z, Roe SM, Marshall CJ, Barford D (September 2009). "Activation of Rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor".
612:
Quilliam LA, Rebhun JF, Castro AF (2002). "A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases".
80:. Small GTPases act as molecular switches in intracellular signaling pathways and have many downstream targets. The most well-known GTPases comprise the
60:
have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.
1783:
1332:
280:, a RhoGTPase, in addition to its role as a GEF for Ras. SOS is therefore a link between the Ras-Family and Rho-Family GTPase signaling pathways.
292:
therapy due to their role in many signaling pathways, particularly cell proliferation. For example, many cancers are caused by mutations in the
1601:
30:
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Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DD (January 2005).
232:
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633:
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Bourne HR, Sanders DA, McCormick F (November 1990). "The GTPase superfamily: a conserved switch for diverse cell functions".
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265:
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Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J (July 1998). "The structural basis of the activation of Ras by Sos".
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Feig LA (April 1994). "Guanine-nucleotide exchange factors: a family of positive regulators of Ras and related GTPases".
337:
252:
activation. The binding of SOS1 to GRB2 localizes it to the plasma membrane, where it can activate the membrane-bound
1412:
1234:"EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation"
1039:
Jackson CL, Casanova JE (February 2000). "Turning on ARF: the Sec7 family of guanine-nucleotide-exchange factors".
387:
167:
86:
1193:"Heterotrimeric G protein βγ subunits stimulate FLJ00018, a guanine nucleotide exchange factor for Rac1 and Cdc42"
660:
Cherfils J, Chardin P (August 1999). "GEFs: structural basis for their activation of small GTP-binding proteins".
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145:
96:
The localization of GEFs can determine where in the cell a particular GTPase will be active. For example, the
824:"The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals"
216:
53:
23:
76:
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains involved in the activation of
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Vetter IR, Wittinghofer A (November 2001). "The guanine nucleotide-binding switch in three dimensions".
257:
163:
49:
957:"Crystal structure of the Dbl and pleckstrin homology domains from the human Son of sevenless protein"
264:, are activated upon phosphorylation in response to upstream signals. Secondary messengers such as
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Ueda H, Nagae R, Kozawa M, Morishita R, Kimura S, Nagase T, Ohara O, Yoshida S, Asano T (2008).
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117:-binding loop of the GTPase interact with the phosphates of the nucleotide and a coordinating
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Cherfils J, Zeghouf M (January 2013). "Regulation of small GTPases by GEFs, GAPs, and GDIs".
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1117:"Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis"
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because mutations in this protein have been found in many cancers. The Rho GTPase
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913:"Guanine nucleotide exchange factors for Rho GTPases: turning on the switch"
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Price N, Proud C (1994). "The guanine nucleotide-exchange factor, eIF-2B".
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Zheng Y (December 2001). "Dbl family guanine nucleotide exchange factors".
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Seki T, Hayashi N, Nishimoto T (August 1996). "RCC1 in the Ran pathway".
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1283:"Regulation of excitatory synapse development by the RhoGEF Ephexin5"
535:"GEFs and GAPs: critical elements in the control of small G proteins"
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Soisson SM, Nimnual AS, Uy M, Bar-Sagi D, Kuriyan J (October 1998).
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The Sec7 domain is responsible for the GEF catalytic activity in
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is the catalytic domain of the DOCK family of Rho GEFs. Like
44:) are proteins or protein domains that activate monomeric
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Progress in
Nucleic Acid Research and Molecular Biology
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is a RhoA GEF involved in neuronal synapse development.
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533:Bos JL, Rehmann H, Wittinghofer A (June 2007).
162:), responsible for GEF catalytic activity for
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1320:MBInfo - Glossary Terms: GAPs, GEFs, and GDIs
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1763:Guanosine nucleotide dissociation inhibitors
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139:The CDC25 homology domain, also called the
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296:that lead to uncontrolled growth. The GEF
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272:can also play a role in GEF activation.
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72:Schematic of GEF activation of a GTPase
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244:, is recruited by the adaptor protein
16:Proteins which remove GDP from GTPases
712:10.1093/oxfordjournals.jbchem.a021400
7:
449:Bruce Alberts; et al. (2002).
300:activates Ras, whose target is the
38:Guanine nucleotide exchange factors
1558:Guanine nucleotide exchange factor
455:. Garland Science. pp. 877–.
14:
1441:Regulator of G protein signalling
1281:Salogiannis, John (2013-10-18).
174:) are associated in tandem with
911:Schmidt A, Hall A (July 2002).
576:Current Opinion in Cell Biology
56:(GTP). A variety of unrelated
1784:GTP-binding protein regulators
1356:GTP-binding protein regulators
873:Trends in Biochemical Sciences
822:Fort P, Blangy A (June 2017).
662:Trends in Biochemical Sciences
288:GEFs are potential target for
48:by stimulating the release of
1:
1053:10.1016/s0962-8924(99)01699-2
974:10.1016/S0092-8674(00)81756-0
885:10.1016/S0968-0004(01)01973-9
674:10.1016/S0968-0004(99)01429-2
626:10.1016/S0079-6603(02)71047-7
452:Molecular Biology of the Cell
1170:10.1016/0300-9084(94)90079-5
588:10.1016/0955-0674(94)90137-6
231:GEFs are often recruited by
338:G protein-coupled receptors
168:Pleckstrin homology domains
1800:
1413:Tuberous sclerosis protein
1250:10.1016/j.cell.2010.09.038
552:10.1016/j.cell.2007.05.018
425:10.1152/physrev.00003.2012
388:Nucleotide exchange factor
256:. Other GEFs, such as the
87:GTPase activating proteins
52:(GDP) to allow binding of
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1565:
1364:GTPase activating protein
1134:10.1016/j.ccr.2004.11.024
126:Structure and specificity
146:Saccharomyces cerevisiae
1091:10.1126/science.8493579
1010:10.1126/science.1174468
917:Genes & Development
747:10.1126/science.1062023
700:Journal of Biochemistry
1298:Cite journal requires
1210:10.1074/jbc.m707037200
1041:Trends in Cell Biology
240:1, the Ras GEF in the
113:These regions and the
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54:guanosine triphosphate
34:
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413:Physiological Reviews
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50:guanosine diphosphate
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930:10.1101/gad.1003302
1004:(5946): 1398–402.
840:10.1093/gbe/evx100
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58:structural domains
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294:MAPK/ERK pathway
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1080:
1073:
1071:
1067:
1062:
1058:
1054:
1050:
1046:
1042:
1035:
1032:
1027:
1023:
1019:
1015:
1011:
1007:
1003:
999:
992:
989:
984:
980:
975:
970:
967:(2): 259–68.
966:
962:
958:
951:
949:
945:
940:
936:
931:
926:
922:
918:
914:
907:
905:
903:
899:
894:
890:
886:
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878:
874:
867:
864:
859:
855:
850:
845:
841:
837:
833:
829:
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816:
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807:
803:
799:
795:
791:
790:10.1038/28548
787:
783:
779:
772:
769:
764:
760:
756:
752:
748:
744:
740:
736:
729:
726:
721:
717:
713:
709:
706:(2): 207–14.
705:
701:
694:
692:
688:
683:
679:
675:
671:
668:(8): 306–11.
667:
663:
656:
654:
650:
645:
641:
637:
635:9780125400718
631:
627:
623:
619:
615:
608:
606:
602:
597:
593:
589:
585:
582:(2): 204–11.
581:
577:
570:
567:
562:
558:
553:
548:
545:(5): 865–77.
544:
540:
536:
529:
526:
521:
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513:
509:
505:
501:
497:
493:
486:
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453:
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439:
434:
430:
426:
422:
418:
414:
407:
404:
398:
394:
393:Small GTPases
391:
389:
386:
384:
381:
379:
376:
375:
371:
366:
363:
361:
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353:
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198:
194:
190:
182:
180:
177:
173:
169:
165:
161:
153:
151:
149:
147:
142:
141:RasGEF domain
134:
132:
125:
123:
120:
116:
107:
105:
103:
99:
94:
90:
88:
83:
79:
78:small GTPases
70:
63:
61:
59:
55:
51:
47:
43:
39:
31:
25:
21:
1557:
1291:cite journal
1276:
1241:
1237:
1227:
1200:
1196:
1186:
1161:
1157:
1151:
1127:(1): 39–49.
1124:
1120:
1082:
1078:
1044:
1040:
1034:
1001:
997:
991:
964:
960:
920:
916:
876:
872:
866:
831:
827:
781:
777:
771:
738:
734:
728:
703:
699:
665:
661:
617:
613:
579:
575:
569:
542:
538:
528:
495:
491:
466:. Retrieved
451:
416:
412:
406:
287:
274:
250:EGF receptor
230:
219:function in
217:ARF proteins
210:
186:
157:
144:
138:
135:CDC25 domain
129:
111:
95:
91:
75:
41:
37:
36:
1121:Cancer Cell
1047:(2): 60–7.
620:: 391–444.
307:. Raf is a
213:ARF GTPases
207:Sec7 domain
189:DHR2 domain
183:DHR2 domain
164:Rho GTPases
468:12 January
462:0815332181
399:References
378:G proteins
334:Met-t-RNA.
227:Regulation
176:DH domains
172:PH domains
1372:Monomeric
1158:Biochimie
806:204998911
193:DH domain
160:DH domain
119:magnesium
115:phosphate
108:Mechanism
1778:Category
1580:Ras-GRF1
1379:Chimerin
1268:21029865
1219:18045877
1143:15652748
1061:10652516
1026:35369555
1018:19745154
939:12101119
893:11738596
858:28541439
755:11701921
682:10431174
644:12102558
561:17540168
433:23303910
372:See also
365:Ephexin5
350:Ras-GRF1
319:Examples
89:(GAPs).
64:Function
1700:DOCK-D
1680:DOCK-C
1665:DOCK-B
1645:DOCK-A
1259:2967209
1178:7893825
1099:8493579
1079:Science
998:Science
983:9790532
849:5499878
798:9690470
763:6636339
735:Science
720:8889801
596:8024811
520:4329238
512:2122258
383:Guanine
360:PLEKHG2
355:Kalirin
270:calcium
221:vesicle
46:GTPases
1739:IQSEC2
1714:Dock11
1709:Dock10
1591:RhoGEF
1396:RasGAP
1266:
1256:
1217:
1176:
1141:
1097:
1059:
1024:
1016:
981:
937:
891:
856:
846:
804:
796:
778:Nature
761:
753:
718:
680:
642:
632:
594:
559:
518:
510:
492:Nature
459:
431:
331:eIF-2b
302:kinase
290:cancer
284:Cancer
1756:Other
1704:Dock9
1694:Dock8
1689:Dock7
1684:Dock6
1674:Dock4
1669:Dock3
1659:Dock5
1654:Dock2
1649:DOCK1
1570:EIF2B
1542:RGS21
1537:RGS20
1532:RGS19
1527:RGS18
1522:RGS17
1517:RGS16
1512:RGS14
1507:RGS13
1502:RGS12
1497:RGS11
1492:RGS10
1406:IQGAP
1022:S2CID
802:S2CID
759:S2CID
516:S2CID
201:Cdc42
100:GEF,
1734:SIL1
1729:ALS2
1637:DOCK
1626:FGD4
1621:FGD3
1616:FGD2
1611:FGD1
1487:RGS9
1482:RGS8
1477:RGS7
1472:RGS6
1467:RGS5
1462:RGS4
1457:RGS3
1452:RGS2
1447:RGS1
1423:TSC2
1418:TSC1
1389:CHN2
1384:CHN1
1304:help
1264:PMID
1238:Cell
1215:PMID
1174:PMID
1139:PMID
1095:PMID
1057:PMID
1014:PMID
979:PMID
961:Cell
935:PMID
889:PMID
854:PMID
794:PMID
751:PMID
716:PMID
678:PMID
640:PMID
630:ISBN
592:PMID
557:PMID
539:Cell
508:PMID
470:2011
457:ISBN
429:PMID
344:RCC1
313:Vav1
298:SOS1
278:Rac1
268:and
266:cAMP
262:Vav1
260:GEF
246:GRB2
199:and
187:The
102:RCC1
42:GEFs
1602:FGD
1401:NF1
1254:PMC
1246:doi
1242:143
1205:doi
1201:283
1166:doi
1129:doi
1087:doi
1083:260
1049:doi
1006:doi
1002:325
969:doi
925:doi
881:doi
844:PMC
836:doi
786:doi
782:394
743:doi
739:294
708:doi
704:120
670:doi
622:doi
584:doi
547:doi
543:129
500:doi
496:348
421:doi
305:Raf
258:Rho
254:Ras
238:SOS
197:Rac
98:Ran
33:GDP
24:GTP
1780::
1443::
1295::
1293:}}
1289:{{
1262:.
1252:.
1240:.
1236:.
1213:.
1199:.
1195:.
1172:.
1162:76
1160:.
1137:.
1123:.
1119:.
1107:^
1093:.
1081:.
1069:^
1055:.
1045:10
1043:.
1020:.
1012:.
1000:.
977:.
965:95
963:.
959:.
947:^
933:.
921:16
919:.
915:.
901:^
887:.
877:26
875:.
852:.
842:.
830:.
826:.
814:^
800:.
792:.
780:.
757:.
749:.
737:.
714:.
702:.
690:^
676:.
666:24
664:.
652:^
638:.
628:.
618:71
616:.
604:^
590:.
578:.
555:.
541:.
537:.
514:.
506:.
494:.
478:^
441:^
427:.
417:93
415:.
215:.
150:.
1348:e
1341:t
1334:v
1306:)
1302:(
1285:.
1270:.
1248::
1221:.
1207::
1180:.
1168::
1145:.
1131::
1125:7
1101:.
1089::
1063:.
1051::
1028:.
1008::
985:.
971::
941:.
927::
895:.
883::
860:.
838::
832:9
808:.
788::
765:.
745::
722:.
710::
684:.
672::
646:.
624::
598:.
586::
580:6
563:.
549::
522:.
502::
472:.
435:.
423::
170:(
148:)
40:(
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
