| Structural highlights
6bc0 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | ARHGEF28, KIAA1998, RGNEF (HUMAN), RHOA, ARH12, ARHA, RHO12 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ARG28_HUMAN] Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors. Functions in axonal branching, synapse formation and dendritic morphogenesis. Functions also in focal adhesion formation, cell motility and B-lymphocytes activation. May regulate NEFL expression and aggregation and play a role in apoptosis (By similarity). [RHOA_HUMAN] Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague, and Yersinia pseudotuberculosis, which causes gastrointestinal disorders. Stimulates PKN2 kinase activity. May be an activator of PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP for GTP. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Rho family GTPases regulate a wide range of cellular processes. This includes cellular dynamics where three subfamilies, Rho, Rac, and Cdc42, are known to regulate cell shape and migration though coordinate action. Activation of Rho proteins largely depends on Rho Guanine nucleotide Exchange Factors (RhoGEFs) through a catalytic Dbl homology (DH) domain linked to a pleckstrin homology (PH) domain that subserves various functions. The PH domains from Lbc RhoGEFs, which specifically activate RhoA, have been shown to bind to activated RhoA. Here, p190RhoGEF is shown to also bind Rac1.GTP. Crystal structures reveal that activated Rac1 and RhoA use their effector-binding surfaces to associate with the same hydrophobic surface on the PH domain. Both activated RhoA and Rac1 can stimulate exchange of nucleotide on RhoA by localization of p190RhoGEF to its substrate, RhoA.GDP, in vitro. The binding of activated RhoA provides a mechanism for positive feedback regulation as previously proposed for the family of Lbc RhoGEFs. In contrast, the novel interaction between activated Rac1 and p190RhoGEF reveals a potential mechanism for cross-talk regulation where Rac can directly effect stimulation of RhoA. The greater capacity of Rac1 to stimulate p190RhoGEF among the Lbc RhoGEFs suggests functional specialization.
Direct regulation of p190RhoGEF by activated Rho and Rac GTPases.,Dada O, Gutowski S, Brautigam CA, Chen Z, Sternweis PC J Struct Biol. 2017 Nov 28. pii: S1047-8477(17)30210-1. doi:, 10.1016/j.jsb.2017.11.014. PMID:29196061[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ. Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling. J Biol Chem. 1996 Nov 15;271(46):28772-6. PMID:8910519
- ↑ Vincent S, Settleman J. The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization. Mol Cell Biol. 1997 Apr;17(4):2247-56. PMID:9121475
- ↑ Wing MR, Snyder JT, Sondek J, Harden TK. Direct activation of phospholipase C-epsilon by Rho. J Biol Chem. 2003 Oct 17;278(42):41253-8. Epub 2003 Aug 4. PMID:12900402 doi:http://dx.doi.org/10.1074/jbc.M306904200
- ↑ Yuce O, Piekny A, Glotzer M. An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 2005 Aug 15;170(4):571-82. PMID:16103226 doi:10.1083/jcb.200501097
- ↑ Kamijo K, Ohara N, Abe M, Uchimura T, Hosoya H, Lee JS, Miki T. Dissecting the role of Rho-mediated signaling in contractile ring formation. Mol Biol Cell. 2006 Jan;17(1):43-55. Epub 2005 Oct 19. PMID:16236794 doi:10.1091/mbc.E05-06-0569
- ↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
- ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
- ↑ Wallace SW, Magalhaes A, Hall A. The Rho target PRK2 regulates apical junction formation in human bronchial epithelial cells. Mol Cell Biol. 2011 Jan;31(1):81-91. doi: 10.1128/MCB.01001-10. Epub 2010 Oct 25. PMID:20974804 doi:10.1128/MCB.01001-10
- ↑ Dada O, Gutowski S, Brautigam CA, Chen Z, Sternweis PC. Direct regulation of p190RhoGEF by activated Rho and Rac GTPases. J Struct Biol. 2017 Nov 28. pii: S1047-8477(17)30210-1. doi:, 10.1016/j.jsb.2017.11.014. PMID:29196061 doi:http://dx.doi.org/10.1016/j.jsb.2017.11.014
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