DOCK180 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound toGuanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding ofguanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
DOCK180 and related proteins differ from other GEFs in that they do not possess the canonical structure of tandemDH-PH domains known to elicit nucleotide exchange. Instead they possess aDHR2 domain which mediates Rac activation by stabilising it in its nucleotide-free state.[9] DOCK180-related proteins also possess aDHR1 domain which has been shown,in vitro, to bindphospholipids[10] and which may be involved in their interaction withcellular membranes. Other structural features of Dock180 include anN-terminalSH3 domain involved in binding to ELMO proteins (see below)[11] and aC-terminalproline-rich region which, inMyoblast city (theDrosophila melanogaster ortholog of DOCK180), was shown to bindDCrk (theDrosophila ortholog ofCrk).[12]
Under physiological conditions DOCK180 alone is inefficient at promoting nucleotide exchange on Rac.[11] Effective GEF activity requires an interaction between Dock180 and its binding partnerELMO.ELMO1 is the most comprehensively describedisoform of this small family of non-catalytically active proteins which function to recruit Dock180 to theplasma membrane and induce conformational changes which increase GEF efficiency.[13][14][15] ELMO1 has also been reported to inhibitubiquitinylation of Dock180 and so prevent its degradation byproteasomes.[16]Receptor-mediated activation ofRhoG (a small G protein of theRac subfamily) is perhaps the best known inducer of Dock180 GEF activity. Active (GTP-bound) RhoG recruits the ELMO/Dock180 complex to the plasma membrane thereby bringing Dock180 into contact with itssubstrate, Rac.[17] Intumour cells DOCK180 is regulated by a complex containing Crk andp130Cas which is in turn regulated by cooperative signalling byβ3-containingintegrin complexes and the membrane-bound proteinuPAR.[18]
^abCôté JF, Vuori K (December 2002). "Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity".J. Cell Sci.115 (Pt 24):4901–13.doi:10.1242/jcs.00219.PMID12432077.S2CID14669715.
^abBrugnera E, Haney L, Grimsley C, et al. (August 2002). "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex".Nat. Cell Biol.4 (8):574–82.doi:10.1038/ncb824.PMID12134158.S2CID36363774.
^Lu M, Kinchen JM, Rossman KL, et al. (2004). "PH domain of ELMO functionsin trans to regulate Rac activation via Dock180".Nature Structural & Molecular Biology.11 (8):756–62.doi:10.1038/nsmb800.PMID15247908.S2CID125990.
^Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS (Aug 2002). "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex".Nat. Cell Biol.4 (8):574–82.doi:10.1038/ncb824.PMID12134158.S2CID36363774.
Takai S, Hasegawa H, Kiyokawa E, et al. (1996). "Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization".Genomics.35 (2):403–4.doi:10.1006/geno.1996.0378.PMID8661160.
Albert ML, Kim JI, Birge RB (2001). "alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells".Nat. Cell Biol.2 (12):899–905.doi:10.1038/35046549.PMID11146654.S2CID7535200.
