title: A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling.
abstract: The evolutionarily conserved DOCK180 protein has an indispensable role in cell migration by functioning as an exchange factor for Rac GTPase via its DOCK homology region (DHR)-2 domain. We report here that the conserved DHR-1 domain also has an important signalling role. A form of DOCK180 that lacks DHR-1 fails to promote cell migration, although it is capable of inducing Rac GTP-loading. The DHR-1 domain interacts with PtdIns(3,4,5)P(3) in vitro and in vivo, and mediates the DOCK180 signalling complex localization at sites of PtdIns(3,4,5)P(3) accumulation in the cell's leading edge. A form of DOCK180 in which the DHR-1 domain has been replaced by a canonical PtdIns(3,4,5)P(3)-binding pleckstrin homology domain is fully functional at inducing cell elongation and migration, suggesting that the main function of DHR-1 is to bind PtdIns(3,4,5)P(3). These results demonstrate that DOCK180, via its DHR-1 and DHR-2 domains, couples PtdIns(3,4,5)P(3) signalling to Rac GTP-loading, which is essential for directional cell movement.
authors: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Jean-François
authors: JF
authors: Côté
authors: Andrea B
authors: AB
authors: Motoyama
authors: Jason A
authors: JA
authors: Bush
authors: Kristiina
authors: K
authors: Vuori
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D048430:Cell Shape / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099818:DOCK1 protein, human; C465214:ELMO1 protein, human; D046912:Multiprotein Complexes; D018129:Phosphatidylinositol Phosphates; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; C060974:phosphatidylinositol 3,4,5-triphosphate; C106336:phosphatidylinositol 3,5-diphosphate; C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases; D020744:rac GTP-Binding Proteins