Nature Cell Biology 7, 797 - 807 (2005)
Published online: 17 July 2005; | doi:10.1038/ncb1280
A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signallingJean-François Côté1, 2, Andrea B. Motoyama1, Jason A. Bush1
& Kristiina Vuori11
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. 2
Present address: Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal (Quebec) Canada, H2W 1R7.
Correspondence should be addressed to Kristiina Vuori kvuori@burnham.org 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)P3 in vitro and in vivo, and mediates the DOCK180 signalling complex localization at sites of PtdIns(3,4,5)P3 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 A form of DOCK180 in which the DHR-1 domain has been replaced by a canonical PtdIns(3,4,5)P3-binding pleckstrin homology domain is fully functional at inducing cell elongation and migration, suggesting that the main function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)P3. These results demonstrate that DOCK180, via its DHR-1 and DHR-2 domains, couples PtdIns(3,4,5)P3 signalling to Rac GTP-loading, which is essential for directional cell movement.
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