Sci. Signal., 21 April 2009
Chemotaxis Nuts and Bolts of Chemotaxis
Stella M. Hurtley
Science, AAAS, Cambridge CB2 1LQ, UK
During chemotaxis, the small GTPase Rac is locally activated to extend membrane protrusions in the direction of migration. This localized Rac activation is achieved, at least in part, by focusing Rac GEFs (guanine nucleotide exchange factors) at the leading edge of the cell, yet the mechanism controlling subcellular localization of Rac GEFs is poorly understood. DOCK2 is a Rac GEF that regulates motility and polarity during neutrophil chemotaxis. Nishikimi et al. (see the Perspective by Côté and Vuori) provide evidence that intracellular DOCK2 dynamics are sequentially regulated by two distinct phospholipids. In response to chemoattractants, DOCK2 rapidly translocates to the plasma membrane of chemotaxing neutrophils. This initial translocation is mediated by phosphatidylinositol 3,4,5-trisphosphate (PIP3), whereas subsequent accumulation of DOCK2 at the leading edge requires de novo synthesis of phosphatidic acid (PA). PA focuses DOCK2 localization through direct binding to DOCK2s C-terminal polybasic clusters, resulting in local induction of actin polymerization. When this interaction is blocked, neutrophils fail to form leading edges properly and exhibit defects in chemotaxis. Thus, PA is critical for leading edge formation and stabilization during chemotaxis.
A. Nishikimi, H. Fukuhara, W. Su, T. Hongu, S. Takasuga, H. Mihara, Q. Cao, F. Sanematsu, M. Kanai, H. Hasegawa, Y. Tanaka, M. Shibasaki, Y. Kanaho, T. Sasaki, M. A. Frohman, Y. Fukui, Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis. Science 324, 384–387 (2009). [Abstract] [Full Text]
Citation: S. M. Hurtley, Nuts and Bolts of Chemotaxis. Sci. Signal. 2, ec142 (2009).
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