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Sci. STKE, 7 August 2001
Vol. 2001, Issue 94, p. tw5
[DOI: 10.1126/stke.2001.94.tw5]

EDITORS' CHOICE

Signal Attenuation Translocation of Dok Inhibits Signals

p62Dok (Dok)-deficient cells proliferate more than Dok+/+ cells do, suggesting that Dok functions as a negative regulator of growth signals. Zhao et al. identified a possible mechanism for Dok-mediated signal attenuation and demonstrated that the Dok pleckstrin homology (PH) domain is critical for this role. Dok-/- cells reconstituted with wild-type Dok regained the ability to inhibit platelet-derived growth factor (PDGF)-dependent signaling, as measured by decreased mitogen-associated protein kinase (MAPK) phosphorylation. However, cells reconstituted with PH domain-deleted Dok ({Delta}PH-Dok) were unable to decrease PDGF-dependent MAPK activation. PDGF-treatment of cells effected the translocation of Dok, but not {Delta}PH-Dok, to the plasma membrane in a phosphatidylinositol 3-kinase (PI3K)-dependent manner, suggesting that PI3K produces lipid substrates at the membrane suitable for Dok binding. Although Dok was originally identified as a protein-binding partner of the 120-kD Ras guanosine triphosphatase-activating protein (RasGAP), the ability of Dok to decrease proliferative signals did not depend on association with RasGAP or the adaptor protein Nck. Thus, the data suggest that Dok is able to repress the Ras-MAPK signaling pathway by translocating to the plasma membrane, and that Dok-dependent signal attenuation might not depend on RasGAP.

M. Zhao, A. A. P. Schmitz, Y. Qin, A. Di Cristofano, P. P. Pandolfi, L. Van Aelst, Phosphoinositide 3-kinase-dependent membrane recruitment of p62dok is essential for its negative effect on mitogen-activated protein (MAP) kinase activation. J. Exp. Med. 194, 265-274 (2001). [Abstract] [Full Text]

Citation: Translocation of Dok Inhibits Signals. Sci. STKE 2001, tw5 (2001).


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