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Originally published In Press as doi:10.1074/jbc.M312098200 on February 5, 2004

J. Biol. Chem., Vol. 279, Issue 16, 16606-16613, April 16, 2004
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Novel Mechanism of PTEN Regulation by Its Phosphatidylinositol 4,5-Bisphosphate Binding Motif Is Critical for Chemotaxis*

Miho Iijima{ddagger}, Yi Elaine Huang{ddagger}, Hongbo R. Luo§, Francisca Vazquez{ddagger}, and Peter N. Devreotes{ddagger}

From the Departments of {ddagger}Cell Biology and §Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205

In chemotaxing cells, localization of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to the leading edge of the cell sets the direction and regulates the formation of pseudopods at the anterior. We show that the lipid phosphatase activity of PTEN mediates chemotaxis and that the sharp localization of PI(3,4,5)P3 requires localization of PTEN to the rear of the cell. Our data suggest that a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) binding motif at the N terminus of PTEN serves the dual role of localizing the enzyme to the membrane and regulating its activity. Mutations in this motif enhance catalytic activity but render the enzyme inactive in vivo by preventing membrane association. The key role of this motif may explain the heretofore puzzling tumor-suppressing mutations occurring within the PI(4,5)P2 binding motif. On the other hand, the localization of PTEN does not depend on its phosphatase activity, the actin cytoskeleton, or the intracellular level of PI(3,4,5)P3, suggesting that events controlling localization are upstream of phosphoinositide signaling.

Received for publication, November 4, 2003 , and in revised form, February 4, 2004.

* Research was supported by United States Public Health Service Grants GM28007 and GM34933 (to P. N. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. E-mail: pnd{at}jhmi.edu.


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