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J. Biol. Chem., Vol. 280, Issue 13, 13129-13136, April 1, 2005

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SH2-containing 5'-Inositol Phosphatase, SHIP2, Regulates Cytoskeleton Organization and Ligand-dependent Down-regulation of the Epidermal Growth Factor Receptor^*

Nagendra K. Prasad and Stuart J. Decker¶

From the Department of Basic Medical Sciences and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907 and ^¶Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48105

Phosphoinositide lipid second messengers are integral components of signaling pathways mediated by insulin, growth factors, and integrins. SHIP2 dephosphorylates phosphatidylinositol 3,4,5-trisphosphate generated by the activated phosphatidylinositol 3'-kinase. SHIP2 down-regulates insulin signaling and is present at higher levels in diabetes and obesity. SHIP2 associates with p130Cas and filamin, regulators of cell adhesion/migration and cytoskeleton, influencing cell adhesion/spreading. Type I collagen specifically induces Src-mediated tyrosine phosphorylation of SHIP2. To better understand SHIP2 function, we employed RNA interference (RNAi) approach to silence the expression of the endogenous SHIP2 in HeLa cells. Suppression of SHIP2 levels caused severe F-actin deformities characterized by weak cortical actin and peripheral actin spikes. SHIP2 RNAi cells displayed cell-spreading defects involving a notable absence of focal contact structures and the formation of multiple slender membrane protrusions capped by actin spikes. Furthermore, decreased SHIP2 levels altered distribution of early endocytic antigen 1 (EEA1)-positive endocytic vesicles and of vesicles containing internalized epidermal growth factor (EGF) and transferrin. EGF treatment of SHIP2 RNAi cells led to the following: enhanced EGF receptor (EGFR) degradation; increased EGFR ubiquitination; and increased association of EGFR with c-Cbl ubiquitin ligase. Taken together, these experiments demonstrate that SHIP2 functions in the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Accordingly, we suggest that, in HeLa cells, SHIP2 plays a distinct role in signaling pathways mediated by integrins and growth factor receptors.

Received for publication, September 8, 2004 , and in revised form, January 5, 2005.

^* The work was supported in part by the Indiana Elks Foundation cancer research grants (to N. K. P.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

To whom correspondence should be addressed: LYNN Hall, School of Veterinary Medicine, Purdue University, 625 Harrison St., West Lafayette, IN 47907-2026. Tel.: 765-494-4717; Fax: 765-494-0781; E-mail: nprasad{at}purdue.edu.

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