HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 4, 2683-2694, January 26, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/4/2683    most recent M608509200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhuang, G. Articles by Chen, J. Search for Related Content PubMed PubMed Citation Articles by Zhuang, G. Articles by Chen, J. Social Bookmarking                      What's this?

Regulation of EphA2 Receptor Endocytosis by SHIP2 Lipid Phosphatase via Phosphatidylinositol 3-Kinase-dependent Rac1 Activation^*

Guanglei Zhuang, Sonja Hunter, Yoonha Hwang, and Jin Chen^¶||1

From the Department of Cancer Biology, Department of Medicine, Division of Rheumatology and Immunology, ^¶Department of Cell and Developmental Biology, and ^||Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Endocytosis of Eph receptors is critical for a number of biological processes, including modulating axon growth cone collapse response and regulating cell surface levels of receptor in epithelial cells. In particular, ephrin-A ligand stimulation of tumor cells induces EphA2 receptor internalization and degradation, a process that has been explored as a means to reduce tumor malignancy. However, the mechanism and regulation of ligand-induced Eph receptor internalization are not well understood. Here we show that SHIP2 (Src homology 2 domain-containing phosphoinositide 5-phosphatase 2) is recruited to activated EphA2 via a heterotypic sterile motif (SAM)-SAM domain interaction, leading to regulation of EphA2 internalization. Overexpression of SHIP2 inhibits EphA2 receptor endocytosis, whereas suppression of SHIP2 expression by small interfering RNA-mediated gene silencing promotes ligand-induced EphA2 internalization and degradation. SHIP2 regulates EphA2 endocytosis via phosphatidylinositol 3-kinase-dependent Rac1 activation. Phosphatidylinositol 3,4,5-trisphosphate levels are significantly elevated in SHIP2 knockdown cells, phosphatidylinositol 3-kinase inhibitor decreases phosphatidylinositol 3,4,5-trisphosphate levels and suppresses increased EphA2 endocytosis. Ephrin-A1 stimulation activates Rac1 GTPase, and the Rac1-GTP levels are further increased in SHIP2 knockdown cells. A dominant negative Rac1 GTPase effectively inhibited ephrin-A1-induced EphA2 endocytosis. Together, our findings provide evidence that recruitment of SHIP2 to EphA2 attenuates a positive signal to receptor endocytosis mediated by phosphatidylinositol 3-kinase and Rac1 GTPase.

Received for publication, September 5, 2006 , and in revised form, November 28, 2006.

^* This work was supported by National Institutes of Health Grants CA95004 and CA114301 (to J. C.) and National Institutes of Health Postdoctoral Fellowship GM072461 (to S. H.). 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, Vanderbilt University School of Medicine, A-4323 MCN, 1161 21st Ave. S., Nashville, TN 37232-2363. Tel.: 615-343-3819; Fax: 615-343-7392; E-mail: jin.chen{at}vanderbilt.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Tashiro, T. Tsunematsu, H. Okubo, T. Ohta, E. Sano, E. Yamauchi, H. Taniguchi, and H. Konishi GAREM, a Novel Adaptor Protein for Growth Factor Receptor-bound Protein 2, Contributes to Cellular Transformation through the Activation of Extracellular Signal-regulated Kinase Signaling J. Biol. Chem., July 24, 2009; 284(30): 20206 - 20214. [Abstract] [Full Text] [PDF]

				B. Annamalai, X. Liu, U. Gopal, and J. S. Isaacs Hsp90 Is an Essential Regulator of EphA2 Receptor Stability and Signaling: Implications for Cancer Cell Migration and Metastasis Mol. Cancer Res., July 1, 2009; 7(7): 1021 - 1032. [Abstract] [Full Text] [PDF]

				N. K. Prasad, M. Tandon, S. Badve, P. W. Snyder, and H. Nakshatri Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover Carcinogenesis, January 1, 2008; 29(1): 25 - 34. [Abstract] [Full Text] [PDF]