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J. Biol. Chem., Vol. 282, Issue 9, 6380-6387, March 2, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/9/6380    most recent M610915200v1 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 Ning, Y. Articles by Hudson, L. G. Search for Related Content PubMed PubMed Citation Articles by Ning, Y. Articles by Hudson, L. G. Social Bookmarking                      What's this?

Activated Epidermal Growth Factor Receptor Induces Integrin 2 Internalization via Caveolae/Raft-dependent Endocytic Pathway^*

Yan Ning, Tione Buranda, and Laurie G. Hudson¹

From the College of Pharmacy and Department of Pathology, University of New Mexico, Albuquerque, New Mexico 87131

Elevated expression or activity of the epidermal growth factor (EGF) receptor is common in ovarian cancer and is associated with poor patient prognosis. Our previous studies demonstrated that expression of the constitutively active mutant form of the EGF receptor (EGFRvIII) in ovarian cancer cells led to reduction in integrin 2 surface expression, defects in cell spreading, and disruption of focal adhesions. Inhibition of EGFRvIII catalytic activity reversed the response, suggesting that EGF receptor activation regulates integrin 2. In this study we found that EGF treatment resulted in a transient loss of integrin 2 from the cell surface. Before EGF stimulation, integrin 2 and EGF receptors were associated based on biochemical and immuno-colocalization approaches. After EGF treatment, EGF receptor and integrin 2 were internalized and segregated into different compartments. Integrin 2, but not EGF receptor, was associated with caveolin-1 and GM1 (Gal_1,3GalNAc_1,4(Neu5Ac-_ 2,3)Gal_1,4Glc_1,1-ceramide) gangliosides, suggesting caveolae-mediated endocytosis. Moreover, integrin 2 was subsequently targeted to the Golgi apparatus and the endoplasmic reticulum. Together, these findings demonstrate that activated EGF receptor transiently modulates integrin 2 cell surface expression and stimulates integrin 2 trafficking via caveolae/raft-mediated endocytosis, representing a novel mechanism by which the EGF receptor may regulate integrin-mediated cell behavior.

Received for publication, November 27, 2006

^* This work was supported by Dept. of Health and Human Services Grant RO1 CA90492 from the National Institutes of Health. Support was also provided by National Institutes of Health Grants P30 CA118100 (UNM Cancer Research and Treatment Center) and K25 AI 60036 and by NIEHS, National Institutes of Health Grant P30 ES-012072. 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 Figs. S1–S3.

¹ To whom correspondence should be addressed: College of Pharmacy, MSC09 5360, University of New Mexico, Albuquerque, NM 87131-0001. Tel.: 505-272-2482; Fax: 505-272-6749; E-mail: lhudson{at}salud.unm.edu.

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