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J. Biol. Chem., Vol. 283, Issue 19, 13233-13242, May 9, 2008

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The Hominoid-specific Oncogene TBC1D3 Activates Ras and Modulates Epidermal Growth Factor Receptor Signaling and Trafficking^*

Marisa J. Wainszelbaum, Audra J. Charron¹, Chen Kong, Donald S. Kirkpatrick², Priya Srikanth, M. Alejandro Barbieri³, Steven P. Gygi, and Philip D. Stahl⁴

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Hominoid- and human-specific genes may have evolved to modulate signaling pathways of a higher order of complexity. TBC1D3 is a hominoid-specific oncogene encoded by a cluster of eight paralogs on chromosome 17. Initial work indicates that TBC1D3 is widely expressed in human tissues ( Hodzic, D., Kong, C., Wainszelbaum, M. J., Charron, A. J., Su, X., and Stahl, P. D. (2006) Genomics 88, 731-736[CrossRef][Medline] [Order article via Infotrieve] ). In this study, we show that TBC1D3 expression has a powerful effect on cell proliferation that is further enhanced by epidermal growth factor (EGF) in both human and mouse cell lines. EGF activation of the Erk and protein kinase B/Akt pathways is enhanced, both in amplitude and duration, by TBC1D3 expression, whereas RNA interference silencing of TBC1D3 suppresses the activation. Light microscopy and Western blot experiments demonstrate that increased signaling in response to EGF is coupled with a significant delay in EGF receptor (EGFR) trafficking and degradation, which significantly extends the life span of EGFR. Moreover, TBC1D3 suppresses polyubiquitination of the EGFR and the recruitment of c-Cbl. Using the Ras binding domain of Raf1 to monitor GTP-Ras we show that TBC1D3 expression enhances Ras activation in quiescent cells, which is further increased by EGF treatment. We speculate that TBC1D3 may alter Ras GTP loading. We conclude that the expression of TBC1D3 generates a delay in EGFR degradation, a decrease in ubiquitination, and a failure to recruit adapter proteins that ultimately dysregulate EGFR signal transduction and enhance cell proliferation. Altered growth factor receptor trafficking and GTP-Ras turnover may be sites where recently evolved genes such as TBC1D3 selectively modulate signaling in hominoids and humans.

Received for publication, January 9, 2008 , and in revised form, February 12, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 GM42259 (to P. D. S.) and R01 GM67945 (to S. P. G.). This work was also supported by the Jose Carreras International Leukemia Foundation (to M. A. B.). 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 (Data 1-3).

¹ Present address: Dept. of Biology, Washington University, St. Louis, MO 63110.

² Present address: Dept. of Protein Chemistry, Genentech, Inc., San Francisco, CA 94080.

³ Present address: Dept. of Biological Sciences, Florida International University Miami, FL 33199.

⁴ To whom correspondence should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110. Tel.: 314-362-6950; Fax: 314-362-1490; E-mail: pstahl{at}wustl.edu.

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