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J. Biol. Chem., Vol. 281, Issue 19, 13188-13198, May 12, 2006

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Cell Cycle- and Apoptosis-regulatory Protein-1 Is Involved in Apoptosis Signaling by Epidermal Growth Factor Receptor^*

Arun K. Rishi^¶1, Liyue Zhang, Yingjie Yu, Yan Jiang, Jyoti Nautiyal^¶, Anil Wali^¶||, Joseph A. Fontana, Edi Levi, and Adhip P. N. Majumdar^¶

From the Veterans Affairs Medical Center and the Departments of Internal Medicine and ^||Surgery and the ^¶Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201

CARP-1, a novel apoptosis inducer, regulates apoptosis signaling by diverse agents, including adriamycin and growth factors. Epidermal growth factor receptor (EGFR)-related protein (ERRP), a pan-ErbB inhibitor, inhibits EGFR and stimulates apoptosis. Treatments of cells with ERRP or Iressa (an EGFR tyrosine kinase inhibitor) results in elevated CARP-1 levels, whereas antisense-dependent depletion of CARP-1 causes inhibition of apoptosis by ERRP. CARP-1 is a tyrosine-phosphorylated protein, and ERRP treatments cause elevated tyrosine phosphorylation of CARP-1. CARP-1 contains multiple, nonoverlapping apoptosis-inducing subdomains; one such subdomain is present within amino acids 1–198. Wild-type or CARP-1-(1–198) proteins that have substitution of tyrosine 192 to phenylalanine abrogate apoptosis by ERRP. In addition, apoptosis mediated by wild type or CARP-1-(1–198), and not CARP-1-(1–198^Y192F), results in activation of caspase-9 and increased phosphorylation of p38 MAPK. However, the expression of dominant-negative forms of p38 MAPK activators MKK3 or MKK6 proteins inhibits apoptosis induced by both the full-length and truncated (amino acids 1–198) proteins. Together, data demonstrate that tyrosine 192 of CARP-1 is a target of apoptosis signaling, and CARP-1, in turn, promotes apoptosis by activating p38 MAPK and caspase-9.

Received for publication, November 15, 2005 , and in revised form, February 28, 2006.

^* This work was supported by the Detroit Medical Center Institute for Oncology and Allied Diseases and Childrens' Leukemia Foundation of Michigan institutional research grants (to A. K. R.), the Susan G. Komen Breast Cancer Foundation (to A. K. R.), the medical research services of the Department of Veterans Affairs (to A. K. R., J. A. F., A. W., and A. P. N. M.), and by National Institutes of Health Grants RO1 AG 14343 (to A. P. N. M.) and RO1 CA109370 (to J. A. F.). 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: Rm. B4334, VA Medical Center, 4646 John R, Detroit, MI 48201. Tel.: 313-576-4492; Fax: 313-576-1112; E-mail: Rishia{at}Karmanos.org.

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