Cell cycle and apoptosis regulatory protein (CARP)-1 is involved in apoptosis signaling by epidermal growth factor receptor (EGFR)

doi:10.1074/jbc.M512279200

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Papers In Press, published online ahead of print March 16, 2006
J. Biol. Chem, 10.1074/jbc.M512279200
Submitted on November 15, 2005
Accepted on March 16, 2006

Cell cycle and apoptosis regulatory protein (CARP)-1 is involved in apoptosis signaling by epidermal growth factor receptor (EGFR)

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

Internal Medicine, Wayne State University, Detroit, MI 48201

Corresponding Author: rishia{at}karmanos.org

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, non-overlapping apoptosis-inducing sub-domains; one such sub-domain is present within 1-198 amino acids. Wild-type or CARP-1 (1-198) proteins that have substitution of tyrosine192 to phenylalanine abrogate apoptosis by ERRP. In addition, apoptosis mediated by wild type or CARP-1 (1-198), and not CARP-1 (1-198Y192>F), results in activation of caspase-9, and increased phosphorylation of p38 MAPK. However, expression of dominant-negative forms of p38 MAPK activators MKK3 or MKK6 proteins inhibit apoptosis induced by both the full length as well as truncated (1-198) proteins. Together, data demonstrate that tyrosine192 of CARP-1 is a target of apoptosis signaling, and CARP-1 in turn, promotes apoptosis by activating p38 MAPK and caspase 9.

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