Cell cycle- and apoptosis-regulatory protein-1 is involved in apoptosis signaling by epidermal growth factor receptor.
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.
Rishi
Arun K
AK
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201. Electronic address: Rishia@Karmanos.org.
Zhang
Liyue
L
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201.
Yu
Yingjie
Y
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201.
Jiang
Yan
Y
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201.
Nautiyal
Jyoti
J
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201.
Wali
Anil
A
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Surgery, Wayne State University, Detroit, Michigan 48201.
Fontana
Joseph A
JA
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201.
Levi
Edi
E
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201.
Majumdar
Adhip P N
APN
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201.
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D011799:Quinazolines; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C477529:CCAR1 protein, human; D018797:Cell Cycle Proteins; D006023:Glycoproteins; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D000077156:Gefitinib