RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis.
Signaling through the CD95/Fas/APO-1 death receptor plays a critical role in the homeostasis of the immune system. RICK, a novel protein kinase that regulates CD95-mediated apoptosis was identified and characterized. RICK is composed of an N-terminal serine-threonine kinase catalytic domain and a C-terminal region containing a caspase-recruitment domain. RICK physically interacts with CLARP, a caspase-like molecule known to bind to Fas-associated protein with death domain (FADD) and caspase-8. Expression of RICK promoted the activation of caspase-8 and potentiated apoptosis induced by Fas ligand, FADD, CLARP, and caspase-8. Deletion mutant analysis revealed that both the kinase domain and caspase-recruitment domain were required for RICK to promote apoptosis. Significantly, expression of a RICK mutant in which the lysine of the putative ATP-binding site at position 38 was replaced by a methionine functioned as an inhibitor of CD95-mediated apoptosis. Thus, RICK represents a novel kinase that may regulate apoptosis induced by the CD95/Fas receptor pathway.
Inohara
N
N
Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
del Peso
L
L
Koseki
T
T
Chen
S
S
Núñez
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D017209:Apoptosis; D001665:Binding Sites; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D018076:DNA, Complementary; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D019014:fas Receptor / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D019014:fas Receptor; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D003546:Cysteine Endopeptidases