Apoptotic regulation by the Crk adapter protein mediated by interactions with Wee1 and Crm1/exportin.
The adapter protein Crk contains an SH2 domain and two SH3 domains. Through binding of particular ligands to the SH2 domain and the N-terminal SH3 domain, Crk has been implicated in a number of signaling processes, including regulation of cell growth, cell motility, and apoptosis. We report here that the C-terminal SH3 domain, never shown to bind any specific signaling molecules, contains a binding site for the nuclear export factor Crm1. We find that a mutant Crk protein, deficient in Crm1 binding, promotes apoptosis. Moreover, this nuclear export sequence mutant [NES(-) Crk] interacts strongly, through its SH2 domain, with the nuclear tyrosine kinase, Wee1. Collectively, these data suggest that a nuclear population of Crk bound to Wee1 promotes apoptotic death of mammalian cells.
Smith
Jesse J
JJ
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Richardson
D Ashley
DA
Kopf
Jan
J
Yoshida
Minoru
M
Hollingsworth
Robert E
RE
Kornbluth
Sally
S
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000502:physiology*; D002451:Cell Compartmentation; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000502:physiology; D006801:Humans; D028884:Karyopherins / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction; D018909:src Homology Domains; D000097606:Exportin 1 Protein
D018797:Cell Cycle Proteins; D028884:Karyopherins; D009687:Nuclear Proteins; D011494:Protein Kinases; D021382:Protein Sorting Signals; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C499349:WEE1 protein, human