Focal adhesion kinase suppresses apoptosis by binding to the death domain of receptor-interacting protein.
Tumor cells resist the apoptotic stimuli associated with invasion and metastasis by activating survival signals that suppress apoptosis. Focal adhesion kinase (FAK), a tyrosine kinase that is overexpressed in a variety of human tumors, mediates one of these survival signals. Attenuation of FAK expression in tumor cells results in apoptosis that is mediated by caspase 8- and FADD-dependent pathways, suggesting that death receptor pathways are involved in the process. Here, we report a functional link between FAK and death receptors. We have demonstrated that FAK binds to the death domain kinase receptor-interacting protein (RIP). RIP is a major component of the death receptor complex and has been shown to interact with Fas and tumor necrosis factor receptor 1 through its binding to adapter proteins. We have shown that RIP provides proapoptotic signals that are suppressed by its binding to FAK. We thus propose that FAK overexpression in human tumors provides a survival signal function by binding to RIP and inhibiting its interaction with the death receptor complex.
Kurenova
Elena
E
Department of Surgery, University of Florida, Gainesville, Florida 32610, USA.
Xu
Li-Hui
LH
Yang
Xihui
X
Baldwin
Albert S
AS
Craven
Rolf J
RJ
Hanks
Steven K
SK
Liu
Zheng-Gang
ZG
Cance
William G
WG
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology
D015703:Antigens, CD; D011506:Proteins; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D019311:Staurosporine