Focal Adhesion Kinase Suppresses Apoptosis by Binding to the Death Domain of Receptor-Interacting Protein

Abstract

Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that plays a key role in maintaining focal adhesion function and cell survival and is implicated in cell migration, adhesion, and cell cycle control (9,13,18,20,33,44). Overexpression of FAK is a common event in numerous tumor systems, including breast, colon, and thyroid carcinomas (2,24,32,41), and occurs at early stages of tumorigenesis, before a tumor has developed the capacity for invasion and metastasis (2). Importantly, FAK has been shown to be one of the critical factors protecting cells from apoptosis, but the exact mechanism is unknown (8,9,12,19,37,43). Attenuation of FAK expression by antisense oligonucleotides led to apoptosis in tumor cells (42), and the treatment of cells with anti-FAK antibody (18, 26) or overexpression of the focal adhesion targeting (FAT) domain of FAK led to cell rounding, detachment, and apoptosis (19,21,40). We have created a model system for the attenuation of FAK function by adenoviral gene transduction of the carboxy-terminal domain of FAK (FAK-CD) and have demonstrated a loss of adhesion and apoptosis in breast cancer cells with this treatment (43). Both anchoragedependent and anchorage-independent apoptotic signaling required Fas-associated death domain protein (FADD) and caspase 8, suggesting an important role for FAK in inhibiting death receptor-related apoptosis (43). This finding provided additional evidence that a death receptor-mediated apoptotic pathway or death receptor-related death domain proteins are involved in the apoptotic process triggered by the expression of FAK-CD.The loss of adhesion and induction of apoptosis upon attenuation of FAK function by the expression of FAK-CD is similar to the phenomenon of anoikis (7-9). Intriguingly, there is evidence for the involvement of death receptor-related, death domain-containing proteins in anoikis (7, 35), whereby the silencer of death domain (SODD) and dominant-negative FADD efficiently inhibited anoikis in Madin-Darby canine kidney (MDCK) cells and in a number of untransformed epithelial cell lines. In these studies, it was also shown that cell matrix detachment activated caspase 8. However, the linkage of the signaling pathways to the death receptors remains unknown.RIP is a serine/threonine kinase that contains a death domain (17, 38) and is named for its association with the death receptor complex. RIP interacts with the death domains of cell surface receptors of the tumor necrosis factor (TNF) superfamily and death domain adaptor proteins (3,5,17) and plays an indispensable role in 39). Recently, it was shown that TNF alpha-mediated activation of NF-B depends on the association of RIP and FAK (11). TNF-induced NF-B DNA binding activity and activation of IB kinases were markedly impaired in FAK Ϫ/Ϫ cells (11). However, it has been well established that RIP has a dual function and is capable of either inducing apoptosis or activating cellular survival signals (14,17,23,27,38,39). Similarly, it has been proposed that RIP is one of the switch...

High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype

“…This further supports the role of FAK as a survival signal. 39 In this study, high FAK expression had a borderline association with positive lymph node status and stage at diagnosis. Owing to the low number of patients presenting with stage III and IV disease we cannot confirm this association in this study.…”

“…38 Recent work has shown FAK association with receptor-interacting protein, a serine/threonine kinase that contains a death domain. 39 When FAK binds to receptor-interacting protein, the proapoptotic signals supplied by receptor-interacting protein are suppressed. This further supports the role of FAK as a survival signal.…”

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

“…Recently, a correlation between STATl expression and cisplatin resistance in cell lines derived from patients with ovarian carcinoma was also reported (Roberts et al, 2005), and inhibitors of the STATl pathway have been shown to induce apoptosis in leukaemic cells from patients (Martinez-Lostao et al, 2005). The pathway analysis showed that STATl is positively influenced by MAPK1 and FAK, two of the most highly connected resistance-associated genes, both of which have been reported to inhibit apoptosis (Shimada et al, 2002;Kurenova et al, 2004). Notably, STATl expression has been reported higher in tumour compared with corresponding normal tissue for a wide range of tumour types (www.oncomine.com).…”

Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis

“…There are suggestions that interfering with cell spreading may be a method of sensitizing tumor cells to TRAIL killing (13)(14)(15). Spreading is mediated by the interaction of integrins with extracellular matrix components.…”