Receptor-interacting Protein Shuttles between Cell Death and Survival Signaling Pathways

Cross-talk between apoptosis and survival signaling pathways is crucial for regulating tissue processes and mitigating disease. We report that anoikis—apoptosis triggered by loss of extracellular matrix contacts—activates a CD95/Fas-mediated signaling pathway regulated by receptor-interacting protein (RIP), a kinase that shuttles between CD95/Fas-mediated cell death and integrin/focal adhesion kinase (FAK)-mediated survival pathways. RIP's death domain was critical for RIP and Fas association to mediate anoikis. Fas or RIP attenuation reduced this association and suppressed anoikis, whereas their overexpression had the reverse effect. Overexpressing FAK restored RIP and FAK association and inhibited anoikis. Thus, RIP shuttles between CD95/Fas death and FAK survival signaling to mediate anoikis.

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

Molecular and Cellular Biology ◽

10.1128/mcb.24.10.4361-4371.2004 ◽

2004 ◽

Vol 24 (10) ◽

pp. 4361-4371 ◽

Cited By ~ 112

Author(s):

Elena Kurenova ◽

Li-Hui Xu ◽

Xihui Yang ◽

Albert S. Baldwin ◽

Rolf J. Craven ◽

...

Keyword(s):

Focal Adhesion Kinase ◽

Tumor Cells ◽

Focal Adhesion ◽

Death Receptor ◽

Human Tumors ◽

Receptor Complex ◽

Death Domain ◽

Functional Link ◽

Interacting Protein ◽

Survival Signals

ABSTRACT 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.

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Focal adhesion kinase: at the crossroads of signal transduction

Journal of Cell Science ◽

10.1242/jcs.110.4.401 ◽

1997 ◽

Vol 110 (4) ◽

pp. 401-407 ◽

Cited By ~ 16

Author(s):

D. Ilic ◽

C.H. Damsky ◽

T. Yamamoto

Keyword(s):

Signal Transduction ◽

Extracellular Matrix ◽

Cell Migration ◽

Tyrosine Kinase ◽

Focal Adhesion Kinase ◽

Signaling Pathways ◽

Focal Adhesion ◽

Nonreceptor Tyrosine Kinase ◽

Definitive Evidence ◽

Multiple Signaling

Morphogenetic processes during development, including cell migration, depend on signals from both the extracellular matrix (ECM) and soluble signaling factors. Extensive evidence has shown that the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is activated in response to both kind of signal. The most definitive evidence that FAK is directly downstream of signals initiated by the ECM comes from comparing the phenotypes of mice deficient for FAK and the ECM molecule, fibronectin: in both cases embryos die at about E8.5 and display almost identical severe vascular and other mesodermal defects. It is now clear that there are additional FAK-like proteins, indicating the existence of a FAK family. Furthermore, FAK is not located at adhesive sites in all cells where it is expressed. This, plus extensive data indicating that FAK becomes activated in response to several soluble signaling factors, suggests that the FAK family may be at the crossroads of multiple signaling pathways that affect cell and developmental processes.

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Lung epithelial cell focal adhesion kinase signaling inhibits lung injury and fibrosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00478.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. L722-L730 ◽

Cited By ~ 15

Author(s):

Amanda K. Wheaton ◽

Manisha Agarwal ◽

Shijing Jia ◽

Kevin K. Kim

Keyword(s):

Extracellular Matrix ◽

Epithelial Cell ◽

Lung Injury ◽

Focal Adhesion Kinase ◽

Signaling Pathways ◽

Focal Adhesion ◽

Intracellular Signaling ◽

Terminal Deoxynucleotidyl Transferase ◽

Integrin Signaling ◽

Dynamic Changes

Progressive pulmonary fibrosis is a devastating consequence of many acute and chronic insults to the lung. Lung injury leads to alveolar epithelial cell (AEC) death, destruction of the basement membrane, and activation of transforming growth factor-β (TGF-β). There is subsequent resolution of the injury and a coordinated and concurrent initiation of fibrosis. Both of these processes may involve activation of similar intracellular signaling pathways regulated in part by dynamic changes to the extracellular matrix. Matrix signaling can augment the profibrotic fibroblast response to TGF-β. However, similar matrix/integrin signaling pathways may also be involved in the inhibition of ongoing TGF-β-induced AEC apoptosis. Focal adhesion kinase (FAK) is an integrin-associated signaling molecule expressed by many cell types. We used mice with AEC-specific FAK deletion to isolate the epithelial aspect of integrin signaling in the bleomycin model of lung injury and fibrosis. Mice with AEC-specific deletion of FAK did not exhibit spontaneous lung injury but did have significantly greater terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling-positive cells (18.6 vs. 7.1) per ×200 field, greater bronchoalveolar lavage protein (3.2 vs. 1.8 mg/ml), and significantly greater death (77 vs. 19%) after bleomycin injury compared with littermate control mice. Within primary AECs, activated FAK directly associates with caspase-8 and inhibits activation of the caspase cascade resulting in less apoptosis in response to TGF-β. Our studies support a model in which dynamic changes to the extracellular matrix after injury promote fibroblast activation and inhibition of epithelial cell apoptosis in response to TGF-β through FAK activation potentially complicating attempts to nonspecifically target this pathway for antifibrotic therapy.

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Early signalling events of autophagy

Essays in Biochemistry ◽

10.1042/bse0550001 ◽

2013 ◽

Vol 55 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Laura E. Gallagher ◽

Edmond Y.W. Chan

Keyword(s):

Protein Kinase ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Mammalian Cells ◽

Mammalian Target Of Rapamycin ◽

Interacting Protein ◽

The Core ◽

Autophagy Gene ◽

Autophagy Induction ◽

Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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Faculty Opinions recommendation of Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718174775.793489069 ◽

2013 ◽

Author(s):

Martin A Schwartz

Keyword(s):

Extracellular Matrix ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Extracellular Matrix Proteins ◽

Matrix Proteins

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The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia

Science ◽

10.1126/science.abg0269 ◽

2021 ◽

Vol 372 (6549) ◽

pp. eabg0269

Author(s):

Zengzhang Zheng ◽

Wanyan Deng ◽

Yang Bai ◽

Rui Miao ◽

Shenglin Mei ◽

...

Keyword(s):

Cell Death ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Host Cells ◽

Caspase 8 ◽

Death Domain ◽

Interacting Protein ◽

A Genome ◽

Infection Inhibition ◽

Guanosine Triphosphatase

Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor–β–activated kinase 1 (TAK1) by pathogenic Yersinia in macrophages triggers receptor-interacting serine-threonine protein kinase 1 (RIPK1)–dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide CRISPR screen to uncover mediators of caspase-8–dependent pyroptosis identified an unexpected role of the lysosomal folliculin (FLCN)–folliculin-interacting protein 2 (FNIP2)–Rag-Ragulator supercomplex, which regulates metabolic signaling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, Fas-associated death domain (FADD), RIPK1, and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag guanosine triphosphatase activity and lysosomal tethering of Rag-Ragulator but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia.

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RIPK1 Is Cleaved by 3C Protease of Rhinovirus A and B Strains and Minor and Major Groups

Viruses ◽

10.3390/v13122402 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2402

Author(s):

Sarah N. Croft ◽

Erin J. Walker ◽

Reena Ghildyal

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Programmed Cell Death ◽

Protease Inhibitor ◽

Phylogenetic Groups ◽

Viral Protease ◽

Interacting Protein ◽

3C Protease ◽

Survival Pathways ◽

Integral Role

Rhinoviruses (RV), like many other viruses, modulate programmed cell death to their own advantage. The viral protease, 3C has an integral role in the modulation, and we have shown that RVA-16 3C protease cleaves Receptor-interacting protein kinase-1 (RIPK1), a key host factor that modulates various cell death and cell survival pathways. In the current study, we have investigated whether this cleavage is conserved across selected RV strains. RIPK1 was cleaved in cells infected with strains representing diversity across phylogenetic groups (A and B) and receptor usage (major and minor groups). The cleavage was abrogated in the presence of the specific 3C protease inhibitor, Rupintrivir. Interestingly, there appears to be involvement of another protease (maybe 2A protease) in RIPK1 cleavage in strains belonging to genotype B. Our data show that 3C protease from diverse RV strains cleaves RIPK1, highlighting the importance of the cleavage to the RV lifecycle.

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Differential activation of focal adhesion kinase, Rho and Rac by the ninth and tenth FIII domains of fibronectin

Journal of Cell Science ◽

10.1242/jcs.112.17.2937 ◽

1999 ◽

Vol 112 (17) ◽

pp. 2937-2946

Author(s):

N.A. Hotchin ◽

A.G. Kidd ◽

H. Altroff ◽

H.J. Mardon

Keyword(s):

Growth Factor ◽

Focal Adhesion Kinase ◽

Signaling Pathways ◽

Focal Adhesion ◽

Cell Attachment ◽

Cell Types ◽

Integrin Receptors ◽

3T3 Cells ◽

Swiss 3T3 ◽

Kinase Phosphorylation

Fibronectins are widely expressed extracellular matrix ligands that are essential for many biological processes. Fibronectin-induced signaling pathways are elicited in diverse cell types when specific integrin receptors bind to the ninth and tenth FIII domains, FIII9-10. Integrin-mediated signal transduction involves activation of signaling pathways of the growth factor-dependent Ras-related small GTP-binding proteins Rho and Rac, and phosphorylation of focal adhesion kinase. We have dissected the requirement of FIII9 and FIII10 for Rho and Rac activity and phosphorylation of focal adhesion kinase in BHK fibroblasts and Swiss 3T3 cells. We demonstrate that FIII10 supports cell attachment but does not induce phosphorylation of focal adhesion kinase. In Swiss 3T3 cells, growth factor-independent phosphorylation of focal adhesion kinase and downstream adhesion events are dependent upon the presence of FIII9 in the intact FIII9-10 pair, whereas FIII10-mediated focal adhesion kinase phosphorylation requires a synergistic signal from growth factors. Furthermore, FIII10 is able to elicit cellular responses mediated by Rho, but not Rac, whereas FIII9-10 can elicit both Rho- and Rac-mediated responses. We propose that activation of specific integrin subunits by the FIII10 and FIII9-10 ligands elicits distinct signaling events. This may represent a general molecular mechanism for activation of receptor-specific signaling pathways by a multi-domain ligand.

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