Focal adhesion kinase: at the crossroads of signal transduction

1997 ◽  
Vol 110 (4) ◽  
pp. 401-407 ◽  
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.

scholarly journals Focal Adhesion Kinase Modulates Cell Adhesion Strengthening via Integrin Activation

2009 ◽  
Vol 20 (9) ◽  
pp. 2508-2519 ◽  
Author(s):  
Kristin E. Michael ◽  
David W. Dumbauld ◽  
Kellie L. Burns ◽  
Steven K. Hanks ◽  
Andrés J. García
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Human Fibroblasts ◽  
Inducible Promoter ◽  
Time Dependent ◽  
Integrin Activation ◽  
Nonreceptor Tyrosine Kinase ◽  
Adhesive Forces

Focal adhesion kinase (FAK) is an essential nonreceptor tyrosine kinase regulating cell migration, adhesive signaling, and mechanosensing. Using FAK-null cells expressing FAK under an inducible promoter, we demonstrate that FAK regulates the time-dependent generation of adhesive forces. During the early stages of adhesion, FAK expression in FAK-null cells enhances integrin activation to promote integrin binding and, hence, the adhesion strengthening rate. Importantly, FAK expression regulated integrin activation, and talin was required for the FAK-dependent effects. A role for FAK in integrin activation was confirmed in human fibroblasts with knocked-down FAK expression. The FAK autophosphorylation Y397 site was required for the enhancements in adhesion strengthening and integrin-binding responses. This work demonstrates a novel role for FAK in integrin activation and the time-dependent generation of cell–ECM forces.

scholarly journals Endothelin-1 stimulates tyrosine phosphorylation of p125 focal adhesion kinase in mesangial cells.

1995 ◽  
Vol 6 (5) ◽  
pp. 1504-1510
Author(s):  
M Haneda ◽  
R Kikkawa ◽  
D Koya ◽  
T Shikano ◽  
T Sugimoto ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Focal Adhesion Kinase ◽  
Tyrosine Phosphorylation ◽  
Focal Adhesion ◽  
Protein Tyrosine Kinase ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Protein Tyrosine ◽  
Endothelin 1

Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. Because ET-1 was found to stimulate the tyrosine phosphorylation of unidentified cellular proteins in cultured mesangial cells, protein tyrosine kinase might serve as one of the important signals leading to various functions of ET-1. Focal adhesion kinase (p125FAK) is a newly identified cytoplasmic protein tyrosine kinase that is activated by the phosphorylation of its own tyrosine residue. Because p125FAK was found to play a role in the signal transduction of not only integrins but also various neurotransmitters, including bombesin, endothelin, and vasopressin in Swiss 3T3 cells and Rat-1 fibroblasts, whether ET-1 could stimulate the tyrosine phosphorylation of p125FAK in glomerular mesangial cells was examined. ET-1 stimulated the tyrosine phosphorylation of p125FAK by threefold to fourfold in cultured mesangial cells. This effect of ET-1 was detected at 1 min and reached a maximum within 5 min and was blocked by BQ-123, an antagonist for ETA receptor. A23187, a calcium ionophore, failed to stimulate the tyrosine phosphorylation of p125FAK, and ET-1 was able to stimulate the tyrosine phosphorylation of p125FAK, even in a calcium-free medium. The activation of protein kinase C (PKC) by phorbol 12, 13-dibutyrate resulted in a stimulation of the tyrosine phosphorylation of p125FAK, and an inhibition of PKC by calphostin C or staurosporine significantly reduced the effect of ET-1. Furthermore, prolonged treatment of the cells with phorbol 12, 13-dibutyrate markedly inhibited the ET-1-induced tyrosine phosphorylation of p125FAK. These results indicate that p125FAK might play a role in a signal transduction system of ET-1 in glomerular mesangial cells and that the ET-1-induced tyrosine phosphorylation of p125FAK is largely dependent on the PKC pathway.

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

2010 ◽  
Vol 21 (3) ◽  
pp. 481-488 ◽  
Author(s):  
Pachiyappan Kamarajan ◽  
Julius Bunek ◽  
Yong Lin ◽  
Gabriel Nunez ◽  
Yvonne L. Kapila
Keyword(s):  
Extracellular Matrix ◽  
Cell Death ◽  
Focal Adhesion Kinase ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Death Domain ◽  
Reverse Effect ◽  
Interacting Protein ◽  
Survival Pathways ◽  
Survival Signaling

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.

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

2017 ◽  
Vol 312 (5) ◽  
pp. L722-L730 ◽  
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.

scholarly journals Phosphorylation of Focal Adhesion Kinase (FAK) on Ser732 Is Induced by Rho-dependent Kinase and Is Essential for Proline-rich Tyrosine Kinase-2–mediated Phosphorylation of FAK on Tyr407 in Response to Vascular Endothelial Growth Factor

2006 ◽  
Vol 17 (8) ◽  
pp. 3508-3520 ◽  
Author(s):  
Fabrice Le Boeuf ◽  
François Houle ◽  
Mark Sussman ◽  
Jacques Huot
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Migration ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Endothelial Cell Migration ◽  
Vascular Endothelial ◽  
Tyrosine Kinase 2 ◽  
Endothelial Growth Factor

Focal adhesion kinase (FAK) is phosphorylated on tyrosine and serine residues after cell activation. In the present work, we investigated the relationship between tyrosine and serine phosphorylation of FAK in promoting endothelial cell migration in response to vascular endothelial growth factor (VEGF). We found that VEGF induces the activation of the Rho-dependent kinase (ROCK) downstream from vascular endothelial growth factor receptor (VEGFR) 2. In turn, activated ROCK directly phosphorylates FAK on Ser732. Proline-rich tyrosine kinase-2 (Pyk2) is also activated in response to VEGF. Its activation requires the clustering of integrin αvβ3 and triggers directly the phosphorylation of Tyr407 within FAK, an event necessary for cell migration. Interestingly, ROCK-mediated phosphorylation of Ser732 is essential for Pyk2-dependent phosphorylation of Tyr407, because the latter is abrogated in cells expressing a FAK mutant that is nonphosphorylatable on Ser732. We suggest that VEGF elicits the activation of the VEGFR2–ROCK pathway, leading to phosphorylation of Ser732 within FAK. In turn, phosphorylation of Ser732 would change the conformation of FAK, making it accessible to Pyk2 activated in response to its association with integrin β3. Then, activated Pyk2 triggers the phosphorylation of FAK on Tyr407, promoting cell migration.

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