The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin

Hayashi, Ikuko; Vuori, Kristiina; Liddington, Robert

doi:10.1038/nsb755

Cited by 192 publications

(222 citation statements)

References 29 publications

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“…However, expression of the FAK-L1034S point mutant failed to rescue spindle orientation defects both in the Z axis and in the XY plane (Figs 3d,e and 4a,b). As the L1034S mutation has recently been shown to affect the structure of the four helix bundle that makes up the FAT domain and in addition, leads to loss of the FAK-RhoGEF interaction 33,38 , we confirmed this result using the FAK-I936E/I998E mutant that specifically abolishes paxillin binding without affecting structure 38 (Fig. 4a,b).…”

Section: Spindle Orientation Is Determined By the Ecm Distributionsupporting

confidence: 73%

FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis

Petridou

Skourides

2014

Nat Commun

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Spindle orientation is critical for proper morphogenesis of organs and tissues as well as for the maintenance of tissue morphology. Although significant progress has been made in understanding the mechanisms linking the cell cortex to the spindle and the well-documented role that extracellular forces play in spindle orientation, how such forces are transduced to the cortex remains poorly understood. Here we report that focal adhesion kinase (FAK) is necessary for correct spindle orientation and as a result, indispensable for proper epithelial morphogenesis in the vertebrate embryo. We show that FAK's role in spindle orientation is dependent on its ability to localize at focal adhesions and its interaction with paxillin, but is kinase activity independent. Finally, we present evidence that FAK is required for external force-induced spindle reorientation, suggesting that FAK's involvement in this process stems from a role in the transduction of external forces to the cell cortex.

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Section: Spindle Orientation Is Determined By the Ecm Distributionsupporting

confidence: 73%

FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis

Petridou

Skourides

2014

Nat Commun

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“…FAK binds paxillin through its COOH-terminal focal adhesion targeting region (25). This focal adhesion targeting region is also contained within a naturally occurring fragment of FAK (26), termed FAK-related non-kinase.…”

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Salah

Maoz

Pokroy

et al. 2007

Molecular Cancer Research

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Although ample evidence point to the central involvement of protease activated receptor-1 (PAR1) in tumor progression, little is known about the fate of the tumor when hPar1 is being silenced. We observed that hPar1 antisense clones exhibit low PAR1 levels, attenuated cell proliferation and invasion in vitro, and tumor formation in vivo. These clones showed noticeably reduced paxillin phosphorylation compared with the parental A375SM cells, whereas no change in the integrin levels was noticed. Antisense clones injected into the mice resulted in very few and only occasional small tumors, whereas advanced and vascularized tumors were observed in A375SM cells. The antisense-derived tumor sections expressed active caspase-3, increased terminal deoxynucleotidyl transferase -mediated nick-end labeling staining, and a markedly reduced proliferating cell nuclear antigen level compared with A375SM cell -derived tissue sections. Likewise, ablation of the hPar1 gene in a tetracyclineinducible hPar1 system leads to apoptosis in immature blood vessels, whereas mature vessels were unaffected. The activation of PAR1-induced pAkt/protein kinase B abrogated serum-deprived Bim EL induction and also markedly inhibited Bax levels. On the other hand, small interfering RNA silencing of the hPar1 gene induced the expression of Bim EL , a direct substrate of Akt/protein kinase B and also induced expression of active caspase-9 and caspase-3. These results altogether identify PAR1 as a survival factor that protects cells from undergoing apoptosis. We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation. (Mol Cancer Res 2007;5(3):229 -40)

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“…Relative to other tyrosine phospho-acceptor sites, tyrosine 925 is a poor substrate for Src, which may be due to occlusion given the close proximity of the binding sites of other FAK binding partners and/or the three-dimensional structure of the domain (Calalb et al, 1995;Arold et al, 2002;Hayashi et al, 2002;Liu et al, 2002). There is evidence linking Src-dependent phosphorylation of tyrosine 925 and motility of Caco-2 colorectal cancer cells plated on collagen IV (Sanders and Basson, 2004).…”

Section: Srcmentioning

confidence: 99%

The interplay between Src and integrins in normal and tumor biology

2004

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Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

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The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin

Cited by 192 publications

References 29 publications

FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis

FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

The interplay between Src and integrins in normal and tumor biology

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