Phosphorylation of Tyrosine 397 in Focal Adhesion Kinase Is Required for Binding Phosphatidylinositol 3-Kinase

Chen, Hong Chen; Appeddu, Paul A.; Isoda, Hiroko; Guan, Jun

doi:10.1074/jbc.271.42.26329

Cited by 506 publications

(448 citation statements)

References 50 publications

(64 reference statements)

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“…14,15 PI-3K activation resulting from its binding to the FAK Tyr-397 site has been implicated as a downstream FAK signaling event that confers a resistance to apoptosis. 16 Therefore, a VEGF 165 or Ang1/integrins/FAK pathway might lead to the activation of PI-3K. However, precise signaling pathways need to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways

Zhou

Yang

et al. 2004

Gene Ther

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Angiogenic growth factors, vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) could decrease myocardial infarct size, which was assumed to be related with newly formed capillaries. We doubted that these capillaries could do this solely and the potential protective mechanisms of VEGF and Ang1 on myocardium need to be evaluated. Three types of adenoviruses encoding human VEGF 165 (Ad-VEGF 165 ), human angiopoietin-1 (Ad-Ang1) and green fluorescent protein (Ad-GFP, as a parallel control) were constructed. Experiments were taken both in vitro and in vivo. As in vitro, the antiapoptosis effect of VEGF 165 , Ang1 and VEGF 165 +Ang1 on cardiac myoblasts was observed, which seemed to be related with the activation of phosphatidylinositol-3 kinase and Bcl-2 pathways. As in vivo, adenoviruses were intramyocardially injected immediately after the ligation of the left anterior descending coronay arteries in rats. The results showed positive effect of VEGF 165 , Ang1 and VEGF 165 +Ang1 on decreasing the myocardial infarct size at the 7th day. Myocardial PI-3K activity and Bcl-2 expression were elevated relatively at the 3rd day. The protective effect of VEGF 165 and Ang1 on the myocardium may broaden their functional research and contribute to their clinical use in the future.

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Section: Discussionmentioning

confidence: 99%

VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways

Zhou

Yang

et al. 2004

Gene Ther

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“…Phosphorylation of FAK at Tyr397 creates a binding site for molecules containing SH2 domains, such as Src (Schaller et al, 1994) and the p85 subunit of phosphatidylinositol-3-kinase (PI3K) (Chen et al, 1996). These interactions are essential for the activation of downstream signal-transduction cascades (Parsons, 2003;Mitra et al, 2005).…”

Section: Merlin Impairs the Interaction Of Fak With Its Binding Partnmentioning

confidence: 99%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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“…Src can also phosphorylate FAK at tyrosine residue 925, creating a binding site for the Grb2-mSOS complex . Finally autophosphorylated FAK can combine with and activate phosphatidyl-inositide-3 kinase (PI-3K) (Chen et al, 1996). FAK is thus linked to a number of intracellular signaling pathways.…”

Section: Focal Adhesion Kinasementioning

confidence: 99%

“…Constitutive activation of p190 Rho-GAP disrupts integrin clustering and focal plaque formation. PI-3 kinase which phosphorylates PI(4) phosphate (PIP) or PI(4,5) biphosphate (PIP2) to generate PI (3,4)P 2 or PI (3,4,5)P 3 respectively has been shown to associate with integrin-associated focal adhesion complexes (Chen et al, 1996). The SH2 domain of the p85 subunit of PI-3 K may be important for its association with tyrosine phosphorylated FAK.…”

Section: Role Of Rho Family Of Proteins In Focal Adhesion Assemblymentioning

confidence: 99%

Signaling by integrin receptors

Kumar¹

1998

Oncogene

256

181

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Adhesive interactions are critical for the proliferation, survival and function of all cells. Integrin receptors as the major family of adhesion receptors have been the focus of study for more than a decade. These studies have tremendously enhanced our understanding of the integrin-mediated adhesive interactions and have unraveled novel integrin functions in cell survival mechanisms and in the activation of divergent signaling pathways. The signals from integrin receptors are integrated from those originating from growth factor receptors in order to organize the cytoskeleton, stimulate cell proliferation and rescue cells from matrix detachment-induced programmed cell death. These functions are critical in the regulation of multiple processes such as tissue development, in¯ammation, angiogenesis, tumor cell growth and metastasis and programmed cell death.

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Phosphorylation of Tyrosine 397 in Focal Adhesion Kinase Is Required for Binding Phosphatidylinositol 3-Kinase

Cited by 506 publications

References 50 publications

VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways

VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Signaling by integrin receptors

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