Focal adhesion kinase regulates insulin resistance in skeletal muscle

Bisht, Bharti; Goel, Hira Lal; Dey, Chinmoy Sankar

doi:10.1007/s00125-007-0591-6

Cited by 51 publications

(60 citation statements)

References 49 publications

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“…Our findings indicated that FAK is involved in modulating EC glucose metabolism as well. A similar effect of FAK levels in regulating glucose uptake in C2C12 skeletal muscle cells was recently observed by Bisht et al (30).…”

Section: Discussionsupporting

confidence: 85%

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Fibronectin Stimulates Endothelial Cell ¹⁸F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Paik¹,

Ko²,

Jung³

et al. 2009

J Nucl Med

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There has been recent interest in the relationship between 18 F-FDG uptake and the angiogenic activity of endothelial cells (ECs). The angiogenic process is strongly dependent on the interaction of ECs with matrix fibronectin (FN), a key regulator of EC survival, migration, and proliferation. Therefore, we investigated how FN influences EC glucose uptake and elucidated the signaling pathways that mediate this effect. Methods: Human umbilical vein ECs were allowed to adhere to FN-coated plates and were compared with control cells for 18 F-FDG uptake, membrane GLUT1 levels, and hexokinase activity. The roles of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), and Akt were evaluated with Western blotting, small interfering RNA (siRNA), and specific inhibitors. Results: FN adhesion significantly enhanced the protein-corrected 18 F-FDG uptake in HUVEC, to 2.1-, 2.7-, and 4.3-fold that in control cells by 2, 3, and 5 d, respectively. This effect was mediated by the upregulation of both membrane GLUT1 expression and hexokinase activity and was accompanied by FAK activation. Silencing of FAK signaling by siRNA completely abrogated both FN-induced FAK phosphorylation and 18 F-FDG uptake. FN also activated PI3K and Akt, well-known angiogenesis mediators, and the inhibition of either pathway totally abolished the effect of FN on 18 F-FDG uptake. Nitric oxide, a downstream Akt effector that stimulates glucose uptake, was not involved in the metabolic effect of FN. Conclusion: The results of this study demonstrated that an EC-FN interaction induces strong enhancement of 18 F-FDG uptake through the upregulation of GLUT1 expression and hexokinase activity. The findings also showed that the response occurs through FAK-mediated activation of PI3K and Akt, indicating a role for this pathway in modulating EC glucose metabolism.

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Section: Discussionsupporting

confidence: 85%

“…In the study of Bisht et al, the effect of FAK on skeletal myocyte glucose metabolism appeared to be mediated mainly through PI3K and protein kinase C rather than Akt (30). In the present study, however, the FN-induced phosphorylation of FAK in HUVEC was accompanied by the activation of both PI3K and Akt.…”

Section: Discussioncontrasting

confidence: 63%

Fibronectin Stimulates Endothelial Cell ¹⁸F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Paik¹,

Ko²,

Jung³

et al. 2009

J Nucl Med

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“…FAK is a cytoplasmic Tyr kinase that has been shown to play critical roles in the development and pathogenesis of human diseases, including insulin resistance (46,47) and cancer (48). A decrease in FAK activity was shown to induce insulin resistance in skeletal muscle cells in vitro (46), and inhibition of FAK expression caused hyperglycemia and hyperinsulinemia in liver and muscle in vivo (47).…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110δ phosphoinositide‐3 kinase

2015

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The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is regulated by various mechanisms that are not fully understood. This includes regulation by Tyr phosphorylation by a mechanism that remains elusive. Here, we show that focal adhesion kinase (FAK) phosphorylates PTEN in vitro, in cell-free systems and in cells. Furthermore, by mass spectrometry, we identified Tyr336 on PTEN as being phosphorylated by FAK. Tyr336 phosphorylation increased phosphatase activity, protein-lipid interaction, and protein stability of PTEN. In cells, including primary mouse macrophages and human cancer cell lines, FAK was found to be negatively regulated by p110d phosphoinositide-3 kinase (PI3K), whereas the activation of FAK was positively regulated by RhoA-associated kinase (ROCK). Indeed, the phosphorylation of FAK was unexpectedly increased in macrophages derived from mice expressing kinase-dead p110d. Pharmacologic inactivation of RhoA/ROCK reduced the phosphorylation of FAK to normal levels in cells with genetically inactivated p110d. Likewise, pharmacologic inactivation of FAK reduced the phosphorylation of PTEN in cells expressing kinase-dead p110d and restored the functional defects of p110d inactivation, including Akt phosphorylation and cell proliferation. This work identifies FAK as a target of p110d PI3K that links RhoA with PTEN and establishes for the first time that PTEN is a substrate of FAK-mediated Tyr phosphorylation.-Tzenaki, N., Aivaliotis, M., Papakonstanti, E. A. Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110d phosphoinositide-3 kinase. FASEB J. 29, 4840-4852 (2015). www.fasebj.org

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“…Baron et al (32) identified that p125Fak focal adhesion kinase is a substrate for the insulin and insulin-like growth factor-I tyrosine kinase receptors. Bisht et al (33) reported that focal adhesion kinase regulates insulin resistance in skeletal muscle. Three DEGs were identified in this pathway, including PIK3CB, ITGA2 and PTEN.…”

Section: Discussionmentioning

confidence: 99%

An insight into the key genes and biological functions associated with insulin resistance in adipose tissue with microarray technology

Zhang

Cui

et al. 2014

Molecular Medicine Reports

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Abstract. In the present study, the key genes and biological functions associated with insulin resistance were investigated by comparing the gene expression profiles of adipose tissue obtained from insulin-sensitive and insulin-resistant patients. The gene expression data set GSE20950 was downloaded from the Gene Expression Omnibus, including 39 adipose tissue samples obtained from insulin-sensitive and insulin-resistant patients undergoing gastric bypass surgery. Adipose samples were divided into two groups (the insulin-sensitive and insulin-resistant groups) and the differentially expressed genes (DEGs) were screened out with packages of R. The interactions among DEGs were retrieved with Osprey and functional enrichment analysis was performed with the WebGestalt system. Information regarding the interaction network and enriched biological functions was combined to construct a functional interaction network. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery. A total of 170 DEGs were detected in the insulin-sensitive group, 8 downregulated and 162 upregulated. Response to glucose stimulus was the most significantly over-represented functional term. The focal adhesion pathway was identified to be significant in the genes of the functional interaction network. The present study revealed key biological functions and DEGs in adipose tissues associated with insulin resistance, which may facilitate the development of novel therapies for insulin resistance and diabetes. IntroductionDiabetes is caused by an absolute or relative deficiency of insulin. It is one of the most prevalent of all chronic diseases, which is characterized by high blood sugar and multiple secondary complications. Obesity is a risk factor for insulin resistance, a precursor of type 2 diabetes, which involves a decreased response to insulin signaling in several peripheral tissues including adipose, liver and muscle (1,2). However, not all obese individuals are insulin-resistant (3).Adipose tissue secretes numerous hormones and cytokines that function to regulate food intake and nutrient homeostasis, including insulin-like growth factor 2, leptin and resistin (4), and its role in the regulation of metabolism has been increasingly recognized in recent years (5). Previous studies have revealed a number of linkages between obesity and insulin resistance. Obesity-associated chronic inflammation in adipose tissue has a crucial role in the development of obesity-related insulin resistance (6-9). Adipocyte-derived cytokines are important in the pathogenesis of insulin resistance and type 2 diabetes (10). Hirosumi et al (11) indicated that the c-Jun amino-terminal kinase is a crucial mediator of obesity and insulin resistance. However, the molecular mechanisms underlying this effect remain elusive.In the present study, the gene expression profiles of adipose tissue samples obtained from insulin-sensitive and insulin-resistant patients were compared with...

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Focal adhesion kinase regulates insulin resistance in skeletal muscle

Cited by 51 publications

References 49 publications

Fibronectin Stimulates Endothelial Cell ¹⁸F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Fibronectin Stimulates Endothelial Cell ¹⁸F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110δ phosphoinositide‐3 kinase

An insight into the key genes and biological functions associated with insulin resistance in adipose tissue with microarray technology

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Focal adhesion kinase regulates insulin resistance in skeletal muscle

Cited by 51 publications

References 49 publications

Fibronectin Stimulates Endothelial Cell 18F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Fibronectin Stimulates Endothelial Cell 18F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110δ phosphoinositide‐3 kinase

An insight into the key genes and biological functions associated with insulin resistance in adipose tissue with microarray technology

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Fibronectin Stimulates Endothelial Cell ¹⁸F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling

Fibronectin Stimulates Endothelial Cell ¹⁸F-FDG Uptake Through Focal Adhesion Kinase–Mediated Phosphatidylinositol 3-Kinase/Akt Signaling