FRNK, the autonomously expressed C‐terminal region of focal adhesion kinase, is uniquely regulated in vascular smooth muscle: Analysis of expression in transgenic mice

Hayasaka, Haruko; Simon, Kate; Hershey, E. Daniel; Masumoto, Kouji; Parsons, J. Thomas

doi:10.1002/jcb.20501

Cited by 18 publications

(26 citation statements)

References 32 publications

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“…Nonetheless, FRNK expression is up-regulated in smooth muscle cells in vivo after balloon-induced vascular injury (37,39). Furthermore, FRNK expression is increased in vascular smooth muscle cells plated on perlecan, with consequent impaired FAK activation and cell proliferation (61).…”

Section: Discussionmentioning

confidence: 99%

“…FAK has been demonstrated to have a critical role in integrin-mediated cell functions, such as cell migration and proliferation (25,(31)(32)(33). FAK has recently been shown to mediate the ␣-SMA up-regulation in response to TGF-␤1 (34, 35), the ␣-SMA inhibition in response to fibroblast growth factor (36).FRNK is an independently expressed cytoplasmic protein that is identical in sequence to the C-terminal region of FAK (25,37,38). It has been demonstrated that FRNK inhibits integrin-mediated FAK activation (Tyr 397 phosphorylation) and blocks FAK-mediated cell migration and proliferation (25,37,39,40).…”

mentioning

confidence: 99%

“…FRNK is an independently expressed cytoplasmic protein that is identical in sequence to the C-terminal region of FAK (25,37,38). It has been demonstrated that FRNK inhibits integrin-mediated FAK activation (Tyr 397 phosphorylation) and blocks FAK-mediated cell migration and proliferation (25,37,39,40).…”

mentioning

confidence: 99%

“…It has been demonstrated that FRNK inhibits integrin-mediated FAK activation (Tyr 397 phosphorylation) and blocks FAK-mediated cell migration and proliferation (25,37,39,40). However, the role of FRNK in TGF-␤1-induced myofibroblast differentiation has not been defined.…”

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confidence: 99%

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Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent Manner

Ding

Gladson²,

et al. 2008

Journal of Biological Chemistry

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Transforming growth factor (TGF)-␤1 induces fibroblast transdifferentiation to myofibroblasts, a process that requires the involvement of integrin-mediated signaling and focal adhesion kinase (FAK). FAK-related non-kinase (FRNK) is known for its role in inhibiting integrin-mediated cell migration; however, its role in myofibroblast differentiation has not been defined. Here, we report that FRNK abrogates TGF-␤1-induced myofibroblast differentiation in vitro and in vivo. TGF-␤1 can induce ␣-smooth muscle actin (␣-SMA) expression in the presence or absence of FAK; however, TGF-␤1-induced ␣-SMA expression is reduced (ϳ73%) in FAK-deficient fibroblasts. Although both ERK and p38 MAPK activation is required for maximal TGF-␤1-induced ␣-SMA expression, ERK is the major signaling intermediate in cells that express FAK. In contrast, p38 MAPK is the dominant mediator of TGF-␤1-induced ␣-SMA expression in FAK-deficient cells. FRNK overexpression blocks TGF-␤1-induced ERK or p38 MAPK activation in the presence, and surprisingly, in the absence of FAK. The loss of FRNK was tested in vivo during experimentally induced pulmonary fibrosis in mice. FRNK knock-out mice have a greater increase in ␣-SMA-expressing cells in response to a pulmonary fibrotic stimulus in vivo, as compared with congenic wild type mice. This is the first time that FRNK loss has been shown to modify the pathobiology in any animal disease model. Together, the data demonstrate that FRNK negatively regulates myofibroblast differentiation in vitro and in vivo. These data further suggest that modulation FRNK expression may be a novel avenue for therapeutic intervention in tissue fibrosis.Deranged tissue repair and remodeling or failed termination of the normal wound healing response may result in tissue fibrosis. After injury, fibroblasts migrate into the wound, proliferate, and differentiate to "activated" fibroblasts (1-4). The differentiated or activated fibroblasts are termed myofibroblasts and are present in abundance within fibrotic lesional areas in the lung, liver, and kidney (2, 4 -6). Myofibroblasts secrete profibrotic cytokines and extracellular matrix proteins, such as collagen and fibronectin, and therefore have been presumed to act as effector cells of the fibrotic process (1, 2, 4 -7).Idiopathic pulmonary fibrosis is a devastating, untreatable, progressive fibrotic disease of the lung (8 -11). In support of the importance of myofibroblasts in the pathogenesis of lung fibrosis, these cells localize to fibroblastic foci in pulmonary fibrotic lungs, and the extent of fibroblastic foci is a major prognostic factor for patients with idiopathic pulmonary fibrosis (8 -11).The phenotypic hallmarks of myofibroblasts are the expression of ␣-SMA 2 and the incorporation of ␣-SMA into well organized cytoplasmic fibers (1, 4, 6). These fibers connect to robust, mature focal adhesions (1). ␣-SMA expression is associated with an enhanced contractile phenotype and can directly enhance the contractility of fibroblasts (12, 13). Inhibition of ␣-SMA integration in...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent Manner

Ding

Gladson²,

et al. 2008

Journal of Biological Chemistry

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“…Upregulation of FRNK expression has been found to be expressed in the medial layer of injured vascular walls [152], and its upregulation after balloon angioplasty injury is concomitant to that of the ECM protein perlecan in animal models [39]. Through its heparan sulfate side chains, perlecan itself may promote EC but not SMC growth after vascular injury [40,153].…”

Section: Inhibiting Smc Proliferation and Migrationmentioning

confidence: 99%

Cardiovascular gene delivery: The good road is awaiting☆

Brewster

Brey

Greisler

2006

Advanced Drug Delivery Reviews

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Atherosclerotic cardiovascular disease is a leading cause of death worldwide. Despite recent improvements in medical, operative, and endovascular treatments, the number of interventions performed annually continues to increase. Unfortunately, the durability of these interventions is limited acutely by thrombotic complications and later by myointimal hyperplasia followed by progression of atherosclerotic disease over time. Despite improving medical management of patients with atherosclerotic disease, these complications appear to be persisting. Cardiovascular gene therapy has the potential to make significant clinical inroads to limit these complications. This article will review the technical aspects of cardiovascular gene therapy; its application for promoting a functional endothelium, smooth muscle cell growth inhibition, therapeutic angiogenesis, tissue engineered vascular conduits, and discuss the current status of various applicable clinical trials.

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Disruption of FRNK expression by gene targeting of the intronic promoter within the focal adhesion kinase gene

Hayasaka

Martin

Hershey

et al. 2007

J of Cellular Biochemistry

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FRNK, a non-catalytic variant of focal adhesion kinase (FAK), is expressed in major blood vessels throughout mouse development and is postulated to play a role in regulating cell adhesion and signaling in vascular smooth muscle cells (VSMCs). The FRNK transcriptional start site lies within an intron of the FAK gene, suggesting that the FRNK gene is a "gene within a gene". Here, we identified a 1 kb intronic sequence of the FAK gene that is necessary for endogenous FRNK expression. Deletion of this sequence in gene-targeted mice abolished FRNK expression, showing the direct involvement of the FAK intron in the regulation of FRNK expression. The level of FAK expression was normal in the FRNK-deficient mice, indicating that FAK and FRNK are transcriptionally regulated by distinct promoters. The FRNK-deficient mice were viable, fertile, and displayed no obvious histological abnormalities in any of the major blood vessels. Western blot analysis showed that FRNK-deficient and wild-type (WT) cells had comparable levels of steady-state and adhesion-dependent FAK autophosphorylation. Despite the fact that ectopic expression of FRNK suppresses focal adhesion formation in cultured cells, these results suggest that endogenous FRNK is not essential for development or the formation of the mouse vasculature.

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FRNK, the autonomously expressed C‐terminal region of focal adhesion kinase, is uniquely regulated in vascular smooth muscle: Analysis of expression in transgenic mice

Cited by 18 publications

References 32 publications

Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent Manner

Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent Manner

Cardiovascular gene delivery: The good road is awaiting☆

Disruption of FRNK expression by gene targeting of the intronic promoter within the focal adhesion kinase gene

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