FAK Is Required for TGFβ-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix-remodeling Phenotype

Liu, Shangxi; Xu, Shiwen; Kennedy, Laura; Pala, Daphne; Chen, Yunliang; Eastwood, Mark; Carter, David E.; Black, Carol M.; Abraham, David; Leask, Andrew

doi:10.1091/mbc.e06-12-1121

Cited by 118 publications

(106 citation statements)

References 44 publications

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“…Binding of TGF-␤1 to the receptor complex can promote several scenarios. Ligand activation of T␤RII receptor kinase leads to phosphorylation and, thereby, to activation of T␤RI, which then activates and phosphorylates Smad2 and Smad3 proteins, which are subsequently moved into the nucleus, where they associate with other transcription factors and activate transcription of target genes 60,61 (Smad-dependent pathway), and activates Smad-independent signals including GTPase Ras and ERK 62,63 , promotes JNK phosphorylation via FAK and Tak1, 34,35 and p38MAPK phosphorylation mediated by Fyn. 42 Up-regulation of all of these pathways has been associated with fibroblast and myofibroblast activation.…”

Section: Discussionmentioning

confidence: 99%

“…42 Up-regulation of all of these pathways has been associated with fibroblast and myofibroblast activation. 32,34,35,42,63 There seems to be signal redundancy, in which both Smad-dependent and Smad-independent pathways are involved in TGF-␤1-mediated responses in cardiac fibroblasts; however, the key signal transducers are T␤Rs. As shown in Figure 2E, when compared with fibroblasts isolated from young mice, the fibroblasts generated from aged cardiac MSCs exhibit reduced T␤RI and T␤RII expression and, therefore, demonstrate reduced responsiveness to TGF-␤1, which translates into decreased phosphorylation of 30 minutes of activation with 10 ng/mL TGF-␤1 in cardiac fibroblasts isolated from young (4 months old) and aged (30 months old) mice.…”

Section: Discussionmentioning

confidence: 99%

“…33 Moreover, focal adhesion kinase (FAK), Tak1, and c-Jun N-terminal kinase (JNK) are essential for TGF-␤-dependent ␣-SMA expression in fibroblasts and contraction of collagen matrices. 34,35 Therefore, we analyzed the activation of these pathways in fibroblasts isolated from 4-and 30-month-old mice (Figure 3, E-G). Phosphorylation of FAK (Tyr576/577), Tak1 (Thr184/Thr187), and JNK (Thr183/Tyr185) in response to TGF-␤1 stimulation was impaired in fibroblasts isolated from aged mice.…”

Section: Final Step Of Fibroblast Maturation Is Impaired By Agingmentioning

confidence: 99%

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Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik

Trial

Entman

2011

The American Journal of Pathology

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Cardiac fibroblasts are the most prevalent cell type in the heart. These cells exert a critical role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs after myocardial infarction (MI). 1 Irreversible cardiomyocyte damage owing to cessation of oxygen supply during MI leads to necrosis, which stimulates inflammatory reactions that trigger reparative pathways and activate cells to form a scar. Cytokines released by inflammatory infiltrating leukocytes promote endogenous mesenchymal stem cell (MSC) proliferation and migration toward the infarct site, followed by differentiation into fibroblasts that deposit scar-forming collagen. The fibroblasts mature into myofibroblasts, expressing scar-contracting ␣-smooth muscle actin (␣-SMA). 2 Resident fibroblasts also become activated and participate in this process. After several weeks, a mature scar is formed, and most of the myofibroblasts undergo apoptosis. [3][4][5] We have previously established in a model of mouse MI that, compared with young animals, aged mice demonstrate greater infarct expansion and less effective myocardial repair. 6 Defective scar formation arises from a decreased number of myofibroblasts and diminished collagen deposition in the infarct, which results in a structurally unstable scar formed by loose connective tissue. 7 Evidence indicates that multipotent cells can be generated in vitro from several adult organs including the heart. 8 Tissue-resident progenitor cells of mesenchymal origin can differentiate into myogenic, adipocytic, chondrocytic, osteoblastic, and fibroblastic lineages. 9 -11 The potential of those stem cells to differentiate decreases

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Final Step Of Fibroblast Maturation Is Impaired By Agingmentioning

confidence: 99%

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Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik

Trial

Entman

2011

The American Journal of Pathology

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“…RNA quality assessment, probe preparation and gene chip hybridization and analysis Microarrays and analysis were performed essentially as previously described (Shi-wen et al 2004;Liu et al 2007;Kennedy et al 2007). All Gene Chips were processed at the London Regional Genomics Centre (Robarts Research Institute, London, ON; http://www.lrgc.ca).…”

Section: Methodsmentioning

confidence: 99%

The gene expression profile induced by Wnt 3a in NIH 3T3 fibroblasts

Chen

McLean

Carter

et al. 2007

J. Cell Commun. Signal.

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Wnt proteins play important roles in regulating cell differentiation, proliferation and polarity. Wnts have been proposed to play roles in tissue repair and fibrosis, yet the gene expression profile of fibroblasts exposed to Wnts has not been examined. We use Affymetrix genome-wide expression profiling to show that a 6-h treatment of fibroblasts of Wnt3a results in the induction of mRNAs encoding known Wnt targets such as the fibrogenic pro-adhesive molecule connective tissue growth factor (CTGF, CCN2). Wnt3a also induces mRNAs encoding potent pro-fibrotic proteins such as TGFβ and endothelin-1 (ET-1). Moreover, Wnt3a promotes genes associated with cell adhesion and migration, vasculature development, cell proliferation and Wnt signaling. Conversely, Wnt3a suppresses gene associated with skeletal development, matrix degradation and cell death. Results were confirmed using real-time polymerase chain reaction of cells exposed to Wnt3a and Wnt10b. These results suggest that Wnts induce genes promoting fibroblast differentiation towards angiogenesis and matrix remodeling, at the expense of skeletal development.

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“…For example, focal adhesion kinase and JNK are required for myofibroblast differentiation and α-SMA expression (Liu et al 2007). Conversely, TGFβ-induced CCN2 expression is blocked by ERK inhibitors (Leask et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Possible strategies for anti-fibrotic drug intervention in scleroderma

Leask

2011

J. Cell Commun. Signal.

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There are no approved drugs for treating the fibrosis in scleroderma (systemic sclerosis, SSc). Myfibroblasts within connective tissue express the highly contractile protein α-smooth muscle actin (α-SMA) and are responsible for the excessive synthesis and remodeling of extracellular matrix (ECM) characterizing SSc. Drugs targeting myofibroblast differentiation, recruitment and activity are currently under consideration as anti-fibrotic treatments in SSc but thus far have principally focused on the transforming growth factor β (TGFβ), endothelin-1 (ET-1), connective tissue growth factor (CCN2/CTGF) and platelet derived growth factor (PDGF) pathways, which display substantial signaling crosstalk. Moreover, peroxisome proliferator-activated receptor (PPAR)γ also appears to act by intervening in TGFβ signaling. This review discusses these potential candidates for antifibrotic therapy in SSc.

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FAK Is Required for TGFβ-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix-remodeling Phenotype

Cited by 118 publications

References 44 publications

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

The gene expression profile induced by Wnt 3a in NIH 3T3 fibroblasts

Possible strategies for anti-fibrotic drug intervention in scleroderma

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