MAP-kinase activity necessary for TGFβ1-stimulated mesangial cell type I collagen expression requires adhesion-dependent phosphorylation of FAK tyrosine 397

Hayashida, Tomoko; Wu, Ming; Pierce, Amy A.; Poncelet, Anne Christine; Varga, John; Schnaper, H. William

doi:10.1242/jcs.03492

Cited by 69 publications

(60 citation statements)

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“…ERK-mediated regulation of Smad signaling is of particular interest due to a specific series of serines and threonines in the Smad linker region that are the targets for ERK, although the function of these phosphorylation events remains yet to be fully uncovered (3,13). In the above mentioned study, we found that a Y397F FAK mutant inhibited ERK activity and ERK-mediated Smad linker region phosphorylation as well as inhibiting collagen production (9), suggesting that integrin engagement-dependent ERK activity via FAK is necessary for the maximal collagen response to TGF-␤1.…”

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confidence: 65%

“…In seeking a common mediator for several signaling pathways that we have previously identified to play roles in TGF-␤ induction of ECM accumulation in renal cells (6 -8), we recently reported that integrin engagement-mediated activation of focal adhesion kinase (FAK) is required for TGF-␤1-induced type I collagen production (9). FAK serves as a molecular "dock," recruiting additional signaling molecules, such as Src family tyrosine kinases (10), for which FAK Tyr-397 phosphorylation subsequent to integrin engagement is critical (11).…”

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confidence: 99%

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Loss of β1-Integrin Enhances TGF-β1-induced Collagen Expression in Epithelial Cells via Increased αvβ3-Integrin and Rac1 Activity

Hayashida

Jones

Lee³

et al. 2010

Journal of Biological Chemistry

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Transforming growth factor ␤ (TGF-␤) promotes tissue fibrosis via the receptor-specific Smad pathway and non-canonical pathways. We recently reported that TGF-␤1-stimulated collagen expression by cultured kidney cells requires integrin-dependent activation of focal adhesion kinase (FAK) and consequent ERK MAP kinase activity leading to Smad3 linker region phosphorylation. Here, we defined a role for ␣v␤3-integrin in this non-canonical pathway. A human kidney tubular cell line in which ␤1-integrin was knocked down (␤1-k/d) demonstrated enhanced type I collagen mRNA expression and promoter activity. A second shRNA to either ␣v-integrin or ␤3-integrin, but not to another ␣v-binding partner, ␤6-integrin, abrogated the enhanced COL1A2 promoter activity in ␤1-k/d cells. Although ␣v␤3-integrin surface expression levels were not different, ␣v␤3-integrins colocalized with sites of focal adhesion significantly more in ␤1-k/d cells, and activated ␣v␤3-integrin was detected only in ␤1-k/d cells. Further, the collagen response was decreased by a function-blocking antibody or a peptide inhibitor of ␣v␤3-integrin. In cells lacking ␣v␤3-integrin, the responses were attenuated, whereas the response was enhanced in ␣v␤3-overexpressing cells. Rac1 and ERK, previously defined mediators for this non-canonical pathway, showed increased activities in ␤1-k/d cells. Finally, inhibition of ␣v␤3-integrin decreased Rac1 activity and COL1A2 promoter activity in ␤1-k/d cells. Together, our results indicate that decreasing ␤1 chain causes ␣v␤3-integrin to become functionally dominant and promotes renal cell fibrogenesis via Rac1-mediated ERK activity.Transforming growth factor ␤ (TGF-␤) is one of the critical cytokines that mediate fibrogenic processes in various organs such as liver, lung, skin, and kidney (1). The canonical signaling pathway for TGF-␤ is seemingly simple. Receptor heterotetramerization after ligand binding leads to phosphorylation of the receptor-specific transcription factors, R-Smads (Smad2 or Smad3), which then multimerize with the co-Smad, Smad4, translocate to the nucleus, and interact with additional cofactors (2) to initiate the transcription of target genes such as those for extracellular matrix (ECM).2 Given the pleiotropic functions of this cytokine, investigating how non-canonical TGF-␤ signaling pathways interact with Smad signaling in a tissue-or cell type-specific manner has become crucial to understanding how TGF-␤/Smad signaling is regulated (3, 4).We have been studying these signaling interactions using cultured renal cell production of type I collagen stimulated by TGF-␤1 as a model system (5). In seeking a common mediator for several signaling pathways that we have previously identified to play roles in TGF-␤ induction of ECM accumulation in renal cells (6 -8), we recently reported that integrin engagement-mediated activation of focal adhesion kinase (FAK) is required for TGF-␤1-induced type I collagen production (9). FAK serves as a molecular "dock," recruiting additional signaling molecules, such as Src...

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confidence: 65%

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confidence: 99%

Loss of β1-Integrin Enhances TGF-β1-induced Collagen Expression in Epithelial Cells via Increased αvβ3-Integrin and Rac1 Activity

Hayashida

Jones

Lee³

et al. 2010

Journal of Biological Chemistry

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“…[25][26][27][28] We had previously identified Egr-1 as a novel TGF-␤ mediator with a significant role in collagen regulation. 10 Whereas induction of Egr-1 by acute injury has been investigated extensively, its regulation by Regulation 4 TGF-␤ in the context of fibrogenesis and its role in fibrosis remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Smad-Independent Transforming Growth Factor-β Regulation of Early Growth Response-1 and Sustained Expression in Fibrosis

Bhattacharyya

Chen

et al. 2008

The American Journal of Pathology

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Transforming growth factor-␤ (TGF-␤) plays a key role in scleroderma pathogenesis. The transcription factor early growth response-1 (Egr-1) mediates the stimulation of collagen transcription elicited by TGF-␤ and is necessary for the development of pulmonary fibrosis in mice. Here, we report that TGF-␤ causes a time-and dose-dependent increase in Egr-1 protein and mRNA levels and enhanced transcription of the Egr-1 gene via serum response elements in normal fibroblasts. The ability of TGF-␤ to stimulate Egr-1 was preserved in Smad3-null mice and in explanted Smad3-null fibroblasts. The response was blocked by a specific mitogen-activated protein kinase kinase 1 (MEK1) inhibitor but not by an ALK5 kinase inhibitor. Furthermore, MEK1 was phosphorylated by TGF-␤, which was sufficient to drive Egr-1 transactivation. Stimulation by TGF-␤ enhanced the transcriptional activity of Elk-1 via the MEK-extracellular signal-regulated kinase 1/2 pathway. Bleomycininduced scleroderma in the mouse was accompanied by increased Egr-1 accumulation in lesional fibroblasts. Furthermore, biopsies of lesional skin and lung from patients with scleroderma showed increased Egr-1 levels, which were highest in early diffuse disease. Moreover, both Egr-1 mRNA and protein were elevated in explanted scleroderma skin fibroblasts in vitro. Together, these findings define a Smadindependent TGF-␤ signal transduction mechanism that underlies the stimulation of Egr-1, demonstrate for the first time sustained Egr-1 up-regulation in fibrotic lesions and suggests that Egr-1 has a role in the induction and progression of fibrosis.

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“…8H). We previously showed that Rho-kinase mediated stretch-induced Erk activation, and Erk may modulate Smad3 transcriptional activity through phosphorylation on the Smad3 linker region (Hayashida et al, 2007;Krepinsky et al, 2005b). Fig.…”

Section: Stretch-induced Smad3 Activation Is Regulated By Rac1/ Pak1 mentioning

confidence: 95%

TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

Chen

Sukumar

et al. 2013

Journal of Cell Science

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SummaryIncreased intraglomerular pressure is an important pathogenic determinant of kidney fibrosis in the progression of chronic kidney disease, and can be modeled by exposing glomerular mesangial cells (MC) to mechanical stretch. MC produce extracellular matrix and profibrotic cytokines, including connective tissue growth factor (CTGF) when stretched. We show that p21-activated kinase 1 (Pak1) is activated by stretch in MC in culture and in vivo in a process marked by elevated intraglomerular pressures. Its activation is essential for CTGF upregulation. Rac1 is an upstream regulator of Pak1 activation. Stretch induces transactivation of the type I transforming growth factor b1 receptor (TbRI) independently of ligand binding. TbRI transactivation is required not only for Rac1/Pak1 activation, but also for activation of the canonical TGFb signaling intermediate Smad3. We show that Smad3 activation is an essential requirement for CTGF upregulation in MC under mechanical stress. Pak1 regulates Smad3 C-terminal phosphorylation and transcriptional activation. However, a second signaling pathway, that of RhoA/Rho-kinase and downstream Erk activation, is also required for stretch-induced CTGF upregulation in MC. Importantly, this is also regulated by Pak1. Thus, Pak1 serves as a novel central mediator in the stretchinduced upregulation of CTGF in MC.

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MAP-kinase activity necessary for TGFβ1-stimulated mesangial cell type I collagen expression requires adhesion-dependent phosphorylation of FAK tyrosine 397

Cited by 69 publications

References 68 publications

Loss of β1-Integrin Enhances TGF-β1-induced Collagen Expression in Epithelial Cells via Increased αvβ3-Integrin and Rac1 Activity

Loss of β1-Integrin Enhances TGF-β1-induced Collagen Expression in Epithelial Cells via Increased αvβ3-Integrin and Rac1 Activity

Smad-Independent Transforming Growth Factor-β Regulation of Early Growth Response-1 and Sustained Expression in Fibrosis

TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

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