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

Chen, Guang; Chen, Xing; Sukumar, Aravin N.; Gao, Bo; Curley, Jessica F.; Schnaper, H. William; Ingram, Alistair J.; Krepinsky, Joan C.

doi:10.1242/jcs.126714

Cited by 20 publications

(15 citation statements)

References 79 publications

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“…17 Previous studies have demonstrated that Smad3 can be phosphorylated by transforming growth factor-β-independent pathways, such as JNK in lung epithelial cells, p38 in breast carcinoma cells, or directly by Pak1 in mesangial cells. [34][35][36] This is consistent with our data showing Pak1-dependent Smad3 phosphorylation through the MKK7-JNK signaling cascade. In addition, previous studies have reported that hypertrophy-induced microtubule network expansion can sequester Smad3, preventing it from being accessed and phosphorylated by the transforming growth factor-β receptor.…”

Section: Discussionsupporting

confidence: 92%

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

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Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC -286 -binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy.

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Section: Discussionsupporting

confidence: 92%

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

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“…TGFβ signalling is mediated by phosphorylation of SMADs, and by up-regulation of FOS, JUN and LXR transcription factors [ 28 , 34 , 36 , 55 , 60 , 61 ]. Consistent with this, we found that although the mRNA expression of SMADs 2 and 3 were not elevated in FCMs, levels of phosphorylated, nuclear localised SMAD2 were increased in granuloma FCMs relative to NFMs and in plaque FCMs, suggesting that TGFβ1 signalling was occurring.…”

Section: Discussionmentioning

confidence: 99%

Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype

et al. 2015

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Formation of foam cell macrophages, which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages that accumulate in the subcutaneous granulomas of fed-fat ApoE null mice and normal chow fed wild-type mice in vivo. Consistent with previous studies, LXR/RXR pathway genes were significantly over-represented among the genes up-regulated in foam cell macrophages. Unexpectedly, the hepatic fibrosis pathway, associated with platelet derived growth factor and transforming growth factor-β action, was also over-represented. Several collagen polypeptides and proteoglycan core proteins as well as connective tissue growth factor and fibrosis-related FOS and JUN transcription factors were up-regulated in foam cell macrophages. Increased expression of several of these genes was confirmed at the protein level in foam cell macrophages from subcutaneous granulomas and in atherosclerotic plaques. Moreover, phosphorylation and nuclear translocation of SMAD2, which is downstream of several transforming growth factor-β family members, was also detected in foam cell macrophages. We conclude that foam cell formation in vivo leads to a pro-fibrotic macrophage phenotype, which could contribute to plaque stability, especially in early lesions that have few vascular smooth muscle cells.

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“…Dynamic regulation was also observed in primary proximal cells whereas a prolonged inhibition of CTGF expression was detected in human distal tubular epithelial cells, reminiscent of the role for Rac1 in SRF activation described in MDCK cells [ 9 ]. Thus far, Rac1 inhibition has been related to CTGF expression primarily in mesenchymal cells such as fibroblasts [ 10 , 33 ], cardiomyocytes [ 34 ] or renal mesangial cells [ 35 ]. In all these studies, pharmacological or genetic inhibition of Rac1 correlated with reduced CTGF expression.…”

Section: Discussionmentioning

confidence: 99%

Actin-Mediated Gene Expression Depends on RhoA and Rac1 Signaling in Proximal Tubular Epithelial Cells

et al. 2015

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Morphological alterations of cells can lead to modulation of gene expression. An essential link is the MKL1-dependent activation of serum response factor (SRF), which translates changes in the ratio of G- and F-actin into mRNA transcription. SRF activation is only partially characterized in non-transformed epithelial cells. Therefore, the impact of GTPases of the Rho family and changes in F-actin structures were analyzed in renal proximal tubular epithelial cells. Activation of SRF signaling was compared to the regulation of a known MKL1/SRF target gene, connective tissue growth factor (CTGF). In the human proximal tubular cell line HKC-8 overexpression of two actin mutants either favoring or preventing the formation of F-actin fibers regulated SRF-mediated transcription as well as CTGF expression. Only overexpression of constitutively active RhoA activated SRF-dependent gene expression whereas no effect was detected upon overexpression of Rac1 mutants. To elucidate the functional role of Rho kinases as downstream mediators of RhoA, pharmacological inhibition and genetic inhibition by transient siRNA knock down were compared. Upon stimulation with lysophosphatidic acid (LPA) Rho kinase inhibitors partially suppressed SRF-mediated transcription, whereas interference with Rho kinase expression by siRNA reduced activation of SRF, but barely affected CTGF expression. Together with the partial inhibition of CTGF expression by the pharmacological inhibitors Y27432 and H1154, Rho kinases seem to be less important in mediating RhoA signaling related to CTGF expression in HKC-8 epithelial cells. Short term pharmacological inhibition of Rac1 activity by EHT1864 reduced SRF-dependent CTGF expression in HKC-8 cells, but was overcome by a stimulatory effect after prolonged incubation after 4-6 h. Similarly, human primary cells of proximal but not of distal tubular origin showed inhibitory as well as stimulatory effects of Rac1 inhibition. Thus, RhoA signaling activates MKL1-SRF-mediated CTGF expression in proximal tubular cells, whereas Rac1 signaling is more complex with adaptive cellular responses.

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

Cited by 20 publications

References 79 publications

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype

Actin-Mediated Gene Expression Depends on RhoA and Rac1 Signaling in Proximal Tubular Epithelial Cells

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