Regulation of Smad activities

Xu, Lan

doi:10.1016/j.bbaexp.2006.11.001

Cited by 84 publications

(79 citation statements)

References 108 publications

(166 reference statements)

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“…These data support a complex regulation of signals from FAK via differential phosphorylation. The list of sites at which R-Smad is phosphorylated by interacting signaling molecules, other than at the receptor-dependent C-termini, is also increasing (Xu, 2006). MAP-kinase-mediated linker-region phosphorylation at Ser203, Ser207, Ser212, Thr8 and Thr178 of Smad3 has been identified (Kamaraju and Roberts, 2005;Matsuura et al, 2005;Mori et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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

Hayashida

Pierce³

et al. 2007

Journal of Cell Science

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The signals mediating transforming growth factor β (TGFβ)-stimulated kidney fibrogenesis are poorly understood. We previously reported TGFβ-stimulated, Smad-mediated collagen production by human kidney mesangial cells, and that ERK MAP kinase activity optimizes collagen expression and enhances phosphorylation of the Smad3 linker region. Furthermore, we showed that disrupting cytoskeletal integrity decreases type I collagen production. Focal adhesion kinase (FAK, PTK2) activity could integrate these findings. Adhesion-dependent FAK Y397 phosphorylation was detected basally, whereas FAK Y925 phosphorylation was TGFβ1-dependent. By immunocytochemistry, TGFβ1 stimulated the merging of phosphorylated FAK with the ends of thickening stress fibers. Cells cultured on poly-L-lysine (pLL) to promote integrin-independent attachment spread less than those on control substrate and failed to demonstrate focal adhesion (FA) engagement with F-actin. FAK Y397 phosphorylation and ERK activity were also decreased under these conditions. In cells with decreased FAK Y397 phosphorylation from either plating on pLL or overexpressing a FAK Y397F point mutant, serine phosphorylation of the Smad linker region, but not of the C-terminus, was reduced. Y397F and Y925F FAK point mutants inhibited TGFβ-induced Elk-Gal activity, but only the Y397F mutant inhibited TGFβ-stimulated collagen-promoter activity. The inhibition by the Y397F mutant or by culture on pLL was prevented by co-transfection of constitutively active ERK MAP kinase kinase (MEK), suggesting that FAK Y397 phosphorylation promotes collagen expression via ERK MAP kinase activity. Finally, Y397 FAK phosphorylation, and both C-terminal and linker-region Smad3 phosphorylation were detected in murine TGFβ-dependent kidney fibrosis. Together, these data demonstrate adhesion-dependent FAK phosphorylation promoting TGFβ-induced responses to regulate collagen production.

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Section: Discussionmentioning

confidence: 99%

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

Hayashida

Pierce³

et al. 2007

Journal of Cell Science

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“…Similar to other TGFβ family members, Activin A influences many facets of cell activities such as proliferation, differentiation, motility and apoptosis through the transmembrane receptor mediated Smad pathway. It has complex regulatory mechanisms modulated by extracellular binding proteins (follistatin, β glycan), intracellular antagonistic I-Smads and post transcription modulators [15,16]. Activin A has been demonstrated to promote granulosa cell proliferation in a dose dependant manner [17,18].…”

Section: Introductionmentioning

confidence: 99%

Activin A inhibits activation of human primordial follicles in vitro

Ding

Thong

Krishna

et al. 2010

J Assist Reprod Genet

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Purpose To determine whether Activin A affects the activation and survival of human primordial follicles in vitro. Methods Ovarian cortical biopsies from eight women undergoing elective caesarean sections or benign gynaecological procedures were taken and cut into small pieces (1-3 mm 3 ), cultured in serum-free medium for 7 days with/without human recombinant Activin A at a concentration of either 50 or 100 ng/ml. Ovarian tissue were analysed by histology for follicle viability, development and density. Result(s) Significant activation of primordial follicles within cultured cortical tissue was observed after 7 days in control medium. However, medium supplemented with Activin A at 50 ng/ml resulted in significant inhibition of follicular activation. Increasing the concentration of Activin A to 100 ng/ml reversed the inhibitory effect. The effect of Activin A appeared to be specific to activation of non-growing (primordial) follicles into the growing population since no significant differences in follicle viability was observed between treatment groups. Conclusion(s) Activin A at a concentration of 50 ng/ml can inhibit the spontaneous activation of human primordial follicles in vitro indicating that this may be a component of the signalling mechanisms that maintain follicular quiescence.

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“…Recent advances have revealed that, besides the kinase activities of the TGF-b type I receptors, other kinases, such as mitogen activated protein kinase (MAPK), cyclin-dependent kinase, calcium calmodulin-dependent protein kinase 2, and G proteincoupled receptor kinase 2, can also phosphorylate Smads. 11,13 In addition, Smad-independent TGF-b responses have been reported in Smad-deficient cell lines and animal models. 11,13 Signal transduction from TGF-b ligands and receptors to Smads is complicated and nonlinear.…”

mentioning

confidence: 99%

“…11,13 In addition, Smad-independent TGF-b responses have been reported in Smad-deficient cell lines and animal models. 11,13 Signal transduction from TGF-b ligands and receptors to Smads is complicated and nonlinear. Thus, to better understand the mechanism by which the urinary tract develops, it is necessary to investigate the precise role of Smad signaling in this context in addition to the studies of the TGF-b ligands and receptors.…”

mentioning

confidence: 99%

Absence of Canonical Smad Signaling in Ureteral and Bladder Mesenchyme Causes Ureteropelvic Junction Obstruction

Tripathi

Wang²,

Casey³

et al. 2012

Journal of the American Society of Nephrology

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Obstruction of the ureteropelvic junction (UPJ) is a common congenital anomaly frequently associated with ureteral defects. To study the molecular mechanisms that modulate ureteral development, we inactivated Smad4, the common Smad critical for transcriptional responses to TGF-b and Bmp signaling, in the ureteral and bladder mesenchyme during embryogenesis. Loss of canonical Smad signaling in these tissues caused bilateral UPJ obstruction and severe hydronephrosis beginning at embryonic day 17.5. Despite a reduction in quantity of ureteral smooth muscle, differentiation proceeded without Smad4, producing a less severe phenotype than Bmp4 mutants; this finding suggests that at least some Bmp4 functions in ureteral smooth muscle may be Smad-independent. The absence of canonical Smad signaling in the ureteral mesenchyme, but not in the urothelium itself, led to urothelial disorganization, highlighting the importance of mesenchymal support for epithelial development. Transcript profiling revealed altered expression in known Bmp targets, smooth muscle-specific genes, and extracellular matrix-related genes in mutant ureters before the onset of hydronephrosis. Expression of the Bmp target Id2 was significantly lower in Smad4 mutants, consistent with the observation that Id2 mutants develop UPJ obstruction. In summary, Smad4 deficiency reduces the number and contractility of ureteral smooth muscle cells, leading to abnormal pyeloureteral peristalsis and functional obstruction. The subsequent bending and luminal constriction of the ureter at the UPJ marks the transition from a functional obstruction to a more intractable physical obstruction, suggesting that early intervention for this disease may prevent more irreversible damage to the urinary tract.

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Regulation of Smad activities

Cited by 84 publications

References 108 publications

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

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

Activin A inhibits activation of human primordial follicles in vitro

Absence of Canonical Smad Signaling in Ureteral and Bladder Mesenchyme Causes Ureteropelvic Junction Obstruction

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