ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development

Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in Xenopus laevis embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-β cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-β1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL–ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling.

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Smad ubiquitination regulatory factor-2 in the fibrotic kidney: regulation, target specificity, and functional implication

AJP Renal Physiology ◽

10.1152/ajprenal.00323.2007 ◽

2008 ◽

Vol 294 (5) ◽

pp. F1076-F1083 ◽

Cited By ~ 52

Author(s):

Ruoyun Tan ◽

Weichun He ◽

Xia Lin ◽

Lawrence P. Kiss ◽

Youhua Liu

Keyword(s):

Epithelial Cells ◽

Ectopic Expression ◽

Fine Tuning ◽

Type I ◽

Renal Tubules ◽

Target Specificity ◽

Tubular Epithelial Cells ◽

Regulatory Factor ◽

Functional Implication ◽

Tgf Β1

Smad ubiquitination regulatory factor-2 (Smurf2) is an E3 ubiqutin ligase that plays a pivotal role in regulating TGF-β signaling via selectively targeting key components of the Smad pathway for degradation. In this study, we have investigated the regulation of Smurf2 expression, its target specificity, and the functional implication of its induction in the fibrotic kidney. Immunohistochemical staining revealed that Smurf2 was upregulated specifically in renal tubules of kidney biopsies from patients with various nephropathies. In vitro, Smurf2 mRNA and protein were induced in human proximal tubular epithelial cells (HKC-8) upon TGF-β1 stimulation. Ectopic expression of Smurf2 was sufficient to reduce the steady-state levels of Smad2, but not Smad1, Smad3, Smad4, and Smad7, in HKC-8 cells. Interestingly, Smurf2 was also able to downregulate the Smad transcriptional corepressors Ski, SnoN, and TG-interacting factor. Inhibition of the proteasomal pathway prevented Smurf2-mediated downregulation of Smad2 and Smad corepressors. Functionally, overexpression of Smurf2 enhanced the transcription of the TGF-β-responsive promoter and augmented TGF-β1-mediated E-cadherin suppression, as well as fibronectin and type I collagen induction in HKC-8 cells. These results indicate that Smurf2 specifically targets both positive and negative Smad regulators for destruction in tubular epithelial cells, thereby providing a complex fine-tuning of TGF-β signaling. It appears that dysregulation of Smurf2 could contribute to an aberrant TGF-β/Smad signaling in the pathogenesis of kidney fibrosis.

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Both TGF-β1 and Smad4 regulate type I collagen expression in the muscle of grass carp, Ctenopharyngodon idella

Fish Physiology and Biochemistry ◽

10.1007/s10695-021-00941-w ◽

2021 ◽

Author(s):

Yun Xia ◽

Ermeng Yu ◽

Zhifei Li ◽

Kai Zhang ◽

Jingjing Tian ◽

...

Keyword(s):

Grass Carp ◽

Type I Collagen ◽

Ctenopharyngodon Idella ◽

Type I ◽

Collagen Expression ◽

Grass Carp Ctenopharyngodon Idella ◽

Tgf Β1

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Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis

Scientific Reports ◽

10.1038/s41598-020-78056-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jonghwa Kim ◽

Wonseok Kang ◽

So Hee Kang ◽

Su Hyun Park ◽

Ji Young Kim ◽

...

Keyword(s):

Liver Fibrosis ◽

Tyrosine Kinase ◽

Focal Adhesion ◽

Transforming Growth Factor ◽

Family Members ◽

Type I ◽

Tyrosine Kinase 2 ◽

The Impact ◽

Tgf Β1

AbstractHepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. We used a CCl4-induced liver fibrosis mice model to evaluate the effect of FAK family kinase inhibitors on liver fibrosis. RT-PCR and Western blot were used to measure the expression of its target genes; α-SMA, collagen, Nox4, TGF-β1, Smad7, and CTGF. Pharmacological inhibitors, siRNA-mediated knock-down, and plasmid-based overexpression were adopted to modulate the function and the expression level of proteins. Association of PYK2 activation with liver fibrosis was confirmed in liver samples from CCl4-treated mice and patients with significant fibrosis or cirrhosis. TGF-β treatment up-regulated expression of α-SMA, type I collagen, NOX4, CTGF, TGF-β1, and Smad7 in LX-2 cells. Inhibition of FAK family members suppressed TGF-β-mediated fibrogenic signaling. SiRNA experiments demonstrated that TGF-β1 and Smad7 were upregulated via Smad-dependent pathway through FAK activation. In addition, CTGF induction was Smad-independent and PYK2-dependent. Furthermore, RhoA activation was essential for TGF-β-mediated CTGF induction, evidenced by using ROCK inhibitor and dominant negative RhoA expression. We identified that TGF-β1-induced activation of PYK2-Src-RhoA triad leads to YAP/TAZ activation for CTGF induction in liver fibrosis. These findings provide new insights into the role of focal adhesion molecules in liver fibrogenesis, and targeting PYK2 may be an attractive target for developing novel therapeutic strategies for the treatment of liver fibrosis.

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Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00563-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Wei Dai ◽

Shenglan Liu ◽

Shubo Wang ◽

Li Zhao ◽

Xiao Yang ◽

...

Keyword(s):

Extracellular Matrix ◽

Cancer Cells ◽

Uveal Melanoma ◽

Specific Inhibitor ◽

Type I ◽

Matrix Remodeling ◽

Metastatic Colonization ◽

Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

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The most severe forms of type I autoimmune hepatitis are associated with genetically determined levels of TGF-β1

Clinical Immunology ◽

10.1016/j.clim.2009.11.004 ◽

2010 ◽

Vol 134 (3) ◽

pp. 305-312 ◽

Cited By ~ 12

Author(s):

Natalia Paladino ◽

Ana Claudia Flores ◽

Hugo Fainboim ◽

Teresa Schroder ◽

Miriam Cuarterolo ◽

...

Keyword(s):

Autoimmune Hepatitis ◽

Type I ◽

Genetically Determined ◽

Tgf Β1

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Autocrine Transforming Growth Factor-β1 Activation Mediated by Integrin αVβ3 Regulates Transcriptional Expression of Laminin-332 in Madin-Darby Canine Kidney Epithelial Cells

Molecular Biology of the Cell ◽

10.1091/mbc.e10-06-0523 ◽

2010 ◽

Vol 21 (21) ◽

pp. 3654-3668 ◽

Cited By ~ 22

Author(s):

Jose V. Moyano ◽

Patricia G. Greciano ◽

Mary M. Buschmann ◽

Manuel Koch ◽

Karl S. Matlin

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Integrin Αvβ3 ◽

Type I ◽

Madin Darby Canine Kidney ◽

Epithelial Regeneration ◽

Tgf Β1 ◽

Darby Canine Kidney ◽

Canine Kidney

Laminin (LM)-332 is an extracellular matrix protein that plays a structural role in normal tissues and is also important in facilitating recovery of epithelia from injury. We have shown that expression of LM-332 is up-regulated during renal epithelial regeneration after ischemic injury, but the molecular signals that control expression are unknown. Here, we demonstrate that in Madin-Darby canine kidney (MDCK) epithelial cells LM-332 expression occurs only in subconfluent cultures and is turned-off after a polarized epithelium has formed. Addition of active transforming growth factor (TGF)-β1 to confluent MDCK monolayers is sufficient to induce transcription of the LM α3 gene and LM-332 protein expression via the TGF-β type I receptor (TβR-I) and the Smad2–Smad4 complex. Significantly, we show that expression of LM-332 in MDCK cells is an autocrine response to endogenous TGF-β1 secretion and activation mediated by integrin αVβ3 because neutralizing antibodies block LM-332 production in subconfluent cells. In confluent cells, latent TGF-β1 is secreted apically, whereas TβR-I and integrin αVβ3 are localized basolaterally. Disruption of the epithelial barrier by mechanical injury activates TGF-β1, leading to LM-332 expression. Together, our data suggest a novel mechanism for triggering the production of LM-332 after epithelial injury.

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Estrogen induces apoptosis in a rat prostatic adenocarcinoma: Association with an increased expression of TGF- β1 and its type-I and type-II receptors

International Journal of Cancer ◽

10.1002/(sici)1097-0215(19960807)67:4<573::aid-ijc17>3.0.co;2-8 ◽

1996 ◽

Vol 67 (4) ◽

pp. 573-579 ◽

Cited By ~ 24

Author(s):

Maréne Landström ◽

Solveig Eklöv ◽

Pascal Colosetti ◽

Sten Nilsson ◽

Jan-Erik Damber ◽

...

Keyword(s):

Prostatic Adenocarcinoma ◽

Type I ◽

Type Ii ◽

Tgf Β1

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Expression of Transforming Growth Factor (TGF)-β1, -β2, and -β3 Isoforms and TGF-β Type I and Type II Receptors in Multiple Sclerosis Lesions and Human Adult Astrocyte Cultures

Journal of Neuropathology & Experimental Neurology ◽

10.1097/00005072-199902000-00007 ◽

1999 ◽

Vol 58 (2) ◽

pp. 174-187 ◽

Cited By ~ 87

Author(s):

Corline J.A. De Groot ◽

Lisette Montagne ◽

Angeliqué D. Barten ◽

Peter Sminia ◽

Paul Van Der Valk

Keyword(s):

Multiple Sclerosis ◽

Growth Factor ◽

Transforming Growth Factor ◽

Type I ◽

Type Ii ◽

Human Adult ◽

Tgf Β1

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Changes in the transferrin requirement of cultured chick embryo mesoderm cells during early differentiation

Development ◽

10.1242/dev.95.1.81 ◽

1986 ◽

Vol 95 (1) ◽

pp. 81-93

Author(s):

E. J. Sanders

Keyword(s):

Chick Embryo ◽

Type I Collagen ◽

Specific Effect ◽

Primitive Streak ◽

Cellular Adhesion ◽

Type I ◽

Surface Binding ◽

Surface Receptors ◽

Early Differentiation ◽

Species Specific

Mesodermal tissue from the chick embryo at various stages of early differentiation was cultured in hydrated gels of type I collagen in the presence and absence of transferrin. Primary mesoderm explants from primitive-streak-stage embryos responded to the presence of avian transferrin by significantly improved outgrowth which appeared to be related to the ability of the cells to attach to, and migrate in, the collagen. No evidence was obtained which suggested that this observation was dependent on increased cell proliferation. This outgrowth enhancement was not duplicated by transferrin of human origin. The avian transferrin did not produce this effect on cells cultured on plastic substrata, suggesting that the species-specific effect involves modulation by the extracellular matrix. Mesoderm explants from somite stages of development showed no increase in outgrowth in the presence of either avian or human transferrin as judged by counting the number of outwandering cells. Ultrastructural immunocytochemistry indicated surface binding of transferrin by cells in the gels, and the presence of endogenous transferrin on the surfaces of mesoderm cells in situ and in their extracellular environment. It is suggested that by binding to cell surface receptors, transferrin may be able to influence the strength of cellular adhesion to collagen and hence the capacity for cell locomotion.

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