Role of Ras and Mapks in TGFβ signaling

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1−/− mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.

Download Full-text

Transforming Growth Factor-Beta (TGFβ) Signaling Pathway in Cholangiocarcinoma

Cells ◽

10.3390/cells8090960 ◽

2019 ◽

Vol 8 (9) ◽

pp. 960 ◽

Cited By ~ 4

Author(s):

Panagiotis Papoutsoglou ◽

Corentin Louis ◽

Cédric Coulouarn

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Tgfβ Signaling ◽

Efficient Treatment ◽

Tumor Onset ◽

Tgfβ Signaling Pathway

Cholangiocarcinoma is a deadly cancer worldwide, associated with a poor prognosis and limited therapeutic options. Although cholangiocarcinoma accounts for less than 15% of liver primary cancer, its silent nature restricts early diagnosis and prevents efficient treatment. Therefore, it is of clinical relevance to better understand the molecular basis of cholangiocarcinoma, including the signaling pathways that contribute to tumor onset and progression. In this review, we discuss the genetic, molecular, and environmental factors that promote cholangiocarcinoma, emphasizing the role of the transforming growth factor β (TGFβ) signaling pathway in the progression of this cancer. We provide an overview of the physiological functions of TGFβ signaling in preserving liver homeostasis and describe how advanced cholangiocarcinoma benefits from the tumor-promoting effects of TGFβ. Moreover, we report the importance of noncoding RNAs as effector molecules downstream of TGFβ during cholangiocarcinoma progression, and conclude by highlighting the need for identifying novel and clinically relevant biomarkers for a better management of patients with cholangiocarcinoma.

Download Full-text

SMAD7 antagonizes key TGFβ superfamily signaling in mouse granulosa cells in vitro

Reproduction ◽

10.1530/rep-13-0093 ◽

2013 ◽

Vol 146 (1) ◽

pp. 1-11 ◽

Cited By ~ 24

Author(s):

Yang Gao ◽

Haixia Wen ◽

Chao Wang ◽

Qinglei Li

Keyword(s):

Granulosa Cell ◽

Granulosa Cells ◽

Transforming Growth Factor ◽

Negative Regulator ◽

Fine Tuning ◽

Female Reproduction ◽

Tgfβ Signaling ◽

Tgfβ Superfamily

Transforming growth factor β (TGFβ) superfamily signaling is essential for female reproduction. Dysregulation of the TGFβ signaling pathway can cause reproductive diseases. SMA and MAD (mothers against decapentaplegic) (SMAD) proteins are downstream signaling transducers of the TGFβ superfamily. SMAD7 is an inhibitory SMAD that regulates TGFβ signalingin vitro. However, the function of SMAD7 in the ovary remains poorly defined. To determine the signaling preference and potential role of SMAD7 in the ovary, we herein examined the expression, regulation, and function of SMAD7 in mouse granulosa cells. We showed that SMAD7 was expressed in granulosa cells and subject to regulation by intraovarian growth factors from the TGFβ superfamily. TGFB1 (TGFβ1), bone morphogenetic protein 4, and oocyte-derived growth differentiation factor 9 (GDF9) were capable of inducingSmad7expression, suggesting a modulatory role of SMAD7 in a negative feedback loop. Using a small interfering RNA approach, we further demonstrated that SMAD7 was a negative regulator of TGFB1. Moreover, we revealed a link between SMAD7 and GDF9-mediated oocyte paracrine signaling, an essential component of oocyte–granulosa cell communication and folliculogenesis. Collectively, our results suggest that SMAD7 may function during follicular development via preferentially antagonizing and/or fine-tuning essential TGFβ superfamily signaling, which is involved in the regulation of oocyte–somatic cell interaction and granulosa cell function.

Download Full-text

Control of microRNA biogenesis by TGFβ signaling pathway—A novel role of Smads in the nucleus

Cytokine & Growth Factor Reviews ◽

10.1016/j.cytogfr.2009.10.004 ◽

2009 ◽

Vol 20 (5-6) ◽

pp. 517-521 ◽

Cited By ~ 44

Author(s):

Akiko Hata ◽

Brandi N. Davis

Keyword(s):

Signaling Pathway ◽

Tgfβ Signaling ◽

Microrna Biogenesis ◽

Tgfβ Signaling Pathway

Download Full-text

Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer

Cancers ◽

10.3390/cancers13215343 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5343

Author(s):

Joseph T. Decker ◽

Jeffrey A. Ma ◽

Lonnie D. Shea ◽

Jacqueline S. Jeruss

Keyword(s):

Breast Cancer ◽

Poor Prognosis ◽

Cell Cycle Control ◽

Tgfβ Signaling ◽

Cyclin Dependent Kinases ◽

C Terminus ◽

Smad3 Phosphorylation ◽

Tumor Suppressive Function ◽

Regulatory Actions

TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFβ signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3.

Download Full-text

Loss of the serine protease HTRA1 impairs smooth muscle cells maturation

Scientific Reports ◽

10.1038/s41598-019-54807-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Ralph Klose ◽

Alexander Prinz ◽

Fabian Tetzlaff ◽

Eva-Maria Weis ◽

Iris Moll ◽

...

Keyword(s):

Smooth Muscle ◽

Small Vessel Disease ◽

Small Vessel ◽

Marker Genes ◽

Transcriptional Repressors ◽

Tgfβ Signaling ◽

Protein Levels ◽

Vessel Disease ◽

Signaling Activity

AbstractVascular smooth muscle cell (VSMC) dysfunction is a hallmark of small vessel disease, a common cause of stroke and dementia. Two of the most frequently mutated genes in familial small vessel disease are HTRA1 and NOTCH3. The protease HTRA1 cleaves the NOTCH3 ligand JAG1 implying a mechanistic link between HTRA1 and Notch signaling. Here we report that HTRA1 is essential for VSMC differentiation into the contractile phenotype. Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC. In addition, the loss of HTRA1 enhanced TGFβ-SMAD2/3 signaling activity. Activation of either NOTCH3 or TGFβ signaling resulted in increased transcription of the HES and HEY transcriptional repressors and promoted the contractile VSMC phenotype. However, their combined over-activation led to an additive accumulation of HES and HEY proteins, which repressed the expression of contractile VSMC marker genes. As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice. These data demonstrate an essential role of HTRA1 in vascular maturation and homeostasis by controlling Notch and TGFβ signaling.

Download Full-text

Abstract 95: The Role of TGFβ Signaling in a Fibrotic cMyBP-C HCM/HF Model

Circulation Research ◽

10.1161/res.119.suppl_1.95 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Qinghang Meng ◽

Bidur Bhandary ◽

Md. Shenuarin Bhuiyan ◽

Hanna Osinska ◽

Jeffrey Robbins

Keyword(s):

Transgenic Mice ◽

Life Span ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Transforming Growth Factor Β ◽

Tgfβ Signaling ◽

Gene Encoding ◽

Western Blots

Purpose: Hypertrophic cardiomyopathy (HCM) is considered one of the most common genetic heart disorders with a prevalence of about 1 in 500 people, with 35% of those affected being attributed to mutations within the gene encoding cardiac myosin-binding protein C (cMyBP-C). Cardiac stress, as well as cMyBP-C mutations, can trigger production of a 40kDa truncated fragment derived from the amino terminus of cMyBP-C. Genetic expression of this 40kDa fragment in mouse cardiomyocytes ( Mybp3 40kDa ) leads to HCM, fibrosis and heart failure, mimicking human disease progression. The transforming growth factor-β (TGFβ) signaling pathway has been implicated in a variety of fibrotic processes. The goal of this study is to define the role of TGFβ signaling in distinct cell populations, the cardiomyocyte and fibroblast, in the cMyBP-C HCM/HF model. Methods and results: Masson’s Trichrome staining, PCR arrays, immunohistochemistry and western blots were performed to characterize the fibrotic progression in Mybp3 40kDa transgenic mice. Cardiac fibrosis was initially detected 4 weeks after transgene expression. Extensive interstitial fibrosis and severe atrial fibrosis were detected at 16 weeks. Both canonical and non-canonical TGFβ pathways were active during fibrotic progression. To specifically block TGFβ signaling in Mybp3 40kDa transgenic mice, compound mutant mice were generated, in which the tgfbr1 or tgfbr2 alleles were ablated, either in cardiomyocytes or in activated fibroblasts (myofibroblasts) by αMHC-Cre or Periostin-MerCreMer-Cre respectively. Blockage of TGFβ signaling in either cardiomyocytes or myofibroblasts alleviated cardiac fibrosis. Furthermore, treatment with the non-canonical TGFβ signaling inhibitor MMI-0100 also alleviated cardiac fibrosis and increased the life span of the Mybp3 40kDa transgenic mice. Conclusions: TGFβ signaling is activated in the Mybp3 40kD HCM/HF model. Genetic or pharmaceutical inhibition of TGFβ signaling inhibited fibrosis and increased the life span in this model.

Download Full-text