A portrait of Transforming Growth Factor β superfamily signalling: Background matters

Horbelt, Daniel; Denkis, Agnieszka; Knaus, Petra

doi:10.1016/j.biocel.2011.12.013

Cited by 183 publications

(144 citation statements)

References 37 publications

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“…To further investigate the downstream effects induced by Bmp5, Bmp4 and Tsg downregulation in Hoxa2 mutants, we analysed the phosphorylation of Smad1, 5 and 8, a hallmark of canonical BMP signal transduction (Heldin and Moustakas, 2012;Horbelt et al, 2012), by anti-phosphoSmad1/5/8 immunostaining. In E14.5 control fetuses, the phosphoSmad1/5/8 + cell distribution is spatially restricted.…”

Section: Temporal Inactivation Of Hoxa2 Results In Altered Bmp Signalmentioning

confidence: 99%

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

et al. 2013

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SUMMARYExternal ear abnormalities are frequent in newborns ranging from microtia to partial auricle duplication. Little is known about the molecular mechanisms orchestrating external ear morphogenesis. In humans, HOXA2 partial loss of function induces a bilateral microtia associated with an abnormal shape of the auricle. In mice, Hoxa2 inactivation at early gestational stages results in external auditory canal (EAC) duplication and absence of the auricle, whereas its late inactivation results in a hypomorphic auricle, mimicking the human HOXA2 mutant condition. By genetic fate mapping we found that the mouse auricle (or pinna) derives from the Hoxa2-expressing neural crest-derived mesenchyme of the second pharyngeal arch, and not from a composite of first and second arch mesenchyme as previously proposed based on morphological observation of human embryos. Moreover, the mouse EAC is entirely lined by Hoxa2-negative first arch mesenchyme and does not develop at the first pharyngeal cleft, as previously assumed. Conditional ectopic Hoxa2 expression in first arch neural crest is sufficient to induce a complete duplication of the pinna and a loss of the EAC, suggesting transformation of the first arch neural crest-derived mesenchyme lining the EAC into an ectopic pinna. Hoxa2 partly controls the morphogenesis of the pinna through the BMP signalling pathway and expression of Eya1, which in humans is involved in branchio-oto-renal syndrome. Thus, Hoxa2 loss-and gain-of-function approaches in mice provide a suitable model to investigate the molecular aetiology of microtia and auricle duplication.

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Section: Temporal Inactivation Of Hoxa2 Results In Altered Bmp Signalmentioning

confidence: 99%

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

et al. 2013

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“…Taken together, our data thus far indicate that an alternative TGF␤ 1 -dependent signaling pathway may be responsible for Scleraxis regulation in the cardiac myofibroblast through a Smad-independent mechanism. TGF␤ 1 has the ability to signal down multiple Smad-independent pathways including Rho/ROCK, PI3K/AKT, and p38/ ERK/MAPK (1,19,21,38). Because TGF␤ 1 may induce Scleraxis expression independent of Smads, we sought to test one of these alternative pathways that lie downstream of the TGF␤ receptors.…”

Section: H244mentioning

confidence: 99%

TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

Zeglinski

Roché

Hnatowich

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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In cardiac wound healing following myocardial infarction (MI), relatively inactive resident cardiac fibroblasts phenoconvert to hypersynthetic/secretory myofibroblasts that produce large quantities of extracellular matrix (ECM) and fibrillar collagen proteins. Our laboratory and others have identified TGF␤ 1 as being a persistent stimulus in the chronic and inappropriate wound healing phase that is marked by hypertrophic scarring and eventual stiffening of the entire myocardium, ultimately leading to the pathogenesis of heart failure following MI. Ski is a potent negative regulator of TGF␤/Smad signaling with known antifibrotic effects. Conversely, Scleraxis is a potent profibrotic basic helix-loop-helix transcription factor that stimulates fibrillar collagen expression. We hypothesize that TGF␤ 1 induces Scleraxis expression by a novel Smad-independent pathway. Our data support the hypothesis that Scleraxis expression is induced by TGF␤ 1 through a Smad-independent pathway in the cardiac myofibroblast. Specifically, we demonstrate that TGF␤ 1 stimulates p42/44 (Erk1/2) kinases, which leads to increased Scleraxis expression. Inhibition of MEK1/2 using U0126 led to a sequential temporal reduction of phosphop42/44 and subsequent Scleraxis expression. We also found that adenoviral Ski expression in primary myofibroblasts caused a significant repression of endogenous Scleraxis expression at both the mRNA and protein levels. Thus we have identified a novel TGF␤ 1-driven, Smad-independent, signaling cascade that may play an important role in regulating the fibrotic response in activated cardiac myofibroblasts following cardiac injury.

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“…Canonically, TGF-␤ binds to TGF-␤RII, which recruits and activates TGF-␤RI, leading to activation of Smad2/3 and accumulation of Smad4 in the nucleus (41). It has been reported previously that deletion or mutation of Smad-binding sites within the FBLN5 promoter attenuates FBLN5 transcriptional activity in response to TGF-␤ treatment in human lung fibroblasts (11).…”

Section: Fbln5 Expression In Pancreaticmentioning

confidence: 99%

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Topalovski¹,

Hagopian²,

Wang

et al. 2016

Journal of Biological Chemistry

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The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of ␣5␤1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECMdriven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-␤-and PI3K-dependent manner. Pharmacologic inhibition of TGF-␤ receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF-␤ receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF-␤ signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.The maintenance of solid tumors relies heavily on cues received from the surrounding environment. The ECM 2 is composed of structural proteins such as FN and collagen, which promote signaling through integrins and receptor tyrosine kinases (1, 2). ECM signaling is modulated by matricellular proteins, which regulate ECM-cell interactions without serving a direct structural function (3-5). The composition of the ECM is dynamic and varies between tumors and tumor types, contributing to intra-and intertumor heterogeneity, which presents challenges for effective therapeutic strategies. Furthermore, mouse studies have revealed anti-and pro-tumorigenic functions for ECM (5-7). In addition to ECM, stromal cells, including endothelial cells, immune cells, and fibroblasts, are present in the tumor microenvironment. These cells contribute to tumor growth, invasion, and chemoresponse (8 -10).During tumor progression, cancer cells release factors that maintain a microenvironment conducive for growth. For example, TGF-␤ is a cytokine expressed in many cancers that enhances the expression of multiple ECM molecules, including but not limited to FN, collagen, elastin, and fibulins (11-13). Fbln5 is a 448-amino acid secretory glycoprotein of the fibulin family of matricellular proteins. Fbln5 is unique among its members as it contains an RGD-integrin binding domain and can ligate a number of integrins (14). Fbln5 is ex...

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A portrait of Transforming Growth Factor β superfamily signalling: Background matters

Cited by 183 publications

References 37 publications

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

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A portrait of Transforming Growth Factor β superfamily signalling: Background matters

Cited by 183 publications

References 37 publications

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

TGFβ1regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

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TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism