Signaling Receptors for TGF-β Family Members

Heldin, Carl‐Henrik; Moustakas, Aristidis

doi:10.1101/cshperspect.a022053

Cited by 575 publications

(539 citation statements)

References 285 publications

(257 reference statements)

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“…HHT type 1 and type 2 result from mutations in the genes encoding endoglin, an auxiliary protein for TGFβ binding to signaling TGFβ receptors, and activin-like kinase 1, a type I receptor for TGFβ, BMP-9 and BMP-10, respectively [58]. It has been found that the majority of mutations result in the retention of these proteins in the ER [115,116].…”

Section: Tgfβ Signaling Is Controlled By Receptor Traffickingmentioning

confidence: 99%

“…It has been shown that activated TGFβ receptors are internalized from plasma membrane via at least two different routes, i.e. clathrin-and caveolin-dependent endocytosis [22,58,59]. The localization of the receptor complexes in the plasma membrane microdomains, clathrin-coated pits or caveolae, predetermines the route they will follow (Fig.…”

Section: Endocytosis Of Tgfβ Receptorsmentioning

confidence: 99%

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Intracellular trafficking of transforming growth factor β receptors

Yakymovych

Heldin

2018

ABBS

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Transforming growth factor β (TGFβ) family members signal via heterotetrameric complexes of type I (TβRI) and type II (TβRII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized TβRI and TβRII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGFβ receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin-and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGFβ signaling, localization of the activated receptor complexes on the early endosomes promotes TGFβ-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGFβ receptors, has been shown to be required for TGFβ signaling via non-Smad pathways. The importance of proper control of TGFβ receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGFβ receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGFβ signaling.

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Section: Tgfβ Signaling Is Controlled By Receptor Traffickingmentioning

confidence: 99%

Section: Endocytosis Of Tgfβ Receptorsmentioning

confidence: 99%

Intracellular trafficking of transforming growth factor β receptors

Yakymovych

Heldin

2018

ABBS

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“…Seven type I receptors and five type II receptors have been identified in humans (Heldin and Moustakas 2016). Type I receptors are also known as activin receptor-like kinases (ALK-1 -b1, -b2, and -b3) are secreted in latent forms that are unable to interact with the receptors.…”

Section: Overview Of Tgf-b Signalingmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…ALK4 forms an activin receptor complex with activin type‐II receptor to transduce activin signal from the cell surface to the cytoplasm,8, 9, 10, 11 thus regulating physiological and pathological processes including embryogenesis,12 tissue homeostasis,13 wound healing,14 extracellular matrix production,15 immunosuppression, and carcinogenesis 16, 17. We recently focused on exploring the role of ALK4 in different cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Activin Receptor‐Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy

Wang

Chen

Zhang

et al. 2018

JAHA

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BackgroundActivin receptor‐like kinase 4 (ALK4) is highly expressed in mammal heart. Atrial fibrillation (AF) is closely related to ventricular pressure overload. Because pressure overload increases atrial pressure and leads to atrial remodeling, it would be informative to know whether ALK4 exerts potential effects on atrial remodeling and AF vulnerability in a pressure‐overload model.Methods and ResultsWild‐type littermates and ALK4+/− mice were subjected to abdominal aortic constriction or a sham operation. After 4 or 8 weeks, echocardiographic and hemodynamic measurements were performed, and inducibility of AF was tested. The hearts were divided into atria and ventricles and then were fixed in formalin for staining, or they were weighted and snap‐frozen for quantitative real‐time polymerase chain reaction and Western blot analysis. Compared with wild‐type littermates, ALK4+/− mice demonstrated a similar extent of atrial hypertrophy but significantly suppressed atrial fibrosis at 8 weeks post–abdominal aortic constriction. ALK4 haplodeficiency partially blocked abdominal aortic constriction–induced upregulation of monocyte chemotactic protein 1 and interleukin‐6, and the increased chemotaxin of macrophages. ALK4 haplodeficiency also blunted a reduction of connexin 40 and redistribution of connexin 43 from the intercalated disk to the lateral membranes, thereby improving localized conduction abnormalities. Meanwhile, ALK4 haplodeficiency inhibited abdominal aortic constriction–induced decreased IN a, IC a‐L and IK 1 densities as well as the accompanying action potential duration shortening. Mechanistically, ALK4 haploinsufficiency resulted in the suppression of Smad2/3 activity in this model.ConclusionsOur results demonstrate that ALK4 haplodeficiency ameliorates atrial remodeling and vulnerability to AF in a pressure‐overload model through inactivation of the Smad2/3 pathway, suggesting that ALK4 might be a potential therapeutic target in combating pressure overload–induced AF.

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Signaling Receptors for TGF-β Family Members

Cited by 575 publications

References 285 publications

Intracellular trafficking of transforming growth factor β receptors

Intracellular trafficking of transforming growth factor β receptors

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Activin Receptor‐Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy

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Signaling Receptors for TGF-β Family Members

Cited by 575 publications

References 285 publications

Intracellular trafficking of transforming growth factor &beta; receptors

Intracellular trafficking of transforming growth factor &beta; receptors

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Activin Receptor‐Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy

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Intracellular trafficking of transforming growth factor β receptors

Intracellular trafficking of transforming growth factor β receptors