The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner

Endothelial mesenchymal transition (EndMT) has been described as a fundamental process during embryogenesis; however, it can occur also in adult age, underlying pathological events, including fibrosis. Indeed, during EndMT, the endothelial cells lose their specific markers, such as vascular endothelial cadherin (VE-cadherin), and acquire a mesenchymal phenotype, expressing specific products, such as α-smooth muscle actin (α-SMA) and type I collagen; moreover, the integrity of the endothelium is disrupted, and cells show a migratory, invasive and proliferative phenotype. Several stimuli can trigger this transition, but transforming growth factor (TGF-β1) is considered the most relevant. EndMT can proceed in a canonical smad-dependent or non-canonical smad-independent manner and ultimately regulate gene expression of pro-fibrotic machinery. These events lead to endothelial dysfunction and atherosclerosis at the vascular level as well as myocardial hypertrophy and fibrosis. Indeed, EndMT is the mechanism which promotes the progression of cardiovascular disorders following hypertension, diabetes, heart failure and also ageing. In this scenario, hydrogen sulfide (H2S) has been widely described for its preventive properties, but its role in EndMT is poorly investigated. This review is focused on the evaluation of the putative role of H2S in the EndMT process.

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Proteomic and genomic analysis of acid dentin lysate with focus on TGF-β signaling

Scientific Reports ◽

10.1038/s41598-021-89996-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jila Nasirzade ◽

Zahra Kargarpour ◽

Goran Mitulović ◽

Franz Josef Strauss ◽

Layla Panahipour ◽

...

Keyword(s):

Cellular Response ◽

Alveolar Bone ◽

Quantitative Polymerase Chain Reaction ◽

Genomic Analysis ◽

Type I ◽

Gingival Fibroblasts ◽

Nadph Oxidase 4 ◽

Major Response ◽

Collagen Membranes ◽

Β Receptor

AbstractParticulate autologous tooth roots are increasingly used for alveolar bone augmentation; however, the proteomic profile of acid dentin lysate and the respective cellular response have not been investigated. Here we show that TGF-β1 is among the 226 proteins of acid dentin lysate (ADL) prepared from porcine teeth. RNA sequencing identified 231 strongly regulated genes when gingival fibroblasts were exposed to ADL. Out of these genes, about one third required activation of the TGF-β receptor type I kinase including interleukin 11 (IL11) and NADPH oxidase 4 (NOX4). Reverse transcription-quantitative polymerase chain reaction and immunoassay confirmed the TGF-β-dependent expression of IL11 and NOX4. The activation of canonical TGF-β signaling by ADL was further confirmed by the phosphorylation of Smad3 and translocation of Smad2/3, using Western blot and immunofluorescence staining, respectively. Finally, we showed that TGF-β activity released from dentin by acid lysis adsorbs to titanium and collagen membranes. These findings suggest that dentin particles are a rich source of TGF-β causing a major response of gingival fibroblasts.

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Similar control mechanisms regulate the insulin and type I insulin-like growth factor receptor kinases. Affinity-purified insulin-like growth factor I receptor kinase is activated by tyrosine phosphorylation of its beta subunit.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)67389-2 ◽

1986 ◽

Vol 261 (24) ◽

pp. 11341-11349 ◽

Cited By ~ 5

Author(s):

K T Yu ◽

M A Peters ◽

M P Czech

Keyword(s):

Growth Factor ◽

Tyrosine Phosphorylation ◽

Growth Factor Receptor ◽

Beta Subunit ◽

Type I ◽

Control Mechanisms ◽

Insulin Like Growth Factor ◽

Receptor Kinase ◽

Factor I ◽

Receptor Kinases

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Mechanisms of Transforming Growth Factor-β Receptor Endocytosis and Intracellular Sorting Differ between Fibroblasts and Epithelial Cells

Molecular Biology of the Cell ◽

10.1091/mbc.12.3.675 ◽

2001 ◽

Vol 12 (3) ◽

pp. 675-684 ◽

Cited By ~ 38

Author(s):

Jules J.E. Doré ◽

Diying Yao ◽

Maryanne Edens ◽

Nandor Garamszegi ◽

Elizabeth L. Sholl ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Ligand Binding ◽

Transforming Growth Factor ◽

Point Mutations ◽

Type I ◽

Receptor Complex ◽

Type Ii ◽

Down Regulation ◽

Β Receptor

Transforming growth factor-βs (TGF-β) are multifunctional proteins capable of either stimulating or inhibiting mitosis, depending on the cell type. These diverse cellular responses are caused by stimulating a single receptor complex composed of type I and type II receptors. Using a chimeric receptor model where the granulocyte/monocyte colony-stimulating factor receptor ligand binding domains are fused to the transmembrane and cytoplasmic signaling domains of the TGF-β type I and II receptors, we wished to describe the role(s) of specific amino acid residues in regulating ligand-mediated endocytosis and signaling in fibroblasts and epithelial cells. Specific point mutations were introduced at Y182, T200, and Y249 of the type I receptor and K277 and P525 of the type II receptor. Mutation of either Y182 or Y249, residues within two putative consensus tyrosine-based internalization motifs, had no effect on endocytosis or signaling. This is in contrast to mutation of T200 to valine, which resulted in ablation of signaling in both cell types, while only abolishing receptor down-regulation in fibroblasts. Moreover, in the absence of ligand, both fibroblasts and epithelial cells constitutively internalize and recycle the TGF-β receptor complex back to the plasma membrane. The data indicate fundamental differences between mesenchymal and epithelial cells in endocytic sorting and suggest that ligand binding diverts heteromeric receptors from the default recycling pool to a pathway mediating receptor down-regulation and signaling.

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Site-specific ubiquitination exposes a linear motif to promote interferon-α receptor endocytosis

The Journal of Cell Biology ◽

10.1083/jcb.200706034 ◽

2007 ◽

Vol 179 (5) ◽

pp. 935-950 ◽

Cited By ~ 100

Author(s):

K.G. Suresh Kumar ◽

Hervé Barriere ◽

Christopher J. Carbone ◽

Jianghuai Liu ◽

Gayathri Swaminathan ◽

...

Keyword(s):

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Interferon Α ◽

Type I ◽

Lysosomal Degradation ◽

Linear Motif ◽

Site Specific ◽

Receptor Endocytosis ◽

Β Receptor

Ligand-induced endocytosis and lysosomal degradation of cognate receptors regulate the extent of cell signaling. Along with linear endocytic motifs that recruit the adaptin protein complex 2 (AP2)–clathrin molecules, monoubiquitination of receptors has emerged as a major endocytic signal. By investigating ubiquitin-dependent lysosomal degradation of the interferon (IFN)-α/β receptor 1 (IFNAR1) subunit of the type I IFN receptor, we reveal that IFNAR1 is polyubiquitinated via both Lys48- and Lys63-linked chains. The SCFβTrcp (Skp1–Cullin1–F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro. Although either polyubiquitin linkage suffices for postinternalization sorting, both types of chains are necessary but not sufficient for robust IFNAR1 turnover and internalization. These processes also depend on the proximity of ubiquitin-acceptor lysines to a linear endocytic motif and on its integrity. Furthermore, ubiquitination of IFNAR1 promotes its interaction with the AP2 adaptin complex that is required for the robust internalization of IFNAR1, implicating cooperation between site-specific ubiquitination and the linear endocytic motif in regulating this process.

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