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TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-? signaling pathway.

ABSTRACT: Transforming growth factor-? (TGF-?) principally relays its effects through the Smad pathway however, accumulating evidence indicate that alternative signaling routes are also employed by this pleiotropic cytokine. For instance recently, we have demonstrated that ligand occupied TGF-? receptors can directly trigger the TRAF6-TAK1 signaling module, resulting in MAP kinase activation. Here we report identification of the adaptor molecule TTRAP as a novel component of this non-canonical TGF-? pathway. We show that the protein associates with TGF-? receptors and components of the TRAF6-TAK1 signaling module, resulting in differential regulation of TGF-? activated p38 and NF-?B responses. Modulation of cellular TTRAP level affects cell viability in the presence of TGF-?, suggesting that the protein is an important component of the TGF-? induced apoptotic process.

SUBMITTER: Varady G

PROVIDER: S-EPMC3182262 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-β signaling pathway.

Várady György G Sarkadi Balázs B Fátyol Károly K

PloS one 20110927 9

Transforming growth factor-β (TGF-β) principally relays its effects through the Smad pathway however, accumulating evidence indicate that alternative signaling routes are also employed by this pleiotropic cytokine. For instance recently, we have demonstrated that ligand occupied TGF-β receptors can directly trigger the TRAF6-TAK1 signaling module, resulting in MAP kinase activation. Here we report identification of the adaptor molecule TTRAP as a novel component of this non-canonical TGF-β pathw ...[more]

PMID: 21980489

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2019-01-27 | GSE104908 | GEO

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Endoglin regulates the activation and quiescence of endothelium by participating in canonical and non-canonical TGF-? signaling pathways.

Project description:Endoglin (Eng) is an auxiliary receptor for transforming growth factor-? (TGF?), with important roles in vascular function. TGF? regulates angiogenesis through balancing the pro-proliferative and pro-differentiation signaling pathways of endothelial cells (EC). However, the contribution of endoglin to these TGF? activities, and more specifically modulation of EC phenotype, remains elusive. Mutations in endoglin cause hereditary hemorrhagic telangiectasia-1 in humans. The Eng+/- mice are viable and exhibit some of the vascular defects seen in humans with endoglin haploinsufficiency. In the present study we show that haploinsufficiency of endoglin results in attenuation of retinal neovascularization during oxygen-induced ischemic retinopathy. Although the importance of endoglin expression in angiogenesis and vascular development has been demonstrated, the underlying mechanisms remain obscure. To gain detailed insight into the cell autonomous regulatory mechanisms that affect angiogenic properties of EC, we prepared retinal EC from Eng+/+ and Eng+/- Immorto mice. The Eng+/- EC were more adherent, less migratory, and failed to undergo capillary morphogenesis. Aortic sprouting angiogenesis was similarly attenuated in aortas from Eng+/- mice. In addition, Eng+/- EC expressed increased levels of VEGF but reduced expression of endothelial NO synthase and NO production. Mechanistically, these changes were consistent with sustained activation of mitogen-activated protein kinase (MAPK) pathways, and aberrant Smad-dependent signaling pathways in Eng+/- EC. Taken together, our results underscore the importance of endoglin in both canonical and non-canonical TGF? signaling pathways modulating both the activation and quiescence of the endothelium during angiogenesis.

| S-EPMC3644140 | biostudies-literature

NUMBL Interacts with TAK1, TRAF6 and NEMO to Negatively Regulate NF-?B Signaling During Osteoclastogenesis.

Project description:NF-?B signaling is essential for osteoclast differentiation and skeletal homeostasis. We have reported recently that NUMB-like (NUMBL) protein modulates osteoclastogenesis by down regulating NF-?B activation. Herein, we decipher the mechanism underlying this phenomenon. We found that whereas NUMBL mRNA expression decreases upon stimulation of wild type (WT) bone marrow macrophages (BMMs) with RANKL, TAK1 deficiency in these cells leads to increased NUMBL and decreased TRAF6 and NEMO expression. These changes were restored upon WT-TAK1 expression, but not with catalytically inactive TAK1-K63W, suggesting that TAK1 enzymatic activity is required for these events. Forced expression of NUMBL inhibits osteoclast differentiation and function as evident by reduction in all hallmarks of osteoclastogenesis. Conversely, NUMBL-null BMMs, show increased osteoclast differentiation and mRNA expression of osteoclast marker genes. Post-translationally, K48-linked poly-ubiquitination of NUMBL is diminished in TAK1-null BMMs compared to elevated K48-poly-ubiquitination in WT cells, indicating increased stability of NUMBL in TAK1-null conditions. Further, our studies show that NUMBL directly interacts with TRAF6 and NEMO, and induces their K48-poly-ubiquitination mediated proteasomal degradation. Collectively, our data suggest that NUMBL and TAK1 are reciprocally regulated and that NUMBL acts as an endogenous regulator of NF-?B signaling and osteoclastogenesis by targeting the TAK1-TRAF6-NEMO axis.

| S-EPMC5626749 | biostudies-literature

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