Summary Smads are nuclear-shuttling transcriptional mediators of transforming growth factor-β (TGF-β) signaling. While their essential nuclear roles in gene regulation during development and carcinogenesis are well established, whether they have important cytoplasmic functions remains unclear. Here we report that Smad2 is a critical determinant of mitochondrial dynamics. We identified mitofusin 2 (Mfn2) and Rab and Ras interactor 1 (RIN1) as new Smad2 binding partners required for mitochondrial fusion. Unlike TGF-β-induced Smad2/3 transcriptional responses underlying mitochondrial fragmentation and apoptosis, inactive cytoplasmic Smad2 rapidly promotes mitochondrial fusion by recruiting RIN1 into a complex with Mfn2. We demonstrate that Smad2 is a key scaffold, allowing RIN1 to act as a GTP exchange factor (GEF) for Mfn2-GTPase activation to promote mitochondrial ATP synthesis and suppress superoxide production. These results reveal functional implications between Smads and mitochondrial dysfunction in cancer, metabolic, and neurodegenerative disorders.
Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although αTAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-β-activated kinase 1 (TAK1) as a key activator of αTAT1. TAK1 directly interacts with and phosphorylates αTAT1 at Ser237 to critically enhance its catalytic activity, as mutating this site to alanine abrogates, whereas a phosphomimetic induces MT hyperacetylation across cell types. Using a custom phospho-αTAT1-Ser237 antibody, we screen various mouse tissues to discover that brain contains some of the highest TAK1-dependent αTAT1 activity, which, accordingly, is diminished rapidly upon intra-cerebral injection of a TAK1 inhibitor. Lastly, we show that TAK1 selectively inhibits AKT to suppress mitogenic and metabolism-related pathways through MT-based mechanisms in culture and in vivo. Collectively, our findings support a fundamental new role for TGF-β signaling in MT-related functions and disease.
Defective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report βIV-spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific βIV-spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina. During sprouting, βIV-spectrin expresses in stalk cells to inhibit their tip cell potential by enhancing VEGFR2 turnover in a manner independent of most cell-fate determining mechanisms. Rather, βIV-spectrin recruits CaMKII to the plasma membrane to directly phosphorylate VEGFR2 at Ser984, a previously undefined phosphoregulatory site that strongly induces VEGFR2 internalization and degradation. These findings support a distinct spectrin-based mechanism of tip-stalk cell specification during vascular development.
Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell–cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis.
Background: Endoglin is a key regulator of TGF- signaling in endothelial cells but its role in autophagy during angiogenesis is unknown. Results: Endoglin relieves Smad2-dependent BECN1 repression. Conclusion: Endoglin promotes autophagy during angiogenesis by regulating Smad2 function. Significance: Endoglin-mediated autophagy may be an effective vascular target.
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