Regulation of molecular interaction between TGF-β and Wnt signalings

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TGF-β signaling regulates cell growth, differentiation, morphogenesis and apoptosis. TGF-β activated kinase 1 (TAK1) and Nemo-like kinase (NLK) function in Xenopus, Drosophila and C.elegans developments. Here we report that serine phosphorylation of STAT3 induced by TAK1-NLK cascade is essential for TGF-β-mediated mesoderm induction in Xenopus embryo. Depletion of TAK1, NLK or STAT3 blocks TGF-β-mediated mesoderm induction. Co-expression of NLK and STAT3 induces mesoderm by a mechanism that requires serine phosphorylation of STAT3. Activin activates NLK, which in turn directly phosphorylates STAT3. Moreover, depletion of either TAK1 or NLK inhibits endogenous serine phosphorylation of STAT3. These results provide the first evidence that TAK1-NLK-STAT3 cascade participates in TGF-β-mediated mesoderm induction.MAFbx/Atrogin-1 has been identified as a regulator for skeletal muscle atrophy, and encodes an F-box-type E3 ubiquitin ligase. However, little is known about how MAFbx/Atrogin-1 regulates cellular signaling. Here we identify and genetically characterize MFB-1, a MAFbx/Atrogin-1 homologue from Caenorhabditis elegans. The mfb-1 deletion mutant significantly enhanced the dauer constitutive (Daf-c) phenotype caused by mutations in the DAF-7/TrGF-β-like signaling pathway, but not the DAF-2/insulin receptor-like signaling pathway. Conversely, the Daf-c phenotypes of DAF-7 pathway mutants were partially suppressed by mfb-1 cDNA transgenes. Thus, MFB-1 acts genetically downstream in the DAF-7 pathway. A mfb-1 :: GFP fusion was found to be expressed in the nervous system, hypodermis and intestine, and overlapped expression of many DAF-7 pathway genes. We propose that MFB-1 is a novel F-box protein that negatively regulates dauer formation in concert with the DAF-7 signaling pathway in C.elegans.