First Author | Nakano N | Year | 2014 |
Journal | J Biol Chem | Volume | 289 |
Issue | 18 | Pages | 12680-92 |
PubMed ID | 24627487 | Mgi Jnum | J:213178 |
Mgi Id | MGI:5583005 | Doi | 10.1074/jbc.M114.558981 |
Citation | Nakano N, et al. (2014) C18 ORF1, a novel negative regulator of transforming growth factor-beta signaling. J Biol Chem 289(18):12680-92 |
abstractText | Transforming growth factor (TGF)-beta signaling is deliberately regulated at multiple steps in its pathway from the extracellular microenvironment to the nucleus. However, how TGF-beta signaling is activated or attenuated is not fully understood. We recently identified transmembrane prostate androgen-induced RNA (TMEPAI), which is involved in a negative feedback loop of TGF-beta signaling. When we searched for a family molecule(s) for TMEPAI, we found C18ORF1, which, like TMEPAI, possesses two PY motifs and one Smad-interacting motif (SIM) domain. As expected, C18ORF1 could block TGF-beta signaling but not bone morphogenetic protein signaling. C18ORF1 bound to Smad2/3 via its SIM and competed with the Smad anchor for receptor activation for Smad2/3 binding to attenuate recruitment of Smad2/3 to the TGF-beta type I receptor (also termed activin receptor-like kinase 5 (ALK5)), in a similar fashion to TMEPAI. Knockdown of C18ORF1 prolonged duration of TGF-beta-induced Smad2 phosphorylation and concomitantly potentiated the expression of JunB, p21, and TMEPAI mRNAs induced by TGF-beta. Consistently, TGF-beta-induced cell migration was enhanced by the knockdown of C18ORF1. These results indicate that the inhibitory function of C18ORF1 on TGF-beta signaling is similar to that of TMEPAI. However, in contrast to TMEPAI, C18ORF1 was not induced upon TGF-beta signaling. Thus, we defined C18ORF1 as a surveillant of steady state TGF-beta signaling, whereas TMEPAI might help C18ORF1 to inhibit TGF-beta signaling in a coordinated manner when cells are stimulated with high levels of TGF-beta. |