C18 ORF1, a novel negative regulator of transforming growth factor-beta signaling.
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Nakano N, Maeyama K, Sakata N, Itoh F, Akatsu R, Nakata M, Katsu Y, Ikeno S, Togawa Y, Vo Nguyen TT, Watanabe Y, Kato M, Itoh S
C18 ORF1, a novel negative regulator of transforming growth factor-beta signaling.
J Biol Chem. 2014 May 2;289(18):12680-92. doi: 10.1074/jbc.M114.558981. Epub 2014 Mar 13.
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- 24627487 [ View in PubMed]
- Abstract
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.