C18 ORF1: A Novel Negative Regulator of TGF-{beta}Signaling [Signal Transduction]

March 13th, 2014 by Nakano, N., Maeyama, K., Sakata, N., Itoh, F., Akatsu, R., Nakata, M., Katsu, Y., Ikeno, S., Togawa, Y., Vo Nguyen, T. T., Watanabe, Y., Kato, M., Itoh, S.

Transforming growth factor (TGF)-β signaling is deliberately regulated at multiple steps in its pathway from the extracellular microenvironment to the nucleus. However, how TGF-β 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-β signaling. When we searched for a family molecule(s) for TMEPAI, we found C18ORF1, which, like TMEPAI, possesses 2 PY motifs and 1 Smad-interacting motif (SIM) domain. Expectedly, C18ORF1 could block TGF-β signaling, but not BMP signaling. C18ORF1 bound to Smad2/3 via its SIM and competed with Smad anchor for receptor activation (SARA) for Smad2/3 binding to attenuate recruitment of Smad2/3 to the TGF-β type I receptor (also termed activin receptor-like kinase 5 [ALK5]), in a similar fashion to TMEPAI. Knockdown of C18ORF1 prolonged duration of TGF-β -induced Smad2 phosphorylation and concomitantly potentiated the expression of JunB, p21, and TMEPAI mRNAs induced by TGF-β. Consistently, TGF-β-induced cell migration was enhanced by the knockdown of C18ORF1. These results indicate that the inhibitory function of C18ORF1 on TGF-β signaling is similar to that of TMEPAI. However, in contrast to TMEPAI, C18ORF1 was not induced upon TGF-β signaling. Thus, we defined C18ORF1 as a surveillant of steady state TGF-β signaling, whereas TMEPAI might help C18ORF1 to inhibit TGF-β signaling in a coordinated manner when cells are stimulated with high levels of TGF-β.