Abstract
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 two PY motifs and one Smad-interacting motif (SIM) domain. As expected, C18ORF1 could block TGF-β 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-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.
Highlights
The structure of C18ORF1 is similar to that of transmembrane prostate androgen-induced RNA (TMEPAI)
We recently identified transmembrane prostate androgen-induced RNA (TMEPAI), which is involved in a negative feedback loop of Transforming growth factor (TGF)- signaling
These results indicate that the inhibitory function of C18ORF1 on TGF- signaling is similar to that of TMEPAI
Summary
The structure of C18ORF1 is similar to that of TMEPAI. Results: C18ORF1 inhibits TGF- signaling, but not BMP signaling, by its competition with SARA for Smad2/3 binding. 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- type I receptor ( termed activin receptor-like kinase 5 (ALK5)), in a similar fashion to TMEPAI. TGF--induced cell migration was enhanced by the knockdown of C18ORF1 These results indicate that the inhibitory function of C18ORF1 on TGF- signaling is similar to that of TMEPAI. We reported that TMEPAI, a direct target gene of TGF-/activin signaling, inhibits TGF-/activin signaling through a negative feedback loop This inhibitory action of TMEPAI is due to its competition with SARA for binding to AR-Smads. We show that C18ORF1 can inhibit TGF- signaling in a similar fashion to TMEPAI as a gatekeeper that abrogates excessive TGF- signaling
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