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Published on: October 19, 2006
C18 ORF1, a novel negative regulator of transforming growth factor-β signaling
Naoko Nakano1, Kota Maeyama, Nobuo Sakata
1From the Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575.
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.
Insights
C18ORF1, a TMEPAI family molecule, inhibits transforming growth factor-beta (TGF-β) signaling by binding Smad2/3. Unlike TMEPAI, C18ORF1 surveils basal TGF-β signaling, suggesting coordinated regulation.
Area of Science:
- Cellular Biology
- Molecular Biology
- Signal Transduction
Background:
- Transforming growth factor-beta (TGF-β) signaling is crucial in cellular processes but its precise regulation remains incompletely understood.
- Transmembrane prostate androgen-induced RNA (TMEPAI) is known to participate in negative feedback of TGF-β signaling.
Purpose of the Study:
- To identify and characterize novel regulators of TGF-β signaling.
- To elucidate the mechanism of action and functional role of C18ORF1 in TGF-β pathway regulation.
Main Methods:
- Bioinformatic search for TMEPAI family members.
- Protein interaction assays (Smad-interacting motif - SIM domain).
- Gene knockdown experiments (siRNA).
- Analysis of gene expression (mRNA levels) and protein phosphorylation (Smad2).
- Assessment of cell migration assays.
Main Results:
- C18ORF1, a TMEPAI family member, was identified with a Smad-interacting motif (SIM) domain.
- C18ORF1 inhibits TGF-β signaling, but not bone morphogenetic protein signaling, by binding Smad2/3 and preventing their recruitment to the TGF-β type I receptor (ALK5).
- Knockdown of C18ORF1 prolonged TGF-β-induced Smad2 phosphorylation and enhanced the expression of downstream genes (JunB, p21, TMEPAI) and cell migration.
- Unlike TMEPAI, C18ORF1 expression is not induced by TGF-β signaling.
Conclusions:
- C18ORF1 functions similarly to TMEPAI in inhibiting TGF-β signaling through Smad2/3 interaction.
- C18ORF1 acts as a surveillant of basal TGF-β signaling, while TMEPAI may contribute to inhibition during high TGF-β stimulation, indicating a coordinated regulatory mechanism.
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