title: C18 ORF1, a novel negative regulator of transforming growth factor-β signaling.
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.
authors.affiliation: From the Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakano
authors.forename: Kota
authors.initials: K
authors.lastname: Maeyama
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakata
authors.forename: Fumiko
authors.initials: F
authors.lastname: Itoh
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Akatsu
authors.forename: Miki
authors.initials: M
authors.lastname: Nakata
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katsu
authors.forename: Souichi
authors.initials: S
authors.lastname: Ikeno
authors.forename: Yoko
authors.initials: Y
authors.lastname: Togawa
authors.forename: Thanh Thao
authors.initials: TT
authors.lastname: Vo Nguyen
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Kato
authors.forename: Susumu
authors.initials: S
authors.lastname: Itoh
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C111334:LDLRAD4 protein, human; D008565:Membrane Proteins; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
keywords: Activin; C18ORF1; EMT; Receptor Serine/threonine Kinase; SARA; SIM; SMAD Transcription Factor; TMEPAI; Transforming Growth Factor β (TGFβ)