title: TMED10 Protein Interferes with Transforming Growth Factor (TGF)-β Signaling by Disrupting TGF-β Receptor Complex Formation.
abstract: The intensity and duration of TGF-β signaling determine the cellular biological response. How this is negatively regulated is not well understood. Here, we identified a novel negative regulator of TGF-β signaling, transmembrane p24-trafficking protein 10 (TMED10). TMED10 disrupts the complex formation between TGF-β type I (also termed ALK5) and type II receptors (TβRII). Misexpression studies revealed that TMED10 attenuated TGF-β-mediated signaling. A 20-amino acid-long region from Thr91to Glu110within the extracellular region of TMED10 was found to be crucial for TMED10 interaction with both ALK5 and TβRII. Synthetic peptides corresponding to this region inhibit both TGF-β-induced Smad2 phosphorylation and Smad-dependent transcriptional reporter activity. In a xenograft cancer model, where previously TGF-β was shown to elicit tumor-promoting effects, gain-of-function and loss-of-function studies for TMED10 revealed a decrease and increase in the tumor size, respectively. Thus, we determined herein that TMED10 expression levels are the key determinant for efficiency of TGF-β receptor complex formation and signaling.
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakano
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Kenro
authors.initials: K
authors.lastname: Kako
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Kenryu
authors.initials: K
authors.lastname: Umezaki
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Sano
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Souichi
authors.initials: S
authors.lastname: Ikeno
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Otsuka
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shigeta
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakata
authors.affiliation: the Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Itoh
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Yota
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: the Translational Research Center, Fukushima Medical University, 11-25 Sakaemachi, Fukushima City, Fukushima 960-8031, Japan.
authors.forename: Shun-Ichiro
authors.initials: SI
authors.lastname: Iemura
authors.affiliation: the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, S-1-P, 2300 RC Leiden, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Dinther
authors.affiliation: the Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan, and.
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.affiliation: the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, S-1-P, 2300 RC Leiden, The Netherlands.|the Science for Life Laboratory, Ludwig Institute for Cancer Research, Uppsala University, Uppsala SE-751 24, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan, sitoh@ac.shoyaku.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Itoh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C548893:Tmed10 protein, mouse; D016212:Transforming Growth Factor beta; D033921:Vesicular Transport Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: SMAD transcription factor; epithelial-mesenchymal transition (EMT); serine/threonine protein kinase; transforming growth factor β (TGF-β); tumor