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TMED10 Protein Interferes with Transforming Growth Factor (TGF)-beta Signaling by Disrupting TGF-beta Receptor Complex Formation
Showa Pharmaceut Univ, Lab Biochem, 3-3165 Higashi Tamagawagakuen, Machida, Tokyo 1948543, Japan..
Showa Pharmaceut Univ, Lab Biochem, 3-3165 Higashi Tamagawagakuen, Machida, Tokyo 1948543, Japan..
Showa Pharmaceut Univ, Lab Biochem, 3-3165 Higashi Tamagawagakuen, Machida, Tokyo 1948543, Japan..
Showa Pharmaceut Univ, Lab Biochem, 3-3165 Higashi Tamagawagakuen, Machida, Tokyo 1948543, Japan..
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2017 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 10, 4099-4112 p.Article in journal (Refereed) Published
Abstract [en]

The intensity and duration of TGF-beta signaling determine the cellular biological response. How this is negatively regulated is not well understood. Here, we identified a novel negative regulator of TGF-beta signaling, transmembrane p24-trafficking protein 10 (TMED10). TMED10 disrupts the complex formation between TGF-beta type I (also termed ALK5) and type II receptors (T beta RII). Misexpression studies revealed that TMED10 attenuated TGF-beta-mediated signaling. A 20-amino acid-long region from Thr(91) to Glu(110) within the extracellular region of TMED10 was found to be crucial for TMED 10 interaction with both ALK5 and T beta RII. Synthetic peptides corresponding to this region inhibit both TGF-beta-induced Smad2 phosphorylation and Smad-dependent transcriptional reporter activity. In a xenograft cancer model, where previously TGF-beta 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-beta receptor complex formation and signaling.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC , 2017. Vol. 292, no 10, 4099-4112 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-330065DOI: 10.1074/jbc.M116.769109ISI: 000404672500001PubMedID: 28115518OAI: oai:DiVA.org:uu-330065DiVA: diva2:1155861
Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2017-11-09Bibliographically approved

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ten Dijke, Peter

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