title: TMEPAI inhibits TGF-β signaling by promoting lysosome degradation of TGF-β receptor and contributes to lung cancer development.
abstract: Transforming growth factor-β (TGF-β) signaling plays important roles in embryogenesis and tumorigenesis by controlling cell growth, differentiation and migration. The transmembrane prostate androgen-induced protein (TMEPAI) is elevated in several cancers. TMEPAI expression is induced by TGF-β signaling, and in turn, expression of TMEPAI negatively regulates TGF-β signaling, but the molecular mechanisms of TMEPAI induced TGF-β signaling inhibition are not well understood. Here we report that TMEPAI is localized to the lysosome and late endosome, and that association of TMEPAI with the E3 ubiquitin ligase Nedd4 is required for its transport to the lysosome. TMEPAI associates with the TGF-β type I receptor (TβRI) and promotes its degradation in the lysosome. Depletion of TMEPAI in A549 lung cancer cells inhibits cell proliferation, migration and invasion, while TMEPAI expression in nude mice promotes tumorigenesis. These results reveal a novel function for TMEPAI in regulating TGF-β signaling through the modulation of TβRI levels, which has important implications for cancer development in vivo.
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
authors.forename: Xilong
authors.initials: X
authors.lastname: Bai
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jing
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
authors.forename: Yinchuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
authors.forename: Yuyin
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
authors.forename: Shenheng
authors.initials: S
authors.lastname: Luo
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China. Electronic address: diaoaipo@tust.edu.cn.
authors.forename: Aipo
authors.initials: A
authors.lastname: Diao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000075702:Nedd4 Ubiquitin Protein Ligases; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; C412868:PMEPA1 protein, human; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Lung cancer; Lysosome; TGF-β receptor; TGF-β signaling; TMEPAI