TMEPAI inhibits TGF-β signaling by promoting lysosome degradation of TGF-β receptor and contributes to lung cancer development

Xilong Bai; Lei Jing; Yinchuan Li; Yuyin Li; Shenheng Luo; Shasha Wang; Jie Zhou; Zhe Liu; Aipo Diao

doi:10.1016/j.cellsig.2014.06.001

TMEPAI inhibits TGF-β signaling by promoting lysosome degradation of TGF-β receptor and contributes to lung cancer development

Cell Signal. 2014 Sep;26(9):2030-9. doi: 10.1016/j.cellsig.2014.06.001. Epub 2014 Jun 13.

Authors

Xilong Bai¹, Lei Jing¹, Yinchuan Li¹, Yuyin Li¹, Shenheng Luo¹, Shasha Wang¹, Jie Zhou¹, Zhe Liu², Aipo Diao³

Affiliations

¹ School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin 300457, China.
² School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
³ 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.

PMID: 24933703
DOI: 10.1016/j.cellsig.2014.06.001

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.

Keywords: Lung cancer; Lysosome; TGF-β receptor; TGF-β signaling; TMEPAI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
Disease Progression
Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
Endosomal Sorting Complexes Required for Transport / genetics
Endosomal Sorting Complexes Required for Transport / metabolism
Endosomes / metabolism
HEK293 Cells
Humans
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Lysosomes / metabolism*
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Nude
Nedd4 Ubiquitin Protein Ligases
RNA Interference
RNA, Small Interfering / metabolism
Receptors, Transforming Growth Factor beta / metabolism*
Signal Transduction
Transforming Growth Factor beta / metabolism*
Transplantation, Heterologous
Ubiquitin-Protein Ligases / antagonists & inhibitors
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

Endosomal Sorting Complexes Required for Transport
Membrane Proteins
PMEPA1 protein, human
RNA, Small Interfering
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta
Nedd4 Ubiquitin Protein Ligases
Nedd4 protein, human
Nedd4l protein, mouse
Ubiquitin-Protein Ligases