YWK-II/APLP2 inhibits TGF-β signaling by interfering with the TGFBR2-Hsp90 interaction

Amannisa Tuersuntuoheti; Qinshan Li; Yu Teng; Xiaolu Li; Rong Huang; Yan Lu; Kai Li; Junbo Liang; Shiying Miao; Wei Wu; Wei Song

doi:10.1016/j.bbamcr.2023.119548

YWK-II/APLP2 inhibits TGF-β signaling by interfering with the TGFBR2-Hsp90 interaction

Biochim Biophys Acta Mol Cell Res. 2023 Oct;1870(7):119548. doi: 10.1016/j.bbamcr.2023.119548. Epub 2023 Jul 20.

Authors

Amannisa Tuersuntuoheti¹, Qinshan Li², Yu Teng¹, Xiaolu Li¹, Rong Huang¹, Yan Lu¹, Kai Li¹, Junbo Liang¹, Shiying Miao¹, Wei Wu³, Wei Song⁴

Affiliations

¹ Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
² Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, China; Department of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical University, Guiyang 550004, Guizhou, China.
³ Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: barzey2004@hotmail.com.
⁴ Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: songwei@ibms.pumc.edu.cn.

PMID: 37479189
DOI: 10.1016/j.bbamcr.2023.119548

Abstract

Transforming growth factor-β (TGF-β) regulates multiple cellular biological processes by activating TGF-β type I receptors (TGFBR1) and type II receptors (TGFBR2), and Hsp90 stabilizes these receptors through specific interactions. In many malignancies, one of the most deregulated signaling pathways is the TGF-β signaling pathway, which is often inactivated by mutations or deregulation of TGF-β type II receptors (TGFBR2). However, the molecular mechanisms are not well understood. In this study, we show that YWK-II/APLP2, an immediately early response gene for TGF-β signaling, inhibits TGF-β signaling by promoting the degradation of the TGFBR2 protein. Knockdown of YWK-II/APLP2 increases the TGFBR2 protein level and sensitizes cells to TGF-β stimulation, while YWK-II/APLP2 overexpression destabilizes TGFBR2 and desensitizes cells to TGF-β. Mechanistically, YWK-II/APLP2 is associated with TGFBR2 in a TGF-β activity-dependent manner, binds to Hsp90 to interfere with the interaction between TGFBR2 and Hsp90, and leads to enhanced ubiquitination and degradation of TGFBR2. Taken together, YWK-II/APLP2 is involved in negatively regulating the duration and intensity of TGF-β/Smad signaling and suggests that aberrantly high expression of YWK-II/APLP2 in malignancies may antagonize the growth inhibition mediated by TGF-β signaling and play a role in carcinogenesis.

Keywords: Hsp90; Receptor degradation; TGF-β signaling; TGFBR2; YWK-II/APLP2.