Furin extracellularly cleaves secreted PTENα/β to generate C-terminal fragment with a tumor-suppressive role.

Autor: Zhang C; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China., Ma HM; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China., Dong SS; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China.; State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China., Zhang N; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China., He P; State Key Laboratory of Oncogenes and Related Genes, and Chinese Academy of Medical Sciences Research Unit (NO .2019RU043), Renji hospital, SJTU-SM, 200127, Shanghai, China., Ge MK; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China., Xia L; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China., Yu JX; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China., Xia Q; State Key Laboratory of Oncogenes and Related Genes, and Chinese Academy of Medical Sciences Research Unit (NO .2019RU043), Renji hospital, SJTU-SM, 200127, Shanghai, China., Chen GQ; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China. chengq@shsmu.edu.cn.; State Key Laboratory of Oncogenes and Related Genes, and Chinese Academy of Medical Sciences Research Unit (NO .2019RU043), Renji hospital, SJTU-SM, 200127, Shanghai, China. chengq@shsmu.edu.cn., Shen SM; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200025, Shanghai, China. smshen@shsmu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Jun 06; Vol. 13 (6), pp. 532. Date of Electronic Publication: 2022 Jun 06.
DOI: 10.1038/s41419-022-04988-2
Abstrakt: PTENα and PTENβ (PTENα/β), two long translational variants of phosphatase and tensin homolog on chromosome 10 (PTEN), exert distinct roles from canonical PTEN, including promoting carcinogenesis and accelerating immune-resistant cancer progression. However, their roles in carcinogenesis remain greatly unknown. Herein, we report that, after secreting into the extracellular space, PTENα/β proteins are efficiently cleaved into a short N-terminal and a long C-terminal fragment by the proprotein convertase Furin at a polyarginine stretch in their N-terminal extensions. Although secreted PTENα/β and their cleaved fragment cannot enter cells, treatment of the purified C-terminal fragment but not cleavage-resistant mutants of PTENα exerts a tumor-suppressive role in vivo. As a result, overexpression of cleavage-resistant PTENα mutants manifest a tumor-promoting role more profound than that of wild-type PTENα. In line with these, the C-terminal fragment is significantly downregulated in liver cancer tissues compared to paired normal tissues, which is consistent with the downregulated expression of Furin. Collectively, we show that extracellular PTENα/β present opposite effects on carcinogenesis from intracellular PTENα/β, and propose that the tumor-suppressive C-terminal fragment of PTENα/β might be used as exogenous agent to treat cancer.
(© 2022. The Author(s).)
Databáze: MEDLINE
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