Furin extracellularly cleaves secreted PTEN alpha/beta to generate C-terminal fragment with a tumor-suppressive role

PTEN alpha and PTEN beta (PTEN alpha/beta), 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, PTEN alpha/beta 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 PTEN alpha/beta and their cleaved fragment cannot enter cells, treatment of the purified C-terminal fragment but not cleavage-resistant mutants of PTEN alpha exerts a tumor-suppressive role in vivo. As a result, overexpression of cleavage-resistant PTEN alpha mutants manifest a tumor-promoting role more profound than that of wild-type PTEN alpha. 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 PTEN alpha/beta present opposite effects on carcinogenesis from intracellular PTEN alpha/beta, and propose that the tumor-suppressive C-terminal fragment of PTEN alpha/beta might be used as exogenous agent to treat cancer.