Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding

Article

关键词: NECROSIS-FACTOR-ALPHA;    PROSTATE-CANCER CELLS;    SECRETORY PHENOTYPE;    CELLULAR SENESCENCE;    DNA-DAMAGE;    CONVERTING ENZYME;    HUMAN FIBROBLASTS;    FACTOR RECEPTOR;    GROWTH-FACTOR;    TUMOR;   

DOI  :  10.1096/fj.14-254565

来源: SCIE

【 摘 要 】

Cellular senescence, a state of persistent cell cycle arrest, has emerged as a potent tumor suppressor mechanism by restricting proliferation of cells at risk for neoplastic transformation. Senescent cells secrete various growth factors, cytokines, and other proteins that can either elicit the clearance of tumor cells or potentially promote tumor progression. In addition, this senescence-associated secretory phenotype (SASP) includes various factors that are synthesized as transmembrane precursors and subsequently converted into their soluble counterparts. Despite the importance of the SASP to tumor biology, it is virtually unknown how transmembrane proteins are released from senescent cancer cells. Here we show in different models of senescence that the metalloprotease A disintegrin and metalloproteinase 17 (ADAM17) is activated and releases the epidermal growth factor receptor ligand amphiregulin and tumor necrosis factor receptor I (TNFRI) from the surface of senescent cells by ectodomain shedding. ADAM17 activation involves phosphorylation of its cytoplasmic tail by mitogen-activated protein kinase (MAPK) p38. Interestingly, unlike amphiregulin and TNFRI, full-length intercellular adhesion molecule 1 (ICAM1) is released from senescent cells by microvesicles independently of ADAM17. Thus, our results suggest that transmembrane proteins can be released by two distinct mechanisms and point to a crucial role for ADAM17 in shaping the secretory profile of senescent cells.Effenberger, T., von der Heyde, J., Bartsch, K., Garbers, C., Schulze-Osthoff, K., Chalaris, A., Murphy, G., Rose-John, S., Rabe, B. Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding.

【 授权许可】

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