title: Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding.
abstract: 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.
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany;
authors: Timo
authors: T
authors: Effenberger
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany;
authors: Jan
authors: J
authors: von der Heyde
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany;
authors: Kareen
authors: K
authors: Bartsch
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany;
authors: Christoph
authors: C
authors: Garbers
authors: Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany, German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany; and.
authors: Klaus
authors: K
authors: Schulze-Osthoff
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany;
authors: Athena
authors: A
authors: Chalaris
authors: Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Gillian
authors: G
authors: Murphy
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany;
authors: Stefan
authors: S
authors: Rose-John
authors: Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany; brabe@biochem.uni-kiel.de.
authors: Björn
authors: B
authors: Rabe
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D002478:Cells, Cultured; D016922:Cellular Senescence; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism*; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ICAM-1; SASP; TNFRI; exosomes; p38