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Members of the Fibroblast Growth Factor Receptor Superfamily Are Proteolytically Cleaved by Two Differently Activated Metalloproteases
Authors:Garima Dixit  Willow Schanz  Benjamin A. Pappas  Thorsten Maretzky
Affiliation:1.Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (G.D.); (W.S.); (B.A.P.);2.Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;3.Immunology Graduate Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;4.Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
Abstract:Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that have been associated not only with various cellular processes, such as embryonic development and adult wound healing but also enhanced tumor survival, angiogenesis, and metastatic spread. Proteolytic cleavage of these single-pass transmembrane receptors has been suggested to regulate biological activities of their ligands during growth and development, yet little is known about the proteases responsible for this process. In this study, we monitored the release of membrane-anchored FGFRs 1, 2, 3, and 4 in cell-based assays. We demonstrate here that metalloprotease-dependent metalloprotease family, ADAM10 and ADAM17. Loss- and gain-of-function studies in murine embryonic fibroblasts showed that constitutive shedding as well as phorbol-ester-induced processing of FGFRs 1, 3, and 4 is mediated by ADAM17. In contrast, treatment with the calcium ionophore ionomycin stimulated ADAM10-mediated FGFR2 shedding. Cell migration assays with keratinocytes in the presence or absence of soluble FGFRs suggest that ectodomain shedding can modulate the function of ligand-induced FGFR signaling during cell movement. Our data identify ADAM10 and ADAM17 as differentially regulated FGFR membrane sheddases and may therefore provide new insight into the regulation of FGFR functions.
Keywords:a disintegrin and metalloprotease 10 (ADAM10)   a disintegrin and metalloprotease 17 (ADAM17)   fibroblast growth factor receptor (FGFR)   epidermal growth factor receptor (EGFR)   receptor tyrosine kinase (RTK)
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