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.
Highlights
Fibroblast growth factor receptors, a family of high-affinity cell surface receptor tyrosine kinases (RTKs), are essential regulators of critical cellular processes such as cell proliferation and differentiation and have important roles in embryonic development and cancer [1,2,3]
Previous studies have shown that the extracellular domains of all four Fibroblast growth factor receptors (FGFRs) family members can be released through membrane-proximal cleavage, leading to generation of Cterminal fragments and soluble N-terminal fragments (NTFs) [15,16,30]
4 N-terminally fused to an alkaline phosphatase (AP) module, such that the AP module was present in the extracellular domains of the FGFRs and was released into the cell culture medium after shedding [23]
Summary
Fibroblast growth factor receptors, a family of high-affinity cell surface receptor tyrosine kinases (RTKs), are essential regulators of critical cellular processes such as cell proliferation and differentiation and have important roles in embryonic development and cancer [1,2,3].
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