Members of the Fibroblast Growth Factor Receptor Superfamily Are Proteolytically Cleaved by Two Differently Activated Metalloproteases

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.

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

“…Consistent with the present findings, Taylor et al, reported a decrease in the protein level of FGFR4 in mice with CKD [37]. Cheng et al, reported a decrease in the expression of FGFRs in the kidneys in diabetic rats, which can be due to an increase in the presence of ADAM10/17 metalloproteinases, which have been recently proven to cleave FGFRs [38,39]. Chen et al, however, found no effect of Klotho on FGFR expression, like we did [38].…”

All Good Things Must End: Termination of Receptor Tyrosine Kinase Signal

“…Indeed, the soluble form of FGFR2 inhibited the FGF7-induced epithelial cell migration of HaCaT cells during wound healing assay. This effect was not induced when a catalytically inactive mutant of ADAM10 was expressed [83]. In support of this, extracellular soluble forms of FGFR1 in the adult retina regulated the bioavailability of FGF2, and in this case, the neurotrophic activity during neuronal degeneration was affected [84].…”

“…RTK cleavage determines the receptor downregulation as it decreases the number of full-length RTKs that can bind ligands and become activated. Recently, two interesting studies on the action of proteases on the cleavage of FGFRs have been published [82,83]. Dixit and colleagues proved that the presence of extracellular FGFR fragments can affect the function of ligand-induced FGFR signaling during cell movement.…”

A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis

“…These receptor tyrosine kinases have been implicated in various cellular processes, such as embryonic development and wound healing, but have also been associated with enhanced tumor survival, angiogenesis and metastases [3]. Interestingly, we found that the ectodomain shedding of FGFRs is mediated by two distinct members of the disintegrin and metalloprotease family, ADAM10 and ADAM17 [4].…”