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

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.

Functional Distinctions of Endometrial Cancer-Associated Mutations in the Fibroblast Growth Factor Receptor 2 Gene.

Functional analysis of somatic mutations in tumorigenesis facilitates the development and optimization of personalized therapy for cancer patients. The fibroblast growth factor receptor 2 (FGFR2) gene is frequently mutated in endometrial cancer (EC), but the functional implications of FGFR2 mutations in cancer development remain largely unexplored. In this study, we introduced a reliable and readily deployable screening method to investigate the effects of FGFR2 mutations. We demonstrated that distinct mutations in FGFR2 can lead to differential downstream consequences, specifically affecting a disintegrin- and metalloprotease 17 (ADAM17)-dependent shedding of the epidermal growth factor receptor (EGFR) ligand heparin-binding EGF-like growth factor (HB-EGF) and phosphorylation of mitogen-activated protein kinases (MAPKs). Furthermore, we showed that the distribution of mutations within the FGFR2 gene can influence their oncogenic effects. Together, these findings provide important insights into the complex nature of FGFR2 mutations and their potential implications for EC. By unraveling the distinct effects of different mutations, our study contributes to the identification of personalized treatment strategies for patients with FGFR2-mutated cancers. This knowledge has the potential to guide the development of targeted therapies that specifically address the underlying molecular alterations associated with FGFR2 mutations, ultimately improving patient outcomes in EC and potentially other cancer types characterized by FGFR2 mutations.