Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Int J Mol Sci. 2021 Mar 20;22(6):3165. doi: 10.3390/ijms22063165.
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.
成纤维细胞生长因子受体 (FGFRs) 是受体酪氨酸激酶家族的成员，不仅与各种细胞过程有关，如胚胎发育和成人伤口愈合，而且还与增强的肿瘤存活、血管生成和转移扩散有关。这些单次跨膜受体的蛋白水解切割被认为可以调节其配体在生长和发育过程中的生物活性，但对于负责该过程的蛋白酶知之甚少。在这项研究中，我们在基于细胞的测定中监测了膜锚定 FGFR1、2、3 和 4 的释放。我们在这里证明，金属蛋白酶依赖性金属蛋白酶家族 ADAM10 和 ADAM17 负责该过程。在鼠胚胎成纤维细胞中的缺失和获得功能研究表明，FGFR1、3 和 4 的组成性脱落以及佛波醇酯诱导的处理均由 ADAM17 介导。相比之下，用钙离子载体离子霉素处理可刺激 ADAM10 介导的 FGFR2 脱落。存在或不存在可溶性 FGFR 时角质形成细胞的细胞迁移测定表明，外显子脱落可以调节配体诱导的 FGFR 信号在细胞运动过程中的功能。我们的数据确定了 ADAM10 和 ADAM17 作为差异调节的 FGFR 膜脱落酶，因此可能为 FGFR 功能的调节提供新的见解。
