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Sprouty2调控胶质母细胞瘤细胞中纤维母细胞生长因子受体1的内吞作用和降解

Sprouty2 Regulates Endocytosis and Degradation of Fibroblast Growth Factor Receptor 1 in Glioblastoma Cells.

作者信息

Hausott Barbara, Pircher Lena, Kind Michaela, Park Jong-Whi, Claus Peter, Obexer Petra, Klimaschewski Lars

机构信息

Institute of Neuroanatomy, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Institute of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany.

出版信息

Cells. 2024 Nov 28;13(23):1967. doi: 10.3390/cells13231967.

DOI:10.3390/cells13231967
PMID:39682716
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11639775/
Abstract

The Sprouty (SPRY) proteins are evolutionary conserved modulators of receptor tyrosine kinase (RTK) signaling. SPRY2 inhibits fibroblast growth factor (FGF) signaling, whereas it enhances epidermal growth factor (EGF) signaling through inhibition of EGF receptor (EGFR) endocytosis, ubiquitination, and degradation. In this study, we analyzed the effects of SPRY2 on endocytosis and degradation of FGF receptor 1 (FGFR1) using two human glioblastoma (GBM) cell lines with different endogenous SPRY2 levels. SPRY2 overexpression (SPRY2-OE) inhibited clathrin- and caveolae-mediated endocytosis of FGFR1, reduced the number of caveolin-1 vesicles and the uptake of transferrin. Furthermore, FGFR1 protein was decreased by SPRY2-OE, whereas EGFR protein was increased. SPRY2-OE enhanced FGFR1 degradation by increased c-casitas b-lineage lymphoma (c-CBL)-mediated ubiquitination, but it diminished binding of phospholipase Cγ1 (PLCγ1) to FGFR1. Consequently, SPRY2-OE inhibited FGF2-induced activation of PLCγ1, whereas it enhanced EGF-induced PLCγ1 activation. Despite the reduction of FGFR1 protein and the inhibition of FGF signaling, SPRY2-OE increased cell viability, and knockdown of SPRY2 enhanced the sensitivity to cisplatin. These results demonstrate that the inhibitory effect of SPRY2-OE on FGF signaling is at least in part due to the reduction in FGFR1 levels and the decreased binding of PLCγ1 to the receptor.

摘要

Sprouty（SPRY）蛋白是受体酪氨酸激酶（RTK）信号传导的进化保守调节因子。SPRY2抑制成纤维细胞生长因子（FGF）信号传导，而通过抑制表皮生长因子（EGF）受体（EGFR）的内吞作用、泛素化和降解来增强EGF信号传导。在本研究中，我们使用两种内源性SPRY2水平不同的人胶质母细胞瘤（GBM）细胞系，分析了SPRY2对FGF受体1（FGFR1）内吞作用和降解的影响。SPRY2过表达（SPRY2-OE）抑制了网格蛋白和小窝介导的FGFR1内吞作用，减少了小窝蛋白-1囊泡的数量和转铁蛋白的摄取。此外，SPRY2-OE使FGFR1蛋白减少，而EGFR蛋白增加。SPRY2-OE通过增加c-casitas b系淋巴瘤（c-CBL）介导的泛素化增强了FGFR1的降解，但减少了磷脂酶Cγ1（PLCγ1）与FGFR1的结合。因此，SPRY2-OE抑制了FGF2诱导的PLCγ1激活，而增强了EGF诱导的PLCγ1激活。尽管FGFR1蛋白减少且FGF信号传导受到抑制，但SPRY2-OE增加了细胞活力，而敲低SPRY2增强了对顺铂的敏感性。这些结果表明，SPRY2-OE对FGF信号传导的抑制作用至少部分归因于FGFR1水平的降低以及PLCγ1与受体结合的减少。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/668c/11639775/b0fab464dd7d/cells-13-01967-g012.jpg
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