Molecular Biology Institute, Jonsson Comprehensive Cancer Center and Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
J Cell Sci. 2012 Dec 1;125(Pt 23):5887-96. doi: 10.1242/jcs.113688. Epub 2012 Sep 12.
Stimulation of epidermal growth factor receptor (EGFR) initiates RAS signaling simultaneously with EGFR internalization. Endocytosed EGFR is then either recycled or degraded. EGFR fate is determined in part by the RAS effector RIN1, a guanine nucleotide exchange factor (GEF) for RAB5 GTPases. EGFR degradation was slowed by RIN1 silencing, enhanced by RIN1 overexpression and accelerated by RIN1 localization to the plasma membrane. RIN1 also directly activates ABL tyrosine kinases, which regulate actin remodeling, a function not previously connected to endocytosis. We report that RIN1-RAB5 signaling favors EGFR downregulation over EGFR recycling, whereas RIN1-ABL signaling stabilizes EGFR and inhibits macropinocytosis. RIN1(QM), a mutant that blocks ABL activation, caused EGF-stimulated membrane ruffling, actin remodeling, dextran uptake and EGFR degradation. An ABL kinase inhibitor phenocopied these effects in cells overexpressing RIN1. EGFR activation also promotes RIN1 interaction with BIN1, a membrane bending protein. These findings suggest that RIN1 orchestrates RAB5 activation, ABL kinase activation and BIN1 recruitment to determine EGFR fate.
表皮生长因子受体 (EGFR) 的刺激会同时启动 RAS 信号转导和 EGFR 内化。内化的 EGFR 随后被回收或降解。EGFR 的命运部分取决于 RAS 效应子 RIN1，它是 RAB5 GTPases 的鸟嘌呤核苷酸交换因子 (GEF)。RIN1 的沉默会减缓 EGFR 的降解，过表达 RIN1 会增强其降解，而 RIN1 定位于质膜会加速其降解。RIN1 还直接激活 ABL 酪氨酸激酶，调节肌动蛋白重塑，这一功能以前与内吞作用无关。我们报告称，RIN1-RAB5 信号通路有利于 EGFR 的下调，而不是 EGFR 的回收，而 RIN1-ABL 信号通路稳定 EGFR 并抑制巨胞饮作用。一种阻断 ABL 激活的 RIN1(QM)突变体可引起 EGF 刺激的细胞膜皱襞、肌动蛋白重塑、葡聚糖摄取和 EGFR 降解。在过表达 RIN1 的细胞中，ABL 激酶抑制剂可模拟这些效应。EGFR 的激活还促进了 RIN1 与 BIN1 的相互作用，BIN1 是一种膜弯曲蛋白。这些发现表明，RIN1 协调 RAB5 的激活、ABL 激酶的激活和 BIN1 的募集，以决定 EGFR 的命运。
