Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya, Japan.
Mol Biol Cell. 2012 Apr;23(7):1294-306. doi: 10.1091/mbc.E11-09-0780. Epub 2012 Feb 15.
Ligand-induced activation of the epidermal growth factor receptor (EGFR) initiates trafficking events that relocalize the receptors from the cell surface to intracellular endocytic compartments. We recently reported that leucine-rich repeat kinase 1 (LRRK1) is involved in the trafficking of EGFR from early to late endosomes. In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity. Mutation of LRRK1 Tyr-944 (Y944F) abolishes EGF-stimulated tyrosine phosphorylation, resulting in hyperactivation of LRRK1 kinase activity and enhanced motility of EGF-containing endosomes toward the perinuclear region. The compartments in which EGFR accumulates are mixed endosomes and are defective in the proper formation of intraluminal vesicles of multivesicular bodies. These results suggest that feedback down-regulation of LRRK1 kinase activity by EGFR plays an important role in the appropriate endosomal trafficking of EGFR.
配体诱导的表皮生长因子受体（EGFR）的激活启动了运输事件，将受体从细胞表面重新定位到细胞内的内吞体隔室。我们最近报道，富含亮氨酸重复激酶 1（LRRK1）参与了 EGFR 从早期到晚期内体的运输。在这项研究中，我们证明 EGFR 通过酪氨酸磷酸化调节 LRRK1 的激酶活性，这对于 EGFR 的适当内体运输是必需的。LRRK1 的 Tyr-944 磷酸化导致 LRRK1 激酶活性降低。LRRK1 Tyr-944（Y944F）的突变消除了 EGF 刺激的酪氨酸磷酸化，导致 LRRK1 激酶活性的过度激活和含有 EGF 的内体向核周区域的运动增强。EGFR 积累的隔室是混合内体，并且在多泡体的腔内小泡的适当形成中存在缺陷。这些结果表明，EGFR 通过反馈下调 LRRK1 激酶活性在 EGFR 的适当的内体运输中发挥重要作用。
