Leucine-rich repeat kinase LRRK1 regulates endosomal trafficking of the EGF receptor.
Leucine-rich repeat kinase LRRK1 regulates endosomal trafficking of the EGF receptor.
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DOI：
10.1038/ncomms1161
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发表时间：
2011-01-18
影响因子：
16.6
通讯作者：
Matsumoto, Kunihiro
中科院分区：
文献类型：
--
作者：
Hanafusa, Hiroshi;Ishikawa, Kouki;Kedashiro, Shin;Saigo, Tsukasa;Iemura, Shun-ichiro;Natsume, Tohru;Komada, Masayuki;Shibuya, Hiroshi;Nara, Atsuki;Matsumoto, Kunihiro
表皮生长因子受体(EGFR)的激活不仅启动了包括MAPK(MAPK)通路在内的多种信号转导途径，而且还触发了将受体从细胞表面重新定位到细胞内间隔的转运事件。在这篇文章中，我们证明了富含亮氨酸的重复蛋白激酶LRRK1通过与Grb2的相互作用与激活的EGFR形成一个复合体，它含有一个类似MAPKKK的激动域。随后，LRRK1和表皮生长因子(EGF)被内化并共同定位于早期内吞体内。LRRK1调节EGFR从早期到晚期的转运，并以一种依赖于其激酶活性的方式调节含有EGF的早期内吞体内的运动。此外，LRRK1作为一种支架促进了EGFR与运输-0复合体所需的内体分选复合体的相互作用，从而使EGFR能够有效地分选到多囊泡体的内部小泡。我们的发现提供了第一个证据，证明MAPKKK样蛋白调节EGFR的内体运输。表皮生长因子受体的激活可导致其内化和随后的细胞内转运。在这项研究中，作者证明了富含亮氨酸的重复蛋白激酶-1可以与受体结合，并调节其在不同的内体隔室之间的转运。
Activation of the epidermal growth factor receptor (EGFR) not only initiates multiple signal-transduction pathways, including the MAP kinase (MAPK) pathway, but also triggers trafficking events that relocalize receptors from the cell surface to intracellular endocytic compartments. In this paper, we demonstrate that leucine-rich repeat kinase LRRK1, which contains a MAPKKK-like kinase domain, forms a complex with activated EGFR through an interaction with Grb2. Subsequently, LRRK1 and epidermal growth factor (EGF) are internalized and co-localized in early endosomes. LRRK1 regulates EGFR transport from early to late endosomes and regulates the motility of EGF-containing early endosomes in a manner dependent on its kinase activity. Furthermore, LRRK1 serves as a scaffold facilitating the interaction of EGFR with the endosomal sorting complex required for transport-0 complex, thus enabling efficient sorting of EGFR to the inner vesicles of multivesicular bodies. Our findings provide the first evidence that a MAPKKK-like protein regulates the endosomal trafficking of EGFR. Activation of the epidermal growth factor receptor can result in its internalization and subsequent intracellular trafficking. In this study, the authors show that leucine-rich repeat kinase-1 can bind to the receptor and regulate its trafficking between different endosomal compartments.
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