Hanafusa Hiroshi, Ishikawa Kouki, Kedashiro Shin, Saigo Tsukasa, Iemura Shun-Ichiro, Natsume Tohru, Komada Masayuki, Shibuya Hiroshi, Nara Atsuki, Matsumoto Kunihiro
Department of Molecular Biology, Graduate school of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
Nat Commun. 2011 Jan 18;2:158. doi: 10.1038/ncomms1161.
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.
表皮生长因子受体（EGFR）的激活不仅会启动多种信号转导途径，包括丝裂原活化蛋白激酶（MAPK）途径，还会引发运输事件，使受体从细胞表面重新定位到细胞内的内吞小室。在本文中，我们证明富含亮氨酸重复序列的激酶LRRK1（其含有类MAPKKK激酶结构域）通过与Grb2相互作用，与活化的EGFR形成复合物。随后，LRRK1和表皮生长因子（EGF）被内化并共定位于早期内体中。LRRK1以依赖其激酶活性的方式调节EGFR从早期内体到晚期内体的运输，并调节含EGF的早期内体的运动性。此外，LRRK1作为一种支架，促进EGFR与运输所需的内体分选复合物-0复合物的相互作用，从而使EGFR能够有效地分选到多囊泡体的内囊泡中。我们的研究结果首次证明了一种类MAPKKK蛋白调节EGFR的内体运输。
