LRRK1-phosphorylated CLIP-170 regulates EGFR trafficking by recruiting p150Glued to microtubule plus ends
LRRK1-phosphorylated CLIP-170 regulates EGFR trafficking by recruiting p150Glued to microtubule plus ends
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DOI：
10.1242/jcs.161547
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发表时间：
2015-01-15
影响因子：
4
通讯作者：
Hanafusa, Hiroshi
中科院分区：
文献类型：
--
作者：
Kedashiro, Shin;Pastuhov, Strahil Iv.;Hanafusa, Hiroshi
配体与表皮生长因子受体（EGFR）结合，使表皮生长因子受体被激活，并刺激表皮生长因子受体的内吞作用。含有活化EGFR的早期核内体在成熟为晚期核内体时沿微管迁移。我们最近的研究表明，与家族性帕金森病基因产物Park8（也称为LRRK2）相关的LRRK1以依赖于LRRK1激酶活性的方式调节EGFR的运输。然而，可能调节这种转运功能的LRRK1下游靶点尚未被确定。在这里，我们确定了CLIP-170（也称为CLIP1），一种微管正端蛋白，作为LRRK1的底物。LRRK1磷酸化CLIP-170 c端锌关节基元Thr1384位点，这促进了CLIP-170与dynein-dynactin复合物的关联。我们发现lrrk1介导的CLIP-170磷酸化导致p150(glue)（也称为DCTN1）一个动力蛋白亚基在微管+端积累，从而促进含有egfr的核内体的迁移。因此，我们的研究结果为动力蛋白驱动的EGFR转运提供了新的机制见解。
The binding of ligand to epidermal growth factor receptor (EGFR) causes the receptor to become activated and stimulates the endocytosis of EGFR. Early endosomes containing activated EGFR migrate along microtubules as they mature into late endosomes. We have recently shown that LRRK1, which is related to the familial Parkinsonism gene product Park8 (also known as LRRK2), regulates this EGFR transport in a manner dependent on LRRK1 kinase activity. However, the downstream targets of LRRK1 that might modulate this transport function have not been identified. Here, we identify CLIP-170 (also known as CLIP1), a microtubule plus-end protein, as a substrate of LRRK1. LRRK1 phosphorylates CLIP-170 at Thr1384, located in its C-terminal zinc knuckle motif, and this promotes the association of CLIP-170 with dynein-dynactin complexes. We find that LRRK1-mediated phosphorylation of CLIP-170 causes the accumulation of p150(Glued) (also known as DCTN1) a subunit of dynactin, at microtubule plus ends, thereby facilitating the migration of EGFR-containing endosomes. Thus, our findings provide new mechanistic insights into the dynein-driven transport of EGFR.