title: LRRK1-phosphorylated CLIP-170 regulates EGFR trafficking by recruiting p150Glued to microtubule plus ends.
abstract: 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.
authors.affiliation: Division of Biological Science, Graduate school of Science, Nagoya University, Nagoya 464-8602, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kedashiro
authors.affiliation: Division of Biological Science, Graduate school of Science, Nagoya University, Nagoya 464-8602, Japan.
authors.forename: Strahil Iv
authors.initials: SI
authors.lastname: Pastuhov
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nishioka
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: Division of Biological Science, Graduate school of Science, Nagoya University, Nagoya 464-8602, Japan g44177a@nucc.cc.nagoya-u.ac.jp g47371a@nucc.cc.nagoya-u.ac.jp.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Biological Science, Graduate school of Science, Nagoya University, Nagoya 464-8602, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hanafusa
mesh_terms: D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000235:genetics; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000606360:DCTN1 protein, human; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C076744:cytoplasmic linker protein 170; C512478:EGFR protein, human; D066246:ErbB Receptors; C510751:LRRK1 protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004398:Dyneins
keywords: CLIP-170; Dynein–dynactin; EGFR trafficking; LRRK1; Microtubule