Phosphorylation of CLIP-170 by LRRK1 regulates EGFR trafficking by promoting recruitment of p150Glued to MT plus-ends

Abstract

Ligand-induced activation of the EGF receptor (EGFR) initiates trafficking events that relocalize the receptors from the cell surface to intracellular endocytic compartments. 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/LRRK2, regulates this EGFR transport in a manner dependent on LRRK1 kinase activity. However, the downstream targets of LRRK1 that may modulate this transport function have not been identified. Here, we identify CLIP-170, a microtubule plus-end protein, as a substrate of LRRK1. LRRK1 phosphorylates CLIP-170 at Thr-1384, located in its C-terminal zinc knuckle motif, and this promotes its association with dynactin–dynein complexes. We find that LRRK1 phosphorylation of CLIP-170 causes the accumulation of p150Glued, 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.