CLIP‐170 spatially modulates receptor tyrosine kinase recycling to coordinate cell migration

Endocytic sorting of activated receptor tyrosine kinases (RTKs), alternating between recycling and degradative processes, controls signal duration, location and surface complement of RTKs. The microtubule (MT) plus‐end tracking proteins (+TIPs) play essential roles in various cellular activities inc...

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Bibliographic Details
Published in:Traffic (Copenhagen, Denmark) Denmark), 2019-03, Vol.20 (3), p.187-201
Main Authors: Zaoui, Kossay, Duhamel, Stephanie, Parachoniak, Christine A., Park, Morag
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - metabolism
c-Met protein
Cell adhesion & migration
Cell migration
Cell Movement
CLIP‐170
endocytosis
Endosomes
Endosomes - metabolism
Golgi apparatus
HEK293 Cells
HeLa Cells
Hepatocyte growth factor
Hepatocyte Growth Factor - metabolism
Humans
Internalization
Lamellipodia
Met
Microtubule-Associated Proteins - metabolism
Neoplasm Proteins - metabolism
Original
Protein Binding
Protein Transport
Protein-tyrosine kinase receptors
Proto-Oncogene Proteins c-met - metabolism
Pseudopodia
trafficking
Vesicles
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Summary:Endocytic sorting of activated receptor tyrosine kinases (RTKs), alternating between recycling and degradative processes, controls signal duration, location and surface complement of RTKs. The microtubule (MT) plus‐end tracking proteins (+TIPs) play essential roles in various cellular activities including translocation of intracellular cargo. However, mechanisms through which RTKs recycle back to the plasma membrane following internalization in response to ligand remain poorly understood. We report that net outward‐directed movement of endocytic vesicles containing the hepatocyte growth factor (HGF) Met RTK, requires recruitment of the +TIP, CLIP‐170, as well as the association of CLIP‐170 to MT plus‐ends. In response to HGF, entry of Met into Rab4‐positive endosomes results in Golgi‐localized γ‐ear‐containing Arf‐binding protein 3 (GGA3) and CLIP‐170 recruitment to an activated Met RTK complex. We conclude that CLIP‐170 co‐ordinates the recycling and the transport of Met‐positive endocytic vesicles to plus‐ends of MTs towards the cell cortex, including the plasma membrane and the lamellipodia, thereby promoting cell migration. The microtubules (MTs) provide tracks for long‐range intracellular transport, which requires the assistance of the MT plus‐end tracking proteins (+TIPs). Our study conclusively demonstrates that in response to HGF, the spatially restricted transport of the Met RTK to the cell cortex of migrating cells, occurs via an MT‐directed mechanism. We identified a novel interaction between the +TIP, CLIP‐170, and Met via the adaptor GGA3 and demonstrate that the CLIP‐170‐dependent regulation of Met vesicle transport to MT plus‐ends is required for HGF‐dependent cell migration.
ISSN:1398-9219
1600-0854
1600-0854
DOI:10.1111/tra.12629