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PMID: 21664574 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

GGA3 functions as a switch to promote Met receptor recycling, essential for sustained ERK and cell migration.

Developmental cell ·Vol. 20 ·No. 6 ·2011-06-14 ·Pages 751-63

Parachoniak CA, Luo Y, Abella JV, Keen JH, Park M

Abstract

Cells are dependent on correct sorting of activated receptor tyrosine kinases (RTKs) for the outcome of growth factor signaling. Upon activation, RTKs are coupled through the endocytic machinery for degradation or recycled to the cell surface. However, the molecular mechanisms governing RTK recycling are poorly understood. Here, we show that Golgi-localized gamma ear-containing Arf-binding protein 3 (GGA3) interacts selectively with the Met/hepatocyte growth factor RTK when stimulated, to sort it for recycling in association with "gyrating" clathrin. GGA3 loss abrogates Met recycling from a Rab4 endosomal subdomain, resulting in pronounced trafficking of Met toward degradation. Decreased Met recycling attenuates ERK activation and cell migration. Met recycling, sustained ERK activation, and migration require interaction of GGA3 with Arf6 and an unexpected association with the Crk adaptor. The data show that GGA3 defines an active recycling pathway and support a broader role for GGA3-mediated cargo selection in targeting receptors destined for recycling.

MeSH Terms
ADP-Ribosylation Factor 6 ADP-Ribosylation Factors/genetics,metabolism Adaptor Proteins, Vesicular Transport/antagonists & inhibitors,genetics,metabolism Animals Blotting, Western COS Cells Cell Membrane/metabolism Cell Movement Cells, Cultured Chlorocebus aethiops Endocytosis/physiology Endosomes Extracellular Signal-Regulated MAP Kinases/genetics,metabolism Humans Protein Transport Proto-Oncogene Proteins c-crk/genetics,metabolism Proto-Oncogene Proteins c-met/genetics,metabolism RNA, Messenger/genetics RNA, Small Interfering/genetics Reverse Transcriptase Polymerase Chain Reaction Signal Transduction rab4 GTP-Binding Proteins/genetics,metabolism
Chemicals
ADP-Ribosylation Factor 6 Adaptor Proteins, Vesicular Transport CRK protein, human GGA adaptor proteins Proto-Oncogene Proteins c-crk RNA, Messenger RNA, Small Interfering Proto-Oncogene Proteins c-met Extracellular Signal-Regulated MAP Kinases ADP-Ribosylation Factors ARF6 protein, human rab4 GTP-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Parachoniak Christine Anna
Department of Biochemistry, McGill University, Montreal, Canada.
Luo Yi
Abella Jasmine Vanessa
Keen James H
Park Morag
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Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1878-1551
DOI
10.1016/j.devcel.2011.05.007
Published
2011-06-14
Pages
751-63
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC3115551
Subset
IM
Grants
CIHR · 106635 · Canada
NIGMS NIH HHS · R01 GM049217 · United States
NIGMS NIH HHS · R01 GM049217-15 · United States
NIGMS NIH HHS · GM-49217 · United States
CIHR · MOP-11545 · Canada
External Links
PubMed source DOI: 10.1016/j.devcel.2011.05.007 PMC Full Text View journal details
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