GGA3 Functions as a Switch to Promote Met Receptor Recycling, Essential for Sustained ERK and Cell Migration

Dev Cell. 2011 Jun 14;20(6):751-63. doi: 10.1016/j.devcel.2011.05.007.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism
  • Adaptor Proteins, Vesicular Transport / antagonists & inhibitors
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Blotting, Western
  • COS Cells
  • Cell Membrane / metabolism
  • Cell Movement*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Endocytosis / physiology*
  • Endosomes
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Protein Transport
  • Proto-Oncogene Proteins c-crk / genetics
  • Proto-Oncogene Proteins c-crk / metabolism
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • rab4 GTP-Binding Proteins / genetics
  • rab4 GTP-Binding Proteins / metabolism

Substances

  • 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
  • ADP-ribosylation factor 6
  • rab4 GTP-Binding Proteins