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

SummaryCells 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.

Graphical AbstractFigure optionsDownload high-quality image (255 K)Download as PowerPoint slideHighlights
► GGA3 is a recycling adaptor for the Met receptor tyrosine kinase (RTK)
► Met RTK is sorted in GGA3-Rab4-positive endosomal compartments
► Crk and Arf6 complex with GGA3 and are required for GGA3-mediated Met recycling
► GGA3 knockdown increases Met degradation, attenuating ERK and cell migration