title: GGA3 mediates TrkA endocytic recycling to promote sustained Akt phosphorylation and cell survival.
abstract: Although TrkA postendocytic sorting significantly influences neuronal cell survival and differentiation, the molecular mechanism underlying TrkA receptor sorting in the recycling or degradation pathways remains poorly understood. Here we demonstrate that Golgi-localized, γ adaptin-ear-containing ADP ribosylation factor-binding protein 3 (GGA3) interacts directly with the TrkA cytoplasmic tail through an internal DXXLL motif and mediates the functional recycling of TrkA to the plasma membrane. We find that GGA3 depletion by siRNA delays TrkA recycling, accelerates TrkA degradation, attenuates sustained NGF-induced Akt activation, and reduces cell survival. We also show that GGA3's effect on TrkA recycling is dependent on the activation of Arf6. This work identifies GGA3 as a key player in a novel DXXLL-mediated endosomal sorting machinery that targets TrkA to the plasma membrane, where it prolongs the activation of Akt signaling and survival responses.
authors.affiliation: Department of Pharmacology and Physiology, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
authors.affiliation: Department of Pharmacology and Physiology, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada Christine.L.Lavoie@USherbrooke.ca.
authors.forename: Christine
authors.initials: C
authors.lastname: Lavoie
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000089982:ADP-Ribosylation Factor 6; D033942:Adaptor Proteins, Vesicular Transport; C407306:GGA adaptor proteins; D020917:Receptor, trkA; D051058:Oncogene Protein v-akt; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715349:Arf6 protein, rat