Extended-synaptotagmin-2 mediates FGF receptor endocytosis and ERK activation in vivo.
Targeting of activated plasma membrane receptors to endocytic pathways is important in determining the outcome of growth factor signaling. However, the molecular mechanisms are still poorly understood. Here, we show that the synaptotagmin-related membrane protein E-Syt2 is essential for rapid endocytosis of the activated FGF receptor and for functional signal transduction during Xenopus development. E-Syt2 depletion prevents an early phase of activated FGF receptor endocytosis that we show is required for ERK activation and the induction of the mesoderm. E-Syt2 interacts selectively with the activated FGF receptor and with Adaptin-2, and is required upstream of Ras activation and of receptor autophosphorylation for ERK activation and the induction of the mesodermal marker Xbra. The data identify E-Syt2 as an endocytic adaptor for the clathrin-mediated pathway whose function is conserved in human and suggest a broader role for the E-Syt subfamily in growth factor signaling.
Jean
Steve
S
Cancer Research Centre and Department of Medical Biology, Medical Biochemistry and Pathology, Laval University, Hôtel-Dieu de Québec, 9 rue McMahon, G1R 2J6 Québec, Canada.
Mikryukov
Alexander
A
Tremblay
Michel G
MG
Baril
Joëlle
J
Guillou
François
F
Bellenfant
Sabrina
S
Moss
Tom
T
D033965:Adaptor Protein Complex alpha Subunits / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050861:Synaptotagmin II / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D033965:Adaptor Protein Complex alpha Subunits; D012333:RNA, Messenger; D050861:Synaptotagmin II; D020825:T-Box Domain Proteins; C116765:TBXT protein, Xenopus; D029867:Xenopus Proteins; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins