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. [Display omitted] ► Synaptotagmin-related E-Syt2 is essential for the induction of mesoderm by FGF ► E-Syt2 mediates rapid clathrin-dependent endocytosis of activated FGF receptor (FGFR) ► Rapid FGFR endocytosis is necessary for ERK activation and functional signaling ► E-Syt2 selectively binds active FGFR1–4 and Adaptin-2 to catalyze rapid endocytosis