Endophilin marks and controls a clathrin-independent endocytic pathway

Nature. 2015 Jan 22;517(7535):460-5. doi: 10.1038/nature14067. Epub 2014 Dec 17.

Abstract

Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. Here we show in mammalian cells that endophilin marks and controls a fast-acting tubulovesicular endocytic pathway that is independent of AP2 and clathrin, activated upon ligand binding to cargo receptors, inhibited by inhibitors of dynamin, Rac, phosphatidylinositol-3-OH kinase, PAK1 and actin polymerization, and activated upon Cdc42 inhibition. This pathway is prominent at the leading edges of cells where phosphatidylinositol-3,4-bisphosphate-produced by the dephosphorylation of phosphatidylinositol-3,4,5-triphosphate by SHIP1 and SHIP2-recruits lamellipodin, which in turn engages endophilin. This pathway mediates the ligand-triggered uptake of several G-protein-coupled receptors such as α2a- and β1-adrenergic, dopaminergic D3 and D4 receptors and muscarinic acetylcholine receptor 4, the receptor tyrosine kinases EGFR, HGFR, VEGFR, PDGFR, NGFR and IGF1R, as well as interleukin-2 receptor. We call this new endocytic route fast endophilin-mediated endocytosis (FEME).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Acyltransferases / metabolism*
  • Cell Line
  • Clathrin
  • Dynamins / metabolism
  • Endocytosis*
  • Humans
  • Ligands
  • Phosphatidylinositol Phosphates / metabolism
  • Pseudopodia / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Interleukin-2 / metabolism
  • Signal Transduction
  • Time Factors

Substances

  • Actins
  • Clathrin
  • Ligands
  • Phosphatidylinositol Phosphates
  • Receptors, G-Protein-Coupled
  • Receptors, Interleukin-2
  • phosphatidylinositol 3,4-diphosphate
  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase
  • Receptor Protein-Tyrosine Kinases
  • Dynamins