Endosomal Type Iγ PIP 5-kinase Controls EGF Receptor Lysosomal Sorting

Dev Cell. 2013 Apr 29;25(2):144-55. doi: 10.1016/j.devcel.2013.03.010. Epub 2013 Apr 18.

Abstract

Endosomal trafficking and degradation of epidermal growth factor receptor (EGFR) play an essential role in the control of its signaling. Phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P(2)) is an established regulator of endocytosis, whereas PtdIns3P modulates endosomal trafficking. However, we demonstrate here that type I gamma phosphatidylinositol phosphate 5-kinase i5 (PIPKIγi5), an enzyme that synthesizes PtdIns4,5P(2), controls endosome-to-lysosome sorting of EGFR. In this pathway, PIPKIγi5 interacts with sorting nexin 5 (SNX5), a protein that binds PtdIns4,5P(2) and other phosphoinositides. PIPKIγi5 and SNX5 localize to endosomes, and loss of either protein blocks EGFR sorting into intraluminal vesicles (ILVs) of the multivesicular body. Loss of ILV sorting greatly enhances and prolongs EGFR signaling. PIPKIγi5 and SNX5 prevent Hrs ubiquitination, and this facilitates the Hrs association with EGFR that is required for ILV sorting. These findings reveal that PIPKIγi5 and SNX5 form a signaling nexus that controls EGFR endosomal sorting, degradation, and signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Endocytosis / physiology
  • Endosomes / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Lysosomes / metabolism*
  • Molecular Sequence Data
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Binding
  • Protein Transport
  • Proteolysis
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Sorting Nexins / genetics
  • Sorting Nexins / metabolism*
  • Tumor Cells, Cultured
  • Two-Hybrid System Techniques
  • Ubiquitination

Substances

  • Phosphatidylinositol 4,5-Diphosphate
  • RNA, Small Interfering
  • SNX5 protein, human
  • Sorting Nexins
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • EGFR protein, human
  • ErbB Receptors