Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Annu Rev Biochem. 2016 Jun 2;85:573-97. doi: 10.1146/annurev-biochem-060815-014659. Epub 2016 Mar 24.


Epidermal growth factor (EGF) and insulin receptor tyrosine kinases (RTKs) exemplify how receptor location is coupled to signal transduction. Extracellular binding of ligands to these RTKs triggers their concentration into vesicles that bud off from the cell surface to generate intracellular signaling endosomes. On the exposed cytosolic surface of these endosomes, RTK autophosphorylation selects the downstream signaling proteins and lipids to effect growth factor and polypeptide hormone action. This selection is followed by the recruitment of protein tyrosine phosphatases that inactivate the RTKs and deliver them by membrane fusion and fission to late endosomes. Coincidentally, proteinases inside the endosome cleave the EGF and insulin ligands. Subsequent inward budding of the endosomal membrane generates multivesicular endosomes. Fusion with lysosomes then results in RTK degradation and downregulation. Through the spatial positioning of RTKs in target cells for EGF and insulin action, the temporal extent of signaling, attenuation, and downregulation is regulated.

Keywords: EGF; insulin; ligand degradation; membrane trafficking; signaling endosome; signaling interactome.

Publication types

  • Review

MeSH terms

  • Cell Membrane / metabolism
  • Endocytosis
  • Endosomes / metabolism
  • Epidermal Growth Factor / genetics*
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Feedback, Physiological
  • Gene Expression Regulation*
  • Humans
  • Insulin / genetics*
  • Insulin / metabolism
  • Intracellular Membranes / metabolism
  • Phosphorylation
  • Protein Transport
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction*


  • Insulin
  • Epidermal Growth Factor
  • insulin receptor tyrosine kinase
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Protein Tyrosine Phosphatases