A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor

Nature. 1999 Sep 16;401(6750):286-90. doi: 10.1038/45816.


A fundamental question in cell biology is how membrane proteins are sorted in the endocytic pathway. The sorting of internalized beta2-adrenergic receptors between recycling endosomes and lysosomes is responsible for opposite effects on signal transduction and is regulated by physiological stimuli. Here we describe a mechanism that controls this sorting operation, which is mediated by a family of conserved protein-interaction modules called PDZ domains. The phosphoprotein EBP50 (for ezrinradixin-moesin(ERM)-binding phosphoprotein-50) binds to the cytoplasmic tail of the beta2-adrenergic receptor through a PDZ domain and to the cortical actin cytoskeleton through an ERM-binding domain. Disrupting the interaction of EBP50 with either domain or depolymerization of the actin cytoskeleton itself causes missorting of endocytosed beta2-adrenergic receptors but does not affect the recycling of transferrin receptors. A serine residue at position 411 in the tail of the beta2-adrenergic receptor is a substrate for phosphorylation by GRK-5 (for G-protein-coupled-receptor kinase-5) and is required for interaction with EBP50 and for proper recycling of the receptor. Our results identify a new role for PDZ-domain-mediated protein interactions and for the actin cytoskeleton in endocytic sorting, and suggest a mechanism by which GRK-mediated phosphorylation could regulate membrane trafficking of G-protein-coupled receptors after endocytosis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Adrenergic beta-Agonists / pharmacology
  • Binding Sites
  • Biotinylation
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cell Line
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Endosomes / metabolism*
  • Humans
  • Isoproterenol / pharmacology
  • Lysosomes / metabolism*
  • Molecular Sequence Data
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Recombinant Proteins / metabolism
  • Serine / metabolism
  • Sodium-Hydrogen Exchangers*
  • Thiazoles / pharmacology
  • Thiazolidines


  • Actins
  • Adrenergic beta-Agonists
  • Bridged Bicyclo Compounds, Heterocyclic
  • Carrier Proteins
  • Phosphoproteins
  • Receptors, Adrenergic, beta-2
  • Recombinant Proteins
  • Sodium-Hydrogen Exchangers
  • Thiazoles
  • Thiazolidines
  • sodium-hydrogen exchanger regulatory factor
  • Serine
  • Receptor Protein-Tyrosine Kinases
  • Isoproterenol
  • latrunculin B

Associated data

  • GENBANK/AF015926