Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex

J Cell Biol. 2002 Aug 5;158(3):563-75. doi: 10.1083/jcb.200202113. Epub 2002 Aug 5.


Internalization of beta-adrenergic receptors (betaARs) occurs by the sequential binding of beta-arrestin, the clathrin adaptor AP-2, and clathrin. D-3 phosphoinositides, generated by the action of phosphoinositide 3-kinase (PI3K) may regulate the endocytic process; however, the precise molecular mechanism is unknown. Here we demonstrate that betaARKinase1 directly interacts with the PIK domain of PI3K to form a cytosolic complex. Overexpression of the PIK domain displaces endogenous PI3K from betaARK1 and prevents betaARK1-mediated translocation of PI3K to activated beta2ARs. Furthermore, disruption of the betaARK1/PI3K interaction inhibits agonist-stimulated AP-2 adaptor protein recruitment to the beta2AR and receptor endocytosis without affecting the internalization of other clathrin dependent processes such as internalization of the transferrin receptor. In contrast, AP-2 recruitment is enhanced in the presence of D-3 phospholipids, and receptor internalization is blocked in presence of the specific phosphatidylinositol-3,4,5-trisphosphate lipid phosphatase PTEN. These findings provide a molecular mechanism for the agonist-dependent recruitment of PI3K to betaARs, and support a role for the localized generation of D-3 phosphoinositides in regulating the recruitment of the receptor/cargo to clathrin-coated pits.

Publication types

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

MeSH terms

  • Adaptor Protein Complex delta Subunits
  • Adaptor Proteins, Vesicular Transport
  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Agonists / pharmacology
  • Arrestins / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Membrane / enzymology*
  • Cell Membrane / ultrastructure
  • Cells, Cultured
  • Clathrin / metabolism
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Endocytosis / physiology*
  • Eukaryotic Cells / enzymology*
  • Eukaryotic Cells / ultrastructure
  • Gene Expression / physiology
  • Humans
  • Isoproterenol / pharmacology
  • Membrane Proteins / metabolism*
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol Phosphates / antagonists & inhibitors
  • Phosphatidylinositol Phosphates / biosynthesis
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Protein Structure, Tertiary / genetics
  • Protein Transport / physiology
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Signal Transduction / physiology
  • Transfection
  • Transferrin / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • beta-Adrenergic Receptor Kinases
  • beta-Arrestins


  • Adaptor Protein Complex delta Subunits
  • Adaptor Proteins, Vesicular Transport
  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Agonists
  • Arrestins
  • Carrier Proteins
  • Clathrin
  • Membrane Proteins
  • Phosphatidylinositol Phosphates
  • Receptors, Adrenergic, beta-2
  • Transferrin
  • Tumor Suppressor Proteins
  • beta-Arrestins
  • phosphatidylinositol 3,4,5-triphosphate
  • Phosphatidylinositol 3-Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Isoproterenol