Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex.
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.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Adaptor Protein Complex delta Subunits, Adaptor Proteins, Vesicular Transport, Adrenergic beta-Agonists, Arrestins, Carrier Proteins, Cell Membrane, Cells, Cultured, Clathrin, Cyclic AMP-Dependent Protein Kinases, Endocytosis, Eukaryotic Cells, Gene Expression, Humans, Isoproterenol, Membrane Proteins, PTEN Phosphohydrolase, Phosphatidylinositol Phosphates, Phosphoric Monoester Hydrolases, Protein Structure, Tertiary, Protein Transport, Receptors, Adrenergic, beta-2, Signal Transduction, Transfection, Transferrin, Tumor Suppressor Proteins, beta-Adrenergic Receptor Kinases
1-Phosphatidylinositol 3-Kinase, Adaptor Protein Complex delta Subunits, Adaptor Proteins, Vesicular Transport, Adrenergic beta-Agonists, Arrestins, Carrier Proteins, Cell Membrane, Cells, Cultured, Clathrin, Cyclic AMP-Dependent Protein Kinases, Endocytosis, Eukaryotic Cells, Gene Expression, Humans, Isoproterenol, Membrane Proteins, PTEN Phosphohydrolase, Phosphatidylinositol Phosphates, Phosphoric Monoester Hydrolases, Protein Structure, Tertiary, Protein Transport, Receptors, Adrenergic, beta-2, Signal Transduction, Transfection, Transferrin, Tumor Suppressor Proteins, beta-Adrenergic Receptor Kinases
J. Cell Biol.
Date: Aug. 05, 2002
PubMed ID: 12163475
View in: Pubmed Google Scholar
Download Curated Data For This Publication
10210
Switch View:
- Interactions 4