Internalization of β-adrenergic receptors (βARs) occurs by the sequential binding of β-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 βARKinase1 directly interacts with the PIK domain of PI3K to form a cytosolic complex. Overexpression of the PIK domain displaces endogenous PI3K from βARK1 and prevents βARK1-mediated translocation of PI3K to activated β2ARs. Furthermore, disruption of the βARK1/PI3K interaction inhibits agonist-stimulated AP-2 adaptor protein recruitment to the β2AR 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 βARs, and support a role for the localized generation of D-3 phosphoinositides in regulating the recruitment of the receptor/cargo to clathrin-coated pits.
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5 August 2002
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August 05 2002
Phosphoinositide 3-kinase regulates β2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/β-arrestin complex
Sathyamangla V. Naga Prasad,
Sathyamangla V. Naga Prasad
1Department of Medicine, Duke University Medical Center, Durham, NC, 27710
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Stéphane A. Laporte,
Stéphane A. Laporte
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
3Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, 27710
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Dean Chamberlain,
Dean Chamberlain
1Department of Medicine, Duke University Medical Center, Durham, NC, 27710
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Marc G. Caron,
Marc G. Caron
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
3Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, 27710
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Larry Barak,
Larry Barak
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
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Howard A. Rockman
Howard A. Rockman
1Department of Medicine, Duke University Medical Center, Durham, NC, 27710
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
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Sathyamangla V. Naga Prasad
1Department of Medicine, Duke University Medical Center, Durham, NC, 27710
Stéphane A. Laporte
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
3Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, 27710
Dean Chamberlain
1Department of Medicine, Duke University Medical Center, Durham, NC, 27710
Marc G. Caron
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
3Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, 27710
Larry Barak
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
Howard A. Rockman
1Department of Medicine, Duke University Medical Center, Durham, NC, 27710
2Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
Address correspondence to Howard A. Rockman, Duke University Medical Center, DUMC 3104, Durham, NC 27710. Tel.: (919) 668-2521. Fax: (919) 668-2524. E-mail: [email protected]
Stéphane A. Laporte's present address is Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada, H3A 1A1.
*
Abbreviations used in this paper: βAR, β-adrenergic receptor; CYP, cyanopindolol; GPCR, G protein–coupled receptor; PI3K, phosphoinositide 3-kinase; PtdIns, phosphatidylinositol(s).
Received:
February 22 2002
Revision Received:
June 12 2002
Accepted:
June 12 2002
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2002
J Cell Biol (2002) 158 (3): 563–575.
Article history
Received:
February 22 2002
Revision Received:
June 12 2002
Accepted:
June 12 2002
Citation
Sathyamangla V. Naga Prasad, Stéphane A. Laporte, Dean Chamberlain, Marc G. Caron, Larry Barak, Howard A. Rockman; Phosphoinositide 3-kinase regulates β2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/β-arrestin complex . J Cell Biol 5 August 2002; 158 (3): 563–575. doi: https://doi.org/10.1083/jcb.200202113
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