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Published 5 August 2002. doi:10.1083/jcb.200202113
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© The Rockefeller University Press, 0021-9525/2002/8/563 $5.00
The Journal of Cell Biology, Volume 158, Number 3, August 5, 2002 563-575

Article

Phosphoinositide 3-kinase regulates ß2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/ß-arrestin complex



Sathyamangla V. Naga Prasad1, Stéphane A. Laporte2,3, Dean Chamberlain1, Marc G. Caron2,3, Larry Barak2 and Howard A. Rockman1,2

1 Department of Medicine, Duke University Medical Center, Durham, NC, 27710
2 Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710
3 Howard Hughes Medical Institute, 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: h.rockman{at}duke.edu

Internalization of ß-adrenergic receptors (ßARs) occurs by the sequential binding of ß-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 ßARKinase1 directly interacts with the PIK domain of PI3K to form a cytosolic complex. Overexpression of the PIK domain displaces endogenous PI3K from ßARK1 and prevents ßARK1-mediated translocation of PI3K to activated ß2ARs. Furthermore, disruption of the ßARK1/PI3K interaction inhibits agonist-stimulated AP-2 adaptor protein recruitment to the ß2AR 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 ßARs, and support a role for the localized generation of D-3 phosphoinositides in regulating the recruitment of the receptor/cargo to clathrin-coated pits.

Key Words: phosphatidylinositols; phosphoinositide 3-kinase; AP-2; ß-adrenergic receptor; endocytosis


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