title: Phosphorylation of Src by phosphoinositide 3-kinase regulates beta-adrenergic receptor-mediated EGFR transactivation.
abstract: β2-Adrenergic receptors (β2AR) transactivate epidermal growth factor receptors (EGFR) through formation of a β2AR-EGFR complex that requires activation of Src to mediate signaling. Here, we show that both lipid and protein kinase activities of the bifunctional phosphoinositide 3-kinase (PI3K) enzyme are required for β2AR-stimulated EGFR transactivation. Mechanistically, the generation of phosphatidylinositol (3,4,5)-tris-phosphate (PIP3) by the lipid kinase function stabilizes β2AR-EGFR complexes while the protein kinase activity of PI3K regulates Src activation by direct phosphorylation. The protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation. This newly identified function for PI3K, whereby Src is a substrate for the protein kinase activity of PI3K, is of importance since Src plays a key role in pathological and physiological signaling.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Watson
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Alexander
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, United States.
authors.forename: Maradumane L
authors.initials: ML
authors.lastname: Mohan
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Bowman
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Thailand.
authors.forename: Supachoke
authors.initials: S
authors.lastname: Mangmool
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States; Department of Pharmacology and Chemical Biology, University of Pittsburg School of Medicine, Pittsburgh, PA 15261, United States.
authors.forename: Kunhong
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, United States. Electronic address: prasads2@ccf.org.
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: h.rockman@duke.edu.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000595:Amino Acid Sequence; D015374:Biosensing Techniques; D004705:Endocytosis / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D013058:Mass Spectrometry; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010768:Phosphoserine; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D007545:Isoproterenol
keywords: Adrenergic receptor; Epidermal growth factor receptor; Phosphatidylinositide 3-kinase; Phosphorylation; Src