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G protein beta gamma subunits stimulate phosphorylation of Shc adapter protein.

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Date
1995-09-26
Authors
Touhara, K
Hawes, BE
van Biesen, T
Lefkowitz, RJ
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Abstract
The mechanism of mitogen-activated protein (MAP) kinase activation by pertussis toxin-sensitive Gi-coupled receptors is known to involve the beta gamma subunits of heterotrimeric G proteins (G beta gamma), p21ras activation, and an as-yet-unidentified tyrosine kinase. To investigate the mechanism of G beta gamma-stimulated p21ras activation, G beta gamma-mediated tyrosine phosphorylation was examined by overexpressing G beta gamma or alpha 2-C10 adrenergic receptors (ARs) that couple to Gi in COS-7 cells. Immunoprecipitation of phosphotyrosine-containing proteins revealed a 2- to 3-fold increase in the phosphorylation of two proteins of approximately 50 kDa (designated as p52) in G beta gamma-transfected cells or in alpha 2-C10 AR-transfected cells stimulated with the agonist UK-14304. The latter response was pertussis toxin sensitive. These proteins (p52) were also specifically immunoprecipitated with anti-Shc antibodies and comigrated with two Shc proteins, 46 and 52 kDa. The G beta gamma- or alpha 2-C10 AR-stimulated p52 (Shc) phosphorylation was inhibited by coexpression of the carboxyl terminus of beta-adrenergic receptor kinase (a G beta gamma-binding pleckstrin homology domain peptide) or by the tyrosine kinase inhibitors genistein and herbimycin A, but not by a dominant negative mutant of p21ras. Worthmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) inhibited phosphorylation of p52 (Shc), implying involvement of PI3K. These results suggest that G beta gamma-stimulated Shc phosphorylation represents an early step in the pathway leading to p21ras activation, similar to the mechanism utilized by growth factor tyrosine kinase receptors.
Type
Journal article
Subject
Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Androstadienes
Animals
Benzoquinones
Calcium-Calmodulin-Dependent Protein Kinases
Cell Line
Cercopithecus aethiops
Enzyme Activation
Enzyme Inhibitors
GTP-Binding Proteins
Genistein
Humans
Isoflavones
Kidney
Kinetics
Lactams, Macrocyclic
Macromolecular Substances
Pertussis Toxin
Phosphates
Phosphatidylinositol 3-Kinases
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor)
Protein-Tyrosine Kinases
Proteins
Proto-Oncogene Proteins p21(ras)
Quinones
Receptors, Adrenergic, alpha-2
Recombinant Proteins
Rifabutin
Shc Signaling Adaptor Proteins
Src Homology 2 Domain-Containing, Transforming Protein 1
Tetradecanoylphorbol Acetate
Transfection
Virulence Factors, Bordetella
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https://hdl.handle.net/10161/7837
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Scholars@Duke

Lefkowitz

Robert J. Lefkowitz

The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win. Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the
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