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Science 17 January 1997:
Vol. 275. no. 5298, pp. 394 - 397
DOI: 10.1126/science.275.5298.394
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Reports

Linkage of G Protein-Coupled Receptors to the MAPK Signaling Pathway Through PI 3-Kinase gamma

Marco Lopez-Ilasaca, * Piero Crespo, * P. Giuseppe Pellici, J. Silvio Gutkind, dagger Reinhard Wetzker

The tyrosine kinase class of receptors induces mitogen-activated protein kinase (MAPK) activation through the sequential interaction of the signaling proteins Grb2, Sos, Ras, Raf, and MEK. Receptors coupled to heterotrimeric guanine triphosphate-binding protein (G protein) stimulate MAPK through Gbeta gamma subunits, but the subsequent intervening molecules are still poorly defined. Overexpression of phosphoinositide 3-kinase gamma  (PI3Kgamma ) in COS-7 cells activated MAPK in a Gbeta gamma -dependent fashion, and expression of a catalytically inactive mutant of PI3Kgamma abolished the stimulation of MAPK by Gbeta gamma or in response to stimulation of muscarinic (m2) G protein-coupled receptors. Signaling from PI3Kgamma to MAPK appears to require a tyrosine kinase, Shc, Grb2, Sos, Ras, and Raf. These findings indicate that PI3Kgamma mediates Gbeta gamma -dependent regulation of the MAPK signaling pathway.

M. Lopez-Ilasaca and R. Wetzker, Max Planck Research Unit Molecular Cell Biology, Medical Faculty, University of Jena, 07747 Jena, Germany.
P. Crespo and J. S. Gutkind, Molecular Signaling Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, Bethesda, MD 20892, USA.
P. G. Pellici, Istituto di Medicina Interna e Scienze Oncologiche, Laboratorio di Biologia Moleculare, Polclinico Monteluce, University of Perugia and European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed at the Molecular Signaling Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, 9000 Rockville Pike, Building 30, Room 212, Bethesda, MD 20892-4330, USA.

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   Abstract »    Full Text »    PDF »
D4 Dopamine Receptor Differentially Regulates Akt/Nuclear Factor-kappa B and Extracellular Signal-Regulated Kinase Pathways in D4MN9D Cells.
X. Zhen, J. Zhang, G. P. Johnson, and E. Friedman (2001)
Mol. Pharmacol. 60, 857-864
   Abstract »    Full Text »    PDF »
Blocking of c-FLIPL-independent cycloheximide-induced apoptosis or Fas-mediated apoptosis by the CC chemokine receptor 9/TECK interaction.
B.-S. Youn, Y. J. Kim, C. Mantel, K.-Y. Yu, and H. E. Broxmeyer (2001)
Blood 98, 925-933
   Abstract »    Full Text »    PDF »
The EphA8 Receptor Regulates Integrin Activity through p110{gamma} Phosphatidylinositol-3 Kinase in a Tyrosine Kinase Activity-Independent Manner.
C. Gu and S. Park (2001)
Mol. Cell. Biol. 21, 4579-4597
   Abstract »    Full Text »    PDF »
Cyclic AMP-Mediated Inhibition of Cell Growth Requires the Small G Protein Rap1.
J. M. Schmitt and P. J. S. Stork (2001)
Mol. Cell. Biol. 21, 3671-3683
   Abstract »    Full Text »
Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions.
G. Pearson, F. Robinson, T. Beers Gibson, B.-e Xu, M. Karandikar, K. Berman, and M. H. Cobb (2001)
Endocr. Rev. 22, 153-183
   Abstract »    Full Text »
{beta}2-Adrenergic Receptors Potentiate Glucocorticoid Receptor Transactivation via G Protein {beta}{{gamma}}-Subunits and the Phosphoinositide 3-Kinase Pathway.
P. Schmidt, F. Holsboer, and D. Spengler (2001)
Mol. Endocrinol. 15, 553-564
   Abstract »    Full Text »
Signal transduction pathways for activation of extracellular signal-regulated kinase by arachidonic acid in rat neutrophils.
L.-C. Chang and J.-P. Wang (2001)
J. Leukoc. Biol. 69, 659-665
   Abstract »    Full Text »
Phosphatidylinositol 3-Kinase in Cumulus Cells and Oocytes Is Responsible for Activation of Oocyte Mitogen-Activated Protein Kinase During Meiotic Progression Beyond the Meiosis I Stage in Pigs.
M. Shimada and T. Terada (2001)
Biol Reprod 64, 1106-1114
   Abstract »    Full Text »
Activation of Phosphatidylinositol-3 Kinase (PI-3K) and Extracellular Regulated Kinases (Erk1/2) Is Involved in Muscarinic Receptor-Mediated DNA Synthesis in Neural Progenitor Cells.
B.-S. Li, W. Ma, L. Zhang, J. L. Barker, D. A. Stenger, and H. C. Pant (2001)
J. Neurosci. 21, 1569-1579
   Abstract »    Full Text »    PDF »
A Specific Role of Phosphatidylinositol 3-Kinase {gamma}: A Regulation of Autonomic Ca2+ Oscillations in Cardiac Cells.
C. Bony, S. Roche, U. Shuichi, T. Sasaki, M. A. Crackower, J. Penninger, H. Mano, and M. Puceat (2001)
J. Cell Biol. 152, 717-728
   Abstract »    Full Text »    PDF »
High-efficiency transient transfection of endothelial cells for functional analysis.
A. T. KOVALA, K. A. HARVEY, P. McGLYNN, G. BOGUSLAWSKI, J. G. N. GARCIA, and D. ENGLISH (2000)
FASEB J 14, 2486-2494
   Abstract »    Full Text »
Src kinase-mediated signaling in leukocytes.
Z. Korade-Mirnics and S. J. Corey (2000)
J. Leukoc. Biol. 68, 603-613
   Abstract »    Full Text »
Role of Phosphoinositide 3-Kinase and Endocytosis in Nerve Growth Factor-Induced Extracellular Signal-Regulated Kinase Activation via Ras and Rap1.
R. D. York, D. C. Molliver, S. S. Grewal, P. E. Stenberg, E. W. McCleskey, and P. J. S. Stork (2000)
Mol. Cell. Biol. 20, 8069-8083
   Abstract »    Full Text »
Mediators of the mitogenic action of human V1 vascular vasopressin receptors.
M. Thibonnier, D. M. Conarty, and C. L. Plesnicher (2000)
Am J Physiol Heart Circ Physiol 279, H2529-H2539
   Abstract »    Full Text »    PDF »
Mechanisms of Proliferation Synergy by Receptor Tyrosine Kinase and G Protein-Coupled Receptor Activation in Human Airway Smooth Muscle.
V. P. Krymskaya, M. J. Orsini, A. J. Eszterhas, K. C. Brodbeck, J. L. Benovic, R. A. Panettieri Jr., and R. B. Penn (2000)
Am. J. Respir. Cell Mol. Biol. 23, 546-554
   Abstract »    Full Text »
Direct Tumor Lysis by NK Cells Uses a Ras-Independent Mitogen-Activated Protein Kinase Signal Pathway.
S. Wei, D. L. Gilvary, B. C. Corliss, S. Sebti, J. Sun, D. B. Straus, P. J. Leibson, J. A. Trapani, A. D. Hamilton, M. J. Weber, et al. (2000)
J. Immunol. 165, 3811-3819
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptor-Mediated Mitogen-Activated Protein Kinase Activation through Cooperation of Galpha q and Galpha i Signals.
A. Blaukat, A. Barac, M. J. Cross, S. Offermanns, and I. Dikic (2000)
Mol. Cell. Biol. 20, 6837-6848
   Abstract »    Full Text »


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