Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. STKE, 11 July 2000
Vol. 2000, Issue 40, p. re1
[DOI: 10.1126/stke.2000.40.re1]


Regulation of Mitogen-Activated Protein Kinase Signaling Networks by G Protein-Coupled Receptors

J. Silvio Gutkind

Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 212, Bethesda, MD 20892-4330, USA. E-mail: sg39v{at}

Gloss: The family of receptors that transmit signals through the activation of heterotrimeric GTP-binding proteins (G proteins) constitutes the largest group of cell surface proteins involved in signal transduction. The best-known family of G protein-coupled receptors (GPCRs) contains a conserved structural motif, consisting of seven α-helical membrane-spanning regions; thus, they are also frequently referred to as heptahelical or serpentine receptors. These receptors participate in a broad range of important biological functions, such as photo- and chemoreception, neurotransmission, regulated secretion from endocrine and exocrine glands, blood pressure control, platelet function, chemotaxis, exocytosis, embryogenesis, angiogenesis, tissue regeneration, and control of normal cell growth. Furthermore, they are also implicated in a number of disease states and are estimated to be the target for more than half of all drugs currently available. Initial studies established that these receptors affect the generation of small molecules that act as intracellular mediators or second messengers. However, recent work has revealed that a growing family of protein kinases, collectively known as extracellular signal-regulated kinases (ERKs) or mitogen-activated protein kinases (MAPKs), plays a central role in transmitting signals from extracellular stimuli to the nucleus. Such signals affect the expression of genes whose products influence many biological processes, including normal and aberrant cell growth. It is now becoming evident that GPCRs transduce signals to the nucleus through a highly interconnected network of biochemical routes that can regulate the activity of members of the MAPK superfamily. This knowledge affords a unique opportunity to begin unraveling the intricacies of how these cell surface receptors affect a very fine balance of nuclear regulatory molecules that control gene expression. Understanding how subtle perturbation of this signaling network can result in pathological situations provides golden opportunities to identify novel molecular targets for pharmacological intervention in a variety of diseases.

Citation: J. S. Gutkind, Regulation of Mitogen-Activated Protein Kinase Signaling Networks by G Protein-Coupled Receptors. Sci. STKE 2000, re1 (2000).

Control Profiles of Complex Networks.
J. Ruths and D. Ruths (2014)
Science 343, 1373-1376
   Abstract »    Full Text »    PDF »
Decoding Signaling and Function of the Orphan G Protein-Coupled Receptor GPR17 with a Small-Molecule Agonist.
S. Hennen, H. Wang, L. Peters, N. Merten, K. Simon, A. Spinrath, S. Blattermann, R. Akkari, R. Schrage, R. Schroder, et al. (2013)
Science Signaling 6, ra93
   Abstract »    Full Text »    PDF »
PAF enhances MMP-2 production in rat aortic VSMCs via a {beta}-arrestin2-dependent ERK signaling pathway.
Y. H. Kim, S. J. Lee, K. W. Seo, J. U. Bae, S. Y. Park, E. K. Kim, S. S. Bae, J. H. Kim, and C. D. Kim (2013)
J. Lipid Res. 54, 2678-2686
   Abstract »    Full Text »    PDF »
Regulation of Yeast G Protein Signaling by the Kinases That Activate the AMPK Homolog Snf1.
S. T. Clement, G. Dixit, and H. G. Dohlman (2013)
Science Signaling 6, ra78
   Abstract »    Full Text »    PDF »
Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in Neuronal and Endocrine Cells.
A. C. Emery, M. V. Eiden, T. Mustafa, and L. E. Eiden (2013)
Science Signaling 6, ra51
   Abstract »    Full Text »    PDF »
Signaling through the neuropeptide GPCR PAC1 induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor.
A. C. Emery and L. E. Eiden (2012)
FASEB J 26, 3199-3211
   Abstract »    Full Text »    PDF »
Dissection of Aberrant GPCR Signaling in Tumorigenesis - A Systems Biology Approach.
J. Wu, N. Xie, X. Zhao, E. C. Nice, and C. Huang (2012)
Cancer Genomics Proteomics 9, 37-50
   Abstract »    Full Text »    PDF »
G{beta}{gamma} Signaling Promotes Breast Cancer Cell Migration and Invasion.
J. K. Kirui, Y. Xie, D. W. Wolff, H. Jiang, P. W. Abel, and Y. Tu (2010)
J. Pharmacol. Exp. Ther. 333, 393-403
   Abstract »    Full Text »    PDF »
ERK Integrates PKA and PKC Signaling in Superficial Dorsal Horn Neurons. I. Modulation of A-Type K+ Currents.
H.-J. Hu, K. S. Glauner, and R. W. Gereau IV (2003)
J Neurophysiol 90, 1671-1679
   Abstract »    Full Text »    PDF »
Lyn- and ERK-mediated vs. Ca2+-mediated neutrophil O2- responses with thermal injury.
N. Fazal, W. M. Al-Ghoul, M. J. Schmidt, M. A. Choudhry, and M. M. Sayeed (2002)
Am J Physiol Cell Physiol 283, C1469-C1479
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882