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  • Review Article
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Review Article

New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades

Oncogene volume 20, pages 1532–1539 (2001)Cite this article

Abstract

Activation of classical second messenger cascades cannot fully explain the recently appreciated roles of heptahelical, or G-protein coupled receptors (GPCRs), in stimulation of mitogen activated protein kinase (MAPK) cascades. Rather, several distinct signaling mechanisms appear to contribute to GPCR-mediated MAPK activation. These include transactivation of the Epidermal Growth Factor Receptor (EGFR) via the autocrine/paracrine release of EGF-like ligands at the cell surface and scaffolding of MAPK cascades. A significant advance in the understanding of how GPCRs activate MAPK cascades is the discovery that β-arrestin, a protein well known for its roles in both receptor desensitization and internalization, serves as a scaffolding protein for at least two GPCR stimulated MAPK cascades, the extracellular signal regulated kinase (ERK) cascade and the c-jun N-terminal kinase 3 (JNK3) cascade. Together, these novel mechanisms of GPCR-mediated MAPK regulation may permit GPCRs in specific situations to control the temporal and spatial activity of MAPKs and thereby determine the consequences of GPCR stimulation with respect to transcriptional activation, cell proliferation and apoptosis.

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Acknowledgements

We would like to thank Mary Holben and Donna Addison for their excellent secretarial assistance. RJ Lefkowitz is an investigator of the Howard Hughes Medical Institute. Supported in part by National Institute of Health Grants HL16037 (to RJ Lefkowitz) and DK55524 (to LM Luttrell).

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Authors and Affiliations

  1. The Howard Hughes Medical Institute, Box 3821, Duke University Medical Center, Durham, 27710, North Carolina, NC, USA

    Kristen L Pierce & Robert J Lefkowitz

  2. Department of Medicine, Box 3821, Duke University Medical Center, Durham, 27710, North Carolina, NC, USA

    Kristen L Pierce & Robert J Lefkowitz

  3. Department of Biochemistry, Box 3821, Duke University Medical Center, Durham, 27710, North Carolina, NC, USA

    Robert J Lefkowitz

  4. The Geriatric Research Education and Clinical Center, Durham Veteran Affairs Medical Center, Durham, 27705, North Carolina, NC, USA

    Louis M Luttrell

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Pierce, K., Luttrell, L. & Lefkowitz, R. New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades. Oncogene 20, 1532–1539 (2001). https://doi.org/10.1038/sj.onc.1204184

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