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Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation.

Publication ,  Journal Article
Cao, W; Luttrell, LM; Medvedev, AV; Pierce, KL; Daniel, KW; Dixon, TM; Lefkowitz, RJ; Collins, S
Published in: J Biol Chem
December 8, 2000

Both beta(2)- and beta(3)-adrenergic receptors (ARs) are able to activate the extracellular signal-regulated kinase (ERK) pathway. We previously showed that c-Src is required for ERK activation by beta(2)AR and that it is recruited to activated beta(2)AR through binding of the Src homology 3 (SH3) domain to proline-rich regions of the adapter protein beta-arrestin1. Despite the absence of sites for phosphorylation and beta-arrestin binding, ERK activation by beta(3)AR still requires c-Src. Agonist activation of beta(2)AR, but not beta(3)AR, led to redistribution of green fluorescent protein-tagged beta-arrestin to the plasma membrane. In beta-arrestin-deficient COS-7 cells, beta-agonist-dependent co-precipitation of c-Src with the beta(2)AR required exogenous beta-arrestin, but activated beta(3)AR co-precipitated c-Src in the absence or presence of beta-arrestin. ERK activation and Src co-precipitation with beta(3)AR also occurred in adipocytes in an agonist-dependent and pertussis toxin-sensitive manner. Protein interaction studies show that the beta(3)AR interacts directly with the SH3 domain of Src through proline-rich motifs (PXXP) in the third intracellular loop and the carboxyl terminus. ERK activation and Src co-precipitation were abolished in cells expressing point mutations in these PXXP motifs. Together, these data describe a novel mechanism of ERK activation by a G protein-coupled receptor in which the intracellular domains directly recruit c-Src.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 8, 2000

Volume

275

Issue

49

Start / End Page

38131 / 38134

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transfection
  • Receptors, Adrenergic, beta-3
  • Proto-Oncogene Proteins pp60(c-src)
  • Propranolol
  • Proline
  • Molecular Sequence Data
  • Mitogen-Activated Protein Kinases
  • Mice
  • Isoproterenol
 

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Cao, W., Luttrell, L. M., Medvedev, A. V., Pierce, K. L., Daniel, K. W., Dixon, T. M., … Collins, S. (2000). Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. J Biol Chem, 275(49), 38131–38134. https://doi.org/10.1074/jbc.C000592200
Cao, W., L. M. Luttrell, A. V. Medvedev, K. L. Pierce, K. W. Daniel, T. M. Dixon, R. J. Lefkowitz, and S. Collins. “Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation.J Biol Chem 275, no. 49 (December 8, 2000): 38131–34. https://doi.org/10.1074/jbc.C000592200.
Cao W, Luttrell LM, Medvedev AV, Pierce KL, Daniel KW, Dixon TM, et al. Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. J Biol Chem. 2000 Dec 8;275(49):38131–4.
Cao, W., et al. “Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation.J Biol Chem, vol. 275, no. 49, Dec. 2000, pp. 38131–34. Pubmed, doi:10.1074/jbc.C000592200.
Cao W, Luttrell LM, Medvedev AV, Pierce KL, Daniel KW, Dixon TM, Lefkowitz RJ, Collins S. Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. J Biol Chem. 2000 Dec 8;275(49):38131–38134.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 8, 2000

Volume

275

Issue

49

Start / End Page

38131 / 38134

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Transfection
  • Receptors, Adrenergic, beta-3
  • Proto-Oncogene Proteins pp60(c-src)
  • Propranolol
  • Proline
  • Molecular Sequence Data
  • Mitogen-Activated Protein Kinases
  • Mice
  • Isoproterenol