pp60Src mediates insulin-stimulated sequestration of the beta(2)-adrenergic receptor: insulin stimulates pp60Src phosphorylation and activation

Mol Biol Cell. 2002 Nov;13(11):3943-54. doi: 10.1091/mbc.e02-03-0174.


Insulin stimulates a rapid phosphorylation and sequestration of the beta(2)-adrenergic receptor. Analysis of the signaling downstream of the insulin receptor with enzyme inhibitors revealed roles for both phosphatidylinositol 3-kinase and pp60Src. Inhibition of Src with PP2, like the inhibition of phosphatidylinositol 3-kinase with LY294002 [2-(4-morpholynyl)-8-phenyl-4H-1-benzopyran-4-one], blocked the activation of Src as well as insulin-stimulated sequestration of the beta(2)-adrenergic receptor. Depletion of Src with antisense morpholinos also suppressed insulin-stimulated receptor sequestration. Src is shown to be phosphorylated/activated in response to insulin in human epidermoid carcinoma A431 cells as well as in mouse 3T3-L1 adipocytes and their derivative 3T3-F422A cells, well-known models of insulin signaling. Inhibition of Src with PP2 blocks the ability of insulin to sequester beta(2)-adrenergic receptors and the translocation of the GLUT4 glucose transporters. Insulin stimulates Src to associate with the beta(2)-adrenergic receptor/AKAP250/protein kinase A/protein kinase C signaling complex. We report a novel positioning of Src, mediating signals from insulin to phosphatidylinositol 3-kinase and to beta(2)-adrenergic receptor trafficking.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Adrenergic beta-Agonists / metabolism
  • Animals
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Glucose Transporter Type 4
  • Humans
  • Insulin / metabolism*
  • Isoproterenol / metabolism
  • Mice
  • Models, Biological
  • Monosaccharide Transport Proteins / genetics
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins*
  • Oligonucleotides, Antisense / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fyn
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology*
  • Tumor Cells, Cultured
  • src-Family Kinases / metabolism


  • Adrenergic beta-Agonists
  • Enzyme Inhibitors
  • Glucose Transporter Type 4
  • Insulin
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins
  • Receptors, Adrenergic, beta-2
  • Recombinant Fusion Proteins
  • SLC2A4 protein, human
  • Slc2a4 protein, mouse
  • Phosphatidylinositol 3-Kinases
  • FYN protein, human
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn
  • Proto-Oncogene Proteins pp60(c-src)
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Isoproterenol