Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.

The Ras-dependent activation of mitogen-activated protein (MAP) kinase pathways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinases. Stimulation of beta2 adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor. Src recruitment was mediated by beta-arrestin, which functions as an adapter protein, binding both c-Src and the agonist-occupied receptor. beta-Arrestin 1 mutants, impaired either in c-Src binding or in the ability to target receptors to clathrin-coated pits, acted as dominant negative inhibitors of beta2 adrenergic receptor-mediated activation of the MAP kinases Erk1 and Erk2. These data suggest that beta-arrestin binding, which terminates receptor-G protein coupling, also initiates a second wave of signal transduction in which the "desensitized" receptor functions as a critical structural component of a mitogenic signaling complex.

[1]  M. Caron,et al.  A β-Arrestin/Green Fluorescent Protein Biosensor for Detecting G Protein-coupled Receptor Activation* , 1997, The Journal of Biological Chemistry.

[2]  R. Lefkowitz,et al.  Desensitization of G protein-coupled receptors. , 1996, Recent progress in hormone research.

[3]  S. Schmid,et al.  Control of EGF Receptor Signaling by Clathrin-Mediated Endocytosis , 1996, Science.

[4]  G. Bokoch,et al.  G Protein-coupled Chemoattractant Receptors Regulate Lyn Tyrosine Kinase·Shc Adapter Protein Signaling Complexes (*) , 1995, The Journal of Biological Chemistry.

[5]  Hsin C. Lin,et al.  Regulation of Dynamin I GTPase Activity by G Protein βγ Subunits and Phosphatidylinositol 4,5-Bisphosphate* , 1996, The Journal of Biological Chemistry.

[6]  H. Bourne,et al.  cAMP and beta gamma subunits of heterotrimeric G proteins stimulate the mitogen-activated protein kinase pathway in COS-7 cells. , 1994, The Journal of biological chemistry.

[7]  R. Lefkowitz,et al.  Antagonism of catecholamine receptor signaling by expression of cytoplasmic domains of the receptors. , 1993, Science.

[8]  R. Lefkowitz,et al.  Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  R. Medema,et al.  Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[10]  P. Crespo,et al.  Ras-dependent activation of MAP kinase pathway mediated by G-protein βγ subunits , 1994, Nature.

[11]  J. Pouysségur,et al.  Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein‐coupled thrombin receptor. , 1996, The EMBO journal.

[12]  A. Strosberg,et al.  Endothelin induces tyrosine phosphorylation and GRB2 association of Shc in astrocytes. , 1994, The Journal of biological chemistry.

[13]  M. Caron,et al.  A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration. , 1994, The Journal of biological chemistry.

[14]  D. Baltimore,et al.  Coordinate activation of c-Src by SH3- and SH2-binding sites on a novel p130Cas-related protein, Sin. , 1996, Genes & development.

[15]  J. Pouysségur,et al.  Activation of Src family kinase activity by the G protein-coupled thrombin receptor in growth-responsive fibroblasts. , 1994, The Journal of biological chemistry.

[16]  M. Caron,et al.  Role of β-Arrestin in Mediating Agonist-Promoted G Protein-Coupled Receptor Internalization , 1996, Science.

[17]  N. Qian,et al.  Involvement of Ras and Raf in the Gi-coupled acetylcholine muscarinic m2 receptor activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. , 1993, The Journal of biological chemistry.

[18]  J. Kuriyan,et al.  Activation of the Sire-family tyrosine kinase Hck by SH3 domain displacement , 1997, Nature.

[19]  M. Caron,et al.  Dynamin and β-Arrestin Reveal Distinct Mechanisms for G Protein-coupled Receptor Internalization* , 1996, The Journal of Biological Chemistry.

[20]  D. Baltimore,et al.  Modular binding domains in signal transduction proteins , 1995, Cell.

[21]  J. Benovic,et al.  β-Arrestin acts as a clathrin adaptor in endocytosis of the β2-adrenergic receptor , 1996, Nature.

[22]  Hsin C. Lin,et al.  Sequestration of the G protein βγ subunit complex inhibits receptor-mediated endocytosis , 1998 .

[23]  R. Lefkowitz,et al.  Ras-dependent activation of fibroblast mitogen-activated protein kinase by 5-HT1A receptor via a G protein beta gamma-subunit-initiated pathway. , 1996, Biochemistry.

[24]  R. Lefkowitz,et al.  Beta-adrenergic receptor sequestration. A potential mechanism of receptor resensitization. , 1993, The Journal of biological chemistry.

[25]  M. Ishida,et al.  Angiotensin II activates pp60c-src in vascular smooth muscle cells. , 1995, Circulation research.

[26]  M. Nakafuku,et al.  Function of Ras as a molecular switch in signal transduction. , 1992, The Journal of biological chemistry.

[27]  Jonathan A. Cooper,et al.  The when and how of Src regulation , 1993, Cell.

[28]  M. Caron,et al.  Essential Role for G Protein-coupled Receptor Endocytosis in the Activation of Mitogen-activated Protein Kinase* , 1998, The Journal of Biological Chemistry.

[29]  R. Lefkowitz,et al.  Clathrin-mediated Endocytosis of the β-Adrenergic Receptor Is Regulated by Phosphorylation/Dephosphorylation of β-Arrestin1* , 1997, The Journal of Biological Chemistry.

[30]  Stephen S. G. Ferguson,et al.  Synergistic Regulation of β2-Adrenergic Receptor Sequestration: Intracellular Complement of β-Adrenergic Receptor Kinase and β-Arrestin Determine Kinetics of Internalization , 1997 .

[31]  M. Caron,et al.  Role of Phosphorylation in Agonist-promoted β2-Adrenergic Receptor Sequestration , 1995, The Journal of Biological Chemistry.

[32]  M. Marrero,et al.  Angiotensin II Controls p21 Activity via pp60(*) , 1996, The Journal of Biological Chemistry.

[33]  Robert J. Lefkowitz,et al.  Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A , 1997, Nature.

[34]  A. Ullrich,et al.  Signal characteristics of G protein‐transactivated EGF receptor , 1997, The EMBO journal.