TI  - <prot>Gastrin</prot> stimulates tyrosine phosphorylation of   <prot><prot><prot>insulin</prot> receptor</prot> substrate
      1</prot>   and its association with  <prot>Grb2</prot>  and the  <prot>phosphatidylinositol 3-kinase</prot> .
PG  - 26356-61
AB  - The growth-promoting effects of <prot>gastrin</prot> on normal and neoplastic
      gastrointestinal tissues have been shown to be mediated by the
      <prot>gastrin</prot>/<prot>CCKB receptor</prot>, which belongs to the family of G protein-coupled
      receptors. However, the downstream signaling pathways activated by <prot>gastrin</prot>
      are not well characterized. In the present study, we demonstrate that
       <prot>gastrin</prot>  stimulates tyrosine phosphorylation of   <prot><prot>insulin</prot> receptor substrate
      1</prot> (<prot>IRS-1</prot>)  , the major cytoplasmic substrate of the  <prot><prot>insulin</prot> receptor</prot> . The
      <prot>gastrin</prot>-induced phosphorylation of <prot>IRS-1</prot> was rapid and transient,
      occurring within 30 s of treatment and diminishing thereafter. <prot>IRS-1</prot> binds
      several proteins containing Src homology 2 domains through its multiple
      tyrosine phosphorylation sites. Following <prot>gastrin</prot> stimulation, we observed
      a time- and dose-dependent association of  <prot>IRS-1</prot>  with the <prot>p85</prot> regulatory
      subunit of  <prot>phosphatidylinositol 3-kinase</prot> (<prot>PI 3-kinase</prot>) . In addition,
      activation of <prot>PI 3-kinase</prot> was detected in anti-<prot>IRS-1</prot> immunoprecipitates
      from <prot>gastrin</prot>-treated cells, suggesting that tyrosine phosphorylation of
      <prot>IRS-1</prot>, which leads to the rapid recruitment of <prot>p85</prot>, might be one mechanism
      used by <prot>gastrin</prot> to activate <prot>PI 3-kinase</prot>. We have previously reported that
      tyrosine phosphorylation of  <prot>Shc</prot>  and its association with the  <prot>Grb2</prot>-<prot>Sos</prot> 
      complex may contribute to the activation of the <prot>mitogen-activated protein
      kinase</prot> pathway by <prot>gastrin</prot>. We report here that  <prot>Grb2</prot>  also interacts with
       tyrosine-phosphorylated <prot>IRS-1</prot>  in response to <prot>gastrin</prot>. Taken together, our
      results suggest that <prot>IRS-1</prot> may serve as a converging target in the
      signaling pathways stimulated by receptors that belong to different
      families, such as the <prot>gastrin</prot>/<prot><prot>CCKB</prot> G protein-coupled receptor</prot> and the
      <prot><prot>insulin</prot> receptor</prot>.
AD  - INSERM U.151, Groupe de Recherche de Biologie et Pathologie digestive,
