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Gastrin Stimulates Tyrosine Phosphorylation of Insulin Receptor Substrate 1 and Its Association with Grb2 and the Phosphatidylinositol 3-Kinase*

  • Aline Kowalski-Chauvel
    Affiliations
    INSERM U.151, Groupe de Recherche de Biologie et Pathologie digestive, Institut Louis Bugnard, CHU Rangueil, 31054 Toulouse, France
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  • Lucien Pradayrol
    Affiliations
    INSERM U.151, Groupe de Recherche de Biologie et Pathologie digestive, Institut Louis Bugnard, CHU Rangueil, 31054 Toulouse, France
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  • Nicole Vaysse
    Affiliations
    INSERM U.151, Groupe de Recherche de Biologie et Pathologie digestive, Institut Louis Bugnard, CHU Rangueil, 31054 Toulouse, France
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  • Catherine Seva
    Correspondence
    To whom correspondence should be addressed
    Affiliations
    INSERM U.151, Groupe de Recherche de Biologie et Pathologie digestive, Institut Louis Bugnard, CHU Rangueil, 31054 Toulouse, France
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  • Author Footnotes
    * This work was supported by funds from INSERM, Association pour la Recherche contre le Cancer Grant 2073, and Conseil Regional Midi Pyrenées Grant 9208647. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:October 18, 1996DOI:https://doi.org/10.1074/jbc.271.42.26356
      The growth-promoting effects of gastrin on normal and neoplastic gastrointestinal tissues have been shown to be mediated by the gastrin/CCKB receptor, which belongs to the family of G protein-coupled receptors. However, the downstream signaling pathways activated by gastrin are not well characterized. In the present study, we demonstrate that gastrin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), the major cytoplasmic substrate of the insulin receptor. The gastrin-induced phosphorylation of IRS-1 was rapid and transient, occurring within 30 s of treatment and diminishing thereafter. IRS-1 binds several proteins containing Src homology 2 domains through its multiple tyrosine phosphorylation sites. Following gastrin stimulation, we observed a time- and dose-dependent association of IRS-1 with the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase). In addition, activation of PI 3-kinase was detected in anti-IRS-1 immunoprecipitates from gastrin-treated cells, suggesting that tyrosine phosphorylation of IRS-1, which leads to the rapid recruitment of p85, might be one mechanism used by gastrin to activate PI 3-kinase. We have previously reported that tyrosine phosphorylation of Shc and its association with the Grb2-Sos complex may contribute to the activation of the mitogen-activated protein kinase pathway by gastrin. We report here that Grb2 also interacts with tyrosine-phosphorylated IRS-1 in response to gastrin. Taken together, our results suggest that IRS-1 may serve as a converging target in the signaling pathways stimulated by receptors that belong to different families, such as the gastrin/CCKB G protein-coupled receptor and the insulin receptor.

      INTRODUCTION

      Gastrin, a peptide hormone produced by antral G cells, has been characterized as a stimulant of gastric acid secretion (
      • Edkings J.S.
      ). Gastrin is also known to function as a growth factor, stimulating proliferation of normal and neoplastic gastrointestinal cells. Indeed, this regulatory peptide has trophic effects on normal mucosa of the gastrointestinal tract (
      • Johnson L.R.
      ) and stimulates the growth of colon, gastric, and pancreatic cancer cell lines in vitro or transplanted in vivo (
      • Watson S.A.
      • Durrant L.G.
      • Morris D.L.
      ,
      • Watson S.A.
      • Durrant L.G.
      • Crosbie J.D.
      • Morris D.L.
      ,
      • Seva C.
      • Scemama J.L.
      • Bastie M.J.
      • Pradayrol L.
      • Vaysse N.
      ,
      • Singh P.
      • Walker J.P.
      • Townsend C.M.
      • Thompson J.C.
      ). Gastrin has been shown to transmit its mitogenic effects via a specific transmembrane G protein-coupled receptor, the G/CCKB
      The abbreviations used are: G/CCKB
      gastrin/CCKB
      MAP
      mitogen-activated protein
      PI 3-kinase
      phosphatidylinositol 3-kinase
      SH
      Src homology
      PtdIns
      phosphatidylinositol
      IGF-I
      insulin-like growth factor I
      IRS-1
      insulin receptor substrate 1
      INSERM
      Institut National de la Santé et de la Recherche Médicale.
      receptor (
      • Seva C.
      • Dickinson C.J.
      • Yamada T.
      ,
      • Sethi T.
      • Herget T.
      • Wu S.U.
      • Walsh J.H.
      • Rozengurt E.
      ,
      • Ito M.
      • Matsui T.
      • Taniguchi T.
      • Tsukamoto T.
      • Murayama T.
      • Arima N.
      • Nakata H.
      • Chiba T.
      • Chihara K.
      ,
      • Taniguchi T.
      • Matsui T.
      • Ito M.
      • Murayama T.
      • Tsukamoto T.
      • Katakami Y.
      • Chiba T.
      • Chiara K.
      ,
      • Seufferlein T.
      • Withers D.J.
      • Braod S.
      • Herget T.
      • Walsh J.H.
      • Rozengurt E.
      ). Gastrin acting via its specific receptor has been reported to initiate numerous early intracellular events that result in the formation of the second messengers inositol triphosphate and diacylglycerol and the subsequent mobilization of Ca2+ and activation of protein kinase C (
      • Seva C.
      • Scemama J.L.
      • Pradayrol L.
      • Sarfati P.D.
      • Vaysse N.
      ,
      • Bertrand V.
      • Bastie M.J.
      • Vaysse N.
      • Pradayrol L.
      ). It is now well established that G protein-coupled receptors that lack intrinsic tyrosine kinase activity are capable of activating cytosolic tyrosine kinases (
      • Malarkey K.
      • Behlham C.M.
      • Paul A.
      • Graham A.
      • McLees A.
      • Scott P.H.
      • Plevin R.
      ). We have recently reported that gastrin induces an increase in tyrosine phosphorylation of several proteins, including the two isoforms of the adapter protein Shc (46 and 52 kDa). Phosphorylated Shc subsequently associates with a complex including a second adapter protein, Grb2, and the p21-Ras activator Sos, which initiates the MAP kinase cascade (
      • Seva C.
      • Kowalski-Chauvel A.
      • Blanchet J.S.
      • Vaysse N.
      • Pradayrol L.
      ). Gastrin has also been shown to stimulate the expression of early growth response genes such as c-fos and c-jun (
      • Todisco A.
      • Takeuchi Y.
      • Seva C.
      • Dickinson C.J.
      • Yamada T.
      ). These intracellular events appear to be a pathway common to both G protein-coupled receptors and tyrosine kinase receptors.
      PI 3-kinase has been reported to play an important role in mitogenesis and cell transformation. This enzyme has been found to be associated with and activated by a large number of oncogene products, growth factor receptors, and nonreceptor tyrosine kinases of the Src family (
      • Cantley L.C.
      • Auger K.R.
      • Carpenter C.
      • Duckworth B.
      • Graviani A.
      • Kapeller R.
      • Soltoff S.
      ). Mutant platelet-derived growth factor receptors deficient in the binding site for PI 3-kinase fail to transmit the mitogenic signal of platelet-derived growth factor (
      • Coughlin S.R.
      • Escobedo J.A.
      • Williams L.T.
      ,
      • Fantl W.J.
      • Escobedo J.A.
      • Martin G.A.
      • Turck C.W.
      • Del Rosario M.
      • McCormick F.
      • Williams L.T.
      ). In a similar fashion, mutant forms of pp60v-src (
      • Fukui Y.
      • Hanafusa H.
      ,
      • Fukui Y.
      • Kornbluth S.
      • Jong S.M.
      • Wang L.H.
      • Hanafusa H.
      ) that fail to associate or activate PI 3-kinase are nontransforming. Furthermore, inhibition of PI 3-kinase activity by specific inhibitors or antibodies results in blockage of growth factor-induced cell proliferation (
      • Roche S.
      • Koegl M.
      • Courtneige S.A.
      ,
      • Vemuri G.S.
      • Rittenhouse S.E.
      ). PI 3-kinase is a heterodimer composed of a 110-kDa catalytic subunit and an 85-kDa regulatory subunit, which contains two SH2 domains and one SH3 domain (
      • Shibasaki F.
      • Homma Y.
      • Takenawa T.
      ). This enzyme is a lipid kinase that phosphorylates phosphatidylinositol (PtdIns) at the D3 position of the inositol ring (
      • Whitman M.
      • Downes C.P.
      • Keeler M.
      • Keller T.
      • Cantley L.
      ). Little is known about the role of the phosphorylated lipid products of PI 3-kinase (PtdIns3-P, PtdIns3,4-P2, and PtdIns3,4,5-P3); however, they may act as new second messengers (
      • Cantley L.C.
      • Auger K.R.
      • Carpenter C.
      • Duckworth B.
      • Graviani A.
      • Kapeller R.
      • Soltoff S.
      ). The SH2 domains of p85 bind directly to specific phosphotyrosine-containing sequences of tyrosine kinase receptors such as the platelet-derived growth factor receptor or the colony-stimulating factor I receptor (
      • Fantl W.J.
      • Escobedo J.A.
      • Martin G.A.
      • Turck C.W.
      • Del Rosario M.
      • McCormick F.
      • Williams L.T.
      ,
      • Kashishian A.
      • Kazlauskas A.
      • Cooper J.A.
      ,
      • Reedijk M.
      • Liu X.
      • Van Der Geer P.
      • Letwin K.
      • Waterfield M.D.
      • Hunter T.
      • Pawson T.
      ). In contrast, the mechanism leading to PI 3-kinase activation by insulin or insulin-like growth factor I (IGF-I) receptors involves an intermediate, IRS-1. This protein is rapidly tyrosine-phosphorylated in response to insulin (
      • White M.F.
      • Kahn C.R.
      ) or IGF-I (
      • Giorgetti S.
      • Ballotti R.
      • Kowalski-Chauvel A.
      • Tartare S.
      • Van Obberghen E.
      ) and associates with various signaling proteins containing SH2 domains, including p85, Grb2, SHPTP2, and Nck (
      • White M.F.
      • Kahn C.R.
      ). Stimulation of certain G protein-coupled receptors has also been reported to activate PI 3-kinase in a number of cell systems (
      • Kumagai N.
      • Morii N.
      • Fujisawa K.
      • Nemoto Y.
      • Narumiya S.
      ,
      • Zhang J.
      • King W.G.
      • Dillon S.
      • Hall A.
      • Feig L.
      • Rittenhouse S.E.
      ,
      • Stephens L.
      • Eguinoa A.
      • Corey S.
      • Jackson T.
      • Hawkins P.T.
      ); however, the mechanisms responsible for this activation are poorly understood. Since we recently reported that gastrin exerts growth-promoting effects on a tumor-derived pancreatic acinar cell line (AR4-2J) through the G/CCKB G protein-coupled receptor (
      • Seva C.
      • Dickinson C.J.
      • Yamada T.
      ), we examined whether this peptide could regulate the activation of the PI 3-kinase in this cellular model. We also investigated the mechanisms responsible for gastrin-induced PI 3-kinase activity. We report here an activation of PI 3-kinase by gastrin receptors occupancy. In addition, we show that gastrin rapidly stimulates both tyrosine phosphorylation of IRS-1 and its association with PI 3-kinase, suggesting that IRS-1 may be an important signaling molecule involved in gastrin-induced PI 3-kinase activation.

      DISCUSSION

      We have recently reported that gastrin stimulates the growth of the pancreatic carcinoma cell line AR4-2J through the G/CCKB G protein-coupled receptors (
      • Seva C.
      • Scemama J.L.
      • Bastie M.J.
      • Pradayrol L.
      • Vaysse N.
      ,
      • Seva C.
      • Dickinson C.J.
      • Yamada T.
      ). Tyrosine phosphorylation is an important intracellular event that is implicated in the transmission of mitogenic signals induced by tyrosine kinase receptors, which bind cytosolic tyrosine kinases (growth hormone and cytokine receptors) as well as G protein-coupled receptors. Activation of insulin or IGF-I receptors that possess intrinsic tyrosine kinase activity regulates both metabolic and mitogenic events. One of the early steps in the insulin and IGF-I receptor signaling pathway is the tyrosine phosphorylation of IRS-1, an adaptor protein that links the receptor to downstream mediators (
      • White M.F.
      • Kahn C.R.
      ). In response to insulin or IGF-I, IRS-1 is phosphorylated on multiple tyrosine residues recognized by the SH2 domains of specific proteins that activate different intracellular pathways. In the AR4-2J cells, G/CCKB receptors, which do not contain intrinsic tyrosine kinase activity, have been shown to mediate protein tyrosine phosphorylation (
      • Seva C.
      • Kowalski-Chauvel A.
      • Blanchet J.S.
      • Vaysse N.
      • Pradayrol L.
      ). We undertook the present study to further characterize the signal transduction events induced by gastrin occupancy of the G/CCKB receptor. The work presented in this article is the first to demonstrate that gastrin, a G protein-coupled receptor agonist, rapidly and transiently stimulates tyrosine phosphorylation of IRS-1, the major cytoplasmic substrate of the insulin and IGF-I receptors. In addition, we showed that PI 3-kinase is associated with phosphorylated IRS-1 and activated following gastrin stimulation. Growth hormone and cytokine receptors have also been shown to mediate IRS-1 tyrosine phosphorylation and its association with PI 3-kinase (
      • Johnston J.A.
      • Wang L.-M.
      • Hanson E.P.
      • Sun X.-J.
      • White M.F.
      • Oakes S.A.
      • Pierce J.H.
      • O'Shea J.J.
      ,
      • Argetsinger L.S.
      • Hsu G.W.
      • Myers Jr., M.G.
      • Billestrup N.
      • White M.F.
      • Carter-Su C.
      ,
      • Uddin S.
      • Yenush L.
      • Sun X.-J.
      • Sweet M.E.
      • White M.F.
      • Platanias L.C.
      ,
      • Yin T.
      • Keller S.R.
      • Quelle F.W.
      • Witthuhn B.A.
      • Tsang M.L.-S.
      • Lienhard G.E.
      • Ihle J.N.
      • Yang Y.C.
      ,
      • Souza S.C.
      • Frick G.P.
      • Yip R.
      • Lobo R.B.
      • Tai L.R.
      • Goodman H.M.
      ). These receptors activate cytosolic tyrosine kinases of the Janus kinase family, which in turn associate and phosphorylate IRS-1. Tyrosine-phosphorylated IRS-1 subsequently associates PI 3-kinase via the SH2 domain of its regulatory subunit. More recently, IRS-1 has also been shown to be phosphorylated on tyrosine residues in response to angiotensin II, a ligand that binds specific seven-transmembrane domain receptors (
      • Saad M.J.A.
      • Velloso L.A.
      • Carvalho C.R.O.
      ). These observations and our findings suggest that the tyrosine phosphorylation of IRS-1 that led to the rapid recruitment of the 85-kDa subunit of PI 3-kinase might represent a common mechanism for PI 3-kinase activation used by different families of receptors. Further studies are required to establish the mechanisms by which gastrin induces tyrosine phosphorylation of IRS-1. In particular, the tyrosine kinases stimulated by G protein-coupled receptor agonists that may be responsible for the phosphorylation of IRS-1 remained to be identified. Protein tyrosine kinases activated by this receptor family are potential candidates. Several published reports have shown that a number of G protein-linked receptors, including the G/CCKB receptors, mediate the autophosphorylation and activation of Src family protein tyrosine kinases (
      • Singh P.
      • Narayan S.
      • Adiga R.B.
      ,
      • Chen Y.
      • Pouyssegur J.
      • Courtneidge S.A.
      • Van Obberghen-Schilling E.
      ,
      • Marrero M.B.
      • Schieffer B.
      • Paxton W.G.
      • Schieffer E.
      • Bernstein K.E.
      ). However, it remains to be answered whether these kinases can phosphorylate IRS-1.
      We have recently demonstrated that gastrin stimulates MAP kinase activation in the AR4-2J cells. We have also characterized the molecular events, upstream of p21-Ras, that may link the MAP kinase pathway to G/CCKB receptors (
      • Seva C.
      • Kowalski-Chauvel A.
      • Blanchet J.S.
      • Vaysse N.
      • Pradayrol L.
      ). Gastrin rapidly induces tyrosine phosphorylation of the adapter protein Shc, which subsequently interacts with the SH2 domain of Grb2, a second intermediate protein. Grb2 also possesses SH3 domains, which constitutively bind the prolin-rich motif of the p21-Ras activator termed Sos. The role of the activated p21-Ras is then to target the serine/threonine kinase c-Raf-1 to the plasma membrane, in which it can be activated by phosphorylation. Dual specific kinases (tyrosine/threonine kinases), termed MAP kinase kinases, are in turn activated by c-Raf-1 and directly phosphorylate the MAP kinases. In the present study, we demonstrate that Grb2 also interacts with tyrosine-phosphorylated IRS-1 in response to gastrin. Thus, the binding of IRS-1 to the Grb2-Sos complex, which is likely involved in insulin stimulation of MAP kinases (
      • White M.F.
      • Kahn C.R.
      ), might be an alternative pathway used by gastrin to activate a Ras-dependent MAP kinase cascade in AR4-2J cells.
      A recent study has demonstrated that activation of the monocyte colony-stimulating factor receptor (a transmembrane protein tyrosine kinase) induces tyrosine phosphorylation of the 85-kDa subunit of PI 3-kinase and its direct association with the Grb2-SOS complex via the SH2 domain of Grb2. This mechanism could contribute to the regulation of the Ras-signaling pathway in monocytes (
      • Saleem A.
      • Kharbanda S.
      • Yuan Z.-M.
      • Kufe D.
      ). Our results also demonstrate that activation of PI 3-kinase in anti-Grb2 immunoprecipitates occurs in response to gastrin. However, we did not detect tyrosine phosphorylation of p85 following gastrin stimulation. Since IRS-1 phosphorylated on tyrosine residues is able to directly interact with the SH2 domains of both p85 and Grb2, PI 3-kinase is likely coprecipitated with anti-Grb2 antibodies via IRS-1 in response to gastrin.
      In summary, our results demonstrate for the first time that tyrosine phosphorylation of IRS-1 and its subsequent interaction with downstream signaling molecules such as Grb2 or PI 3-kinase can be induced by gastrin. This finding suggests that IRS-1 may serve as a converging target in the signaling pathways stimulated by receptors that belong to different families, such as the G/CCKB G protein-coupled receptor and the insulin receptor.

      Acknowledgments

      We thank Drs. Y. Le Marchand-Brustel and J. F. Tanti (INSERM U.145, Nice, France) for antibodies to p85 and Drs. E. Van Obberghen and I. Mothe (INSERM U.145, Nice, France) for Anti-IRS-1 antibodies.

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