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Growth Hormone and Prolactin Stimulate Tyrosine Phosphorylation of Insulin Receptor Substrate-1, -2, and -3, Their Association with p85 Phosphatidylinositol 3-Kinase (PI3-kinase), and Concomitantly PI3-kinase Activation via JAK2 Kinase*

Open AccessPublished:June 19, 1998DOI:https://doi.org/10.1074/jbc.273.25.15719
      Growth hormone (GH) and prolactin (PRL) binding to their receptors, which belong to the cytokine receptor superfamily, activate Janus kinase (JAK) 2 tyrosine kinase, thereby leading to their biological actions. We recently showed that GH mainly stimulated tyrosine phosphorylation of epidermal growth factor receptor and its association with Grb2, and concomitantly stimulated mitogen-activated protein kinase activity in liver, a major target tissue. Using specific antibodies, we now show that GH was also able to induce tyrosine phosphorylation of insulin receptor substrate (IRS)-1/IRS-2 in liver. In addition, the major tyrosine-phosphorylated protein in anti-p85 phosphatidylinositol 3-kinase (PI3-kinase) immunoprecipitate from liver of wild-type mice was IRS-1, and IRS-2 in IRS-1 deficient mice, but not epidermal growth factor receptor. These data suggest that tyrosine phosphorylation of IRS-1 may be a major mechanism for GH-induced PI3-kinase activation in physiological target organ of GH, liver. We also show that PRL was able to induce tyrosine phosphorylation of both IRS-1 and IRS-2 in COS cells transiently transfected with PRLR and in CHO-PRLR cells. Moreover, we show that tyrosine phosphorylation of IRS-3 was induced by both GH and PRL in COS cells transiently transfected with IRS-3 and their cognate receptors. By using the JAK2-deficient cell lines or by expressing a dominant negative JAK2 mutant, we show that JAK2 is required for the GH- and PRL-dependent tyrosine phosphorylation of IRS-1, -2, and -3. Finally, a specific PI3-kinase inhibitor, wortmannin, completely blocked the anti-lipolytic effect of GH in 3T3 L1 adipocytes. Taken together, the role of IRS-1, -2, and -3 in GH and PRL signalings appears to be phosphorylated by JAK2, thereby providing docking sites for p85 PI3-kinase and activating PI3-kinase and its downstream biological effects.
      Growth hormone (GH)
      The abbreviations used are: GH, growth hormone; PRL, prolactin; JAK, Janus kinase; STAT, signal transducers and activators of transcription; MAP, mitogen-activated protein; EGFR, epidermal growth factor receptor; IRS-1, insulin receptor substrate-1; PI3-kinase; phosphatidylinositol 3-kinase; SH2, Src homology 2; CHO, Chinese hamster ovary; HA, hemagglutinin; NE, norepinephrine; αPY, anti-phosphotyrosine.
      1The abbreviations used are: GH, growth hormone; PRL, prolactin; JAK, Janus kinase; STAT, signal transducers and activators of transcription; MAP, mitogen-activated protein; EGFR, epidermal growth factor receptor; IRS-1, insulin receptor substrate-1; PI3-kinase; phosphatidylinositol 3-kinase; SH2, Src homology 2; CHO, Chinese hamster ovary; HA, hemagglutinin; NE, norepinephrine; αPY, anti-phosphotyrosine.
      and prolactin (PRL) initiate their wide variety of biological effects by binding and dimerization of their membrane receptors (
      • Leung D.W.
      • Spencer S.A.
      • Cachianes G.
      • Hammonds R.G.
      • Collins C.
      • Henzel W.J.
      • Barnard R.
      • Waters M.J.
      • Wood W.I.
      ,
      • Cunningham B.C.
      • Ultsch M.
      • De Vos A.
      • Mulkerrin M.G.
      • Causer K.R.
      • Wells J.A.
      ). The GH and PRL receptors belong to the cytokine/hematopoietin receptor superfamily, characterized by homologies in the extracellular domains and lack of intrinsic tyrosine kinase activity (
      • Leung D.W.
      • Spencer S.A.
      • Cachianes G.
      • Hammonds R.G.
      • Collins C.
      • Henzel W.J.
      • Barnard R.
      • Waters M.J.
      • Wood W.I.
      ), however, ligands binding to their receptors activate JAK2 tyrosine kinase (
      • Argetsinger L.S.
      • Campbell G.S.
      • Yang X.
      • Witthuhn B.A.
      • Silvennoinen O.
      • Ihle J.N.
      • Carter-Su C.
      ,
      • Rui H.
      • Kirken R.A.
      • Farrar W.L.
      ). JAK2 tyrosine phosphorylates their receptors and JAK2 itself along with STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins translocate into the nucleus and bind to DNA, thereby activating transcription of specific genes (). In addition, a number of intracellular key proteins have been suggested to be involved in their signaling (
      • Roupas P.
      • Herington A.C.
      ).
      One of the signaling molecules known to be activated by GH and PRL (
      • Winston L.A.
      • Bertics P.J.
      ,
      • Moller C.
      • Hanson A.
      • Enberg B.
      • Lobie P.E.
      • Norstedt G.
      ) is the mitogen-activated protein kinase (MAP kinase), which is believed to play a pivotal role in the regulation of cellular growth and differentiation (
      • Peraldi P.
      • Scimeca J.
      • Filloux C.
      • Van Obberghen E.
      ). Association of tyrosine-phosphorylated proteins with Grb2 (growth factor receptor bound protein 2) is known to represent a crucial step in the activation of MAP kinase cascade (
      • Rozakis-Adcock M.
      • McGlade J.
      • Mbamalu G.
      • Pelicii G.
      • Daly R.
      • Li W.
      • Batzer A.
      • Thomas S.
      • Brugge J.
      • Pelicci P.G.
      • Schlessinger J.
      • Pawson T.
      ). In the case of GH and PRL, epidermal growth factor receptor (EGFR) and Shc have been shown to be tyrosyl phosphorylated by JAK2 and bind Grb2, leading to MAP kinase activation (
      • VanderKuur J.
      • Allevato G.
      • Billestrup N.
      • Norstedt G.
      • Carter-Su C.
      ,
      • Yamauchi T.
      • Ueki K.
      • Tobe K.
      • Tamemoto H.
      • Sekine N.
      • Wada M.
      • Honjo M.
      • Takahashi M.
      • Takahashi T.
      • Hirai H.
      • Tushima T.
      • Akanuma Y.
      • Fujita T.
      • Komuro I.
      • Yazaki Y.
      • Kadowaki T.
      ).
      Another signaling molecule known to be activated by GH and PRL is phosphatidylinositol 3-kinase (PI3-kinase), which may play a role in initiating insulin-like effects of GH and PRL including glucose transport, glycogenesis, anti-lipolysis, and lipogenesis (
      • Nicoll C.S.
      • Anderson T.R.
      • Hebert N.J.
      • Russell S.M.
      ,
      • Birnbaum R.S.
      • Goodman H.M.
      ,
      • Honeyman T.W.
      • Goodman H.M.
      ), because the selective PI3-kinase inhibitor wortmannin can block at least some of these effects such as anti-lipolysis and lipogenesis (
      • Ridderstrale M.
      • Tornqvist H.
      ).
      Insulin receptor substrate-1 (IRS-1) is the principal substrate of the insulin receptor kinase whose molecular mass is approximately 170 kDa and has many tyrosine phosphorylation sites (
      • Sun X.J.
      • Rothenberg P.
      • Kahn C.R.
      • Backer J.M.
      • Araki E.
      • Wilden P.A.
      • Cahill D.A.
      • Goldstein B.J.
      • White M.F.
      ), which provides binding sites for several distinct Src homology 2 (SH2) proteins (e.g. Grb2, the 85-kDa subunit of PI3-kinase (PI3-kinase p85), Syp, Nck, and Csk) and has been shown to mediate multiple signaling pathways (
      • White M.F.
      • Kahn C.R.
      ,
      • Kadowaki T.
      • Tobe K.
      • Honda-Yamamoto R.
      • Tamemoto H.
      • Kaburagi Y.
      • Momomura K.
      • Ueki K.
      • Takahashi Y.
      • Yamauchi T.
      • Akanuma Y.
      • Yazaki Y.
      ). IRS-1 binds the PI3-kinase p85 when tyrosine phosphorylated, thereby activating PI3-kinase (
      • Backer J.M.
      • Myers Jr., M.G.
      • Shoelson S.E.
      • Chin D.J.
      • Sun X.J.
      • Miralpeix M.
      • Hu P.
      • Margolis B.
      • Skolnik E.Y.
      • Schlessinger J.
      • White M.F.
      ,
      • Lavan B.E.
      • Kuhne M.R.
      • Garner C.W.
      • Anderson D.
      • Reedijk M.
      • Pawson T.
      • Lienhard G.E.
      ), leading to exert metabolic effects of insulin such as glucose transport, glycogen synthesis, and anti-lipolysis (
      • Cheatham B.
      • Vlahos C.J.
      • Cheatham L.
      • Wang L.
      • Blenis J.
      • Kahn C.R.
      ,
      • Okada T.
      • Kawano Y.
      • Sakakibara T.
      • Hazeki O.
      • Ui M.
      ,
      • Yamamoto-Honda R.
      • Tobe K.
      • Kaburagi Y.
      • Ueki K.
      • Asai S.
      • Yachi M.
      • Shirouzu M.
      • Akanuma Y.
      • Yokoyama S.
      • Yazaki Y.
      • Kadowaki T.
      ).
      To better understand the role of IRS-1 in vivo, we and others generated mice with a targeted disruption of the IRS-1 gene and demonstrated that they exhibited mild growth retardation and had partial resistance to the glucose-lowering effect of insulin, which was an unexpectedly mild phenotype, suggesting the presence of IRS-1 independent pathways (
      • Araki E.
      • Lipes M.A.
      • Patti M.E.
      • Brüning J.C.
      • Haag III., B.
      • Johnson R.S.
      • Kahn C.R.
      ,
      • Tamemoto H.
      • Kadowaki T.
      • Tobe K.
      • Yagi T.
      • Sakura H.
      • Hayakawa T.
      • Terauchi Y.
      • Ueki K.
      • Kaburagi Y.
      • Satoh S.
      • Sekihara H.
      • Yoshioka S.
      • Horikoshi H.
      • Furuta Y.
      • Ikawa Y.
      • Kasuga M.
      • Yazaki Y.
      • Aizawa S.
      ). In liver and also muscle extracts from IRS-1-deficient mice, tyrosine phosphorylation of IRS-2, whose molecular mass is approximately 180 kDa (
      • Araki E.
      • Lipes M.A.
      • Patti M.E.
      • Brüning J.C.
      • Haag III., B.
      • Johnson R.S.
      • Kahn C.R.
      ,
      • Wang L-M.
      • Myers Jr., M.G.
      • Sun X-J.
      • Aaronson S.A.
      • White M.F.
      • Pierce J.H.
      ,
      • Sun X.J.
      • Wang L.M.
      • Zhang Y.
      • Yenush L.
      • Myers M.G.J.
      • Glasheen E.
      • Lane W.S.
      • Pierce J.H.
      • White M.F.
      ), was significantly induced in IRS-1-deficient mice compared with that in wild-type mice (
      • Tobe K.
      • Tamemoto H.
      • Yamauchi T.
      • Aizawa S.
      • Yazaki Y.
      • Kadowaki T.
      ) and has been suggested to be the mechanism of compensation for IRS-1 deficiency in liver and muscle (
      • Patti M.-E.
      • Sun X.-J.
      • Bruening J.C.
      • Araki E.
      • Lipes M.A.
      • White M.F.
      • Kahn C.R.
      ,
      • Yamauchi T.
      • Tobe K.
      • Tamemoto H.
      • Ueki K.
      • Kaburagi Y.
      • Yamamoto-Honda R.
      • Takahashi Y.
      • Yoshizawa F.
      • Aizawa S.
      • Akanuma Y.
      • Sonenberg N.
      • Yazaki Y.
      • Kadowaki T.
      ). In another target tissue of insulin, adipocytes, both IRS-1 and IRS-3 (pp60) (
      • Momomura K.
      • Tobe K.
      • Seyama Y.
      • Takaku F.
      • Kasuga M.
      ,
      • Lavan B.E.
      • Lane W.S.
      • Lienhard G.E.
      ) was suggested to play a major role in insulin-induced PI3-kinase activation, and IRS-3 (pp60) was suggested to be involved in regulating this process in the absence of IRS-1 (
      • Kaburagi Y.
      • Satoh S.
      • Tamemoto H.
      • Yamamoto-Honda R.
      • Tobe K.
      • Ueki K.
      • Yamauchi T.
      • Kono-Sugita E.
      • Sekihara H.
      • Aizawa S.
      • Cushman S.W.
      • Akanuma Y.
      • Yazaki Y.
      • Kadowaki T.
      ).
      Recently, IRS-1/IRS-2 have been shown to be tyrosine-phosphorylated and associated with PI3-kinase p85 in response to GH in primary rat adipocytes (
      • Souza S.C.
      • Frick G.P.
      • Yip R.
      • Lobo R.B.
      • Tai L.R.
      • Goodman H.M.
      ,
      • Ridderstrale M.
      • Degerman E.
      • Tornqvist H.
      ) and in 3T3-F442A fibroblasts (
      • Argetsinger L.S.
      • Hsu G.W.
      • Myers Jr., M.G.
      • Billestrup N.
      • White M.F.
      • Carter-Su C.
      ,
      • Argetsinger L.S.
      • Norstedt G.
      • Billestrup N.
      • White M.F.
      • Carter-Su C.
      ). However, the following important issues remained unresolved. First, whether GH was able to induce tyrosine phosphorylation of IRS-1/IRS-2 in physiological target organ, liver, in vivo. Second, the relative contributions of IRS-1 and IRS-2 in the signaling pathways for GH to activate PI3-kinase. Third, the identity of the kinase responsible for the GH-stimulated tyrosine phosphorylation of IRS proteins. Fourth, whether additional cytokine receptor superfamily/IRS proteins signaling pathways could also operate. Using specific antibodies, we show here that GH was able to induce tyrosine phosphorylation of IRS-1/IRS-2, and that tyrosine phosphorylation of IRS-1 may be a major mechanism for GH-induced PI3-kinase activation in physiological target organ, liver, using IRS-1-deficient mice. Finally, by using the JAK2-deficient cell lines or by expressing a dominant negative JAK2 mutant, we show that JAK2 is required for the GH- and PRL-dependent tyrosine phosphorylation of IRS-1, -2, and -3, their association with p85 PI3-kinase and activation of PI3-kinase. Taken together, the role of IRS-1, -2, and -3 in GH and PRL signalings is to be phosphorylated by JAK2, thereby providing docking sites for p85 PI3-kinase and activating PI3-kinase. A specific PI3-kinase inhibitor, wortmannin, completely blocked the anti-lipolytic effect of GH in 3T3 L1 adipocytes, as reported in isolated rat adipocytes (
      • Ridderstrale M.
      • Tornqvist H.
      ). Thus our data may provide the biochemical fundamentals to understand the insulin-like effects of GH such as anti-lipolysis.

      ACKNOWLEDGEMENTS

      We thank J. Ihle for JAK2 cDNA, K. Arai for expression vectors of JAK2 and dominant negative JAK2 (ΔJAK2), M. Takahashi, M. Wada, and M. Honjo for CHO-PRLR and CHO-GHR cells, and S. Kakinuma for technical assistance.

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