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CrkII Participation in the Cellular Effects of Growth Hormone and Insulin-like Growth Factor-1

PHOSPHATIDYLINOSITOL-3 KINASE DEPENDENT AND INDEPENDENT EFFECTS*
Open AccessPublished:June 09, 2000DOI:https://doi.org/10.1074/jbc.M001972200
      We have examined the role of CrkII in the cellular response to both human growth hormone (hGH) and human insulin-like growth factor-1 (hIGF-1). We have demonstrated that overexpression of the adaptor molecule enhances both basal phosphatidylinositol 3-kinase (PI 3-kinase) activity and also dramatically enhances the ability of both hormones to stimulate PI 3-kinase activity in the cell. Many of the effects of CrkII overexpression on hGH- and hIGF-1-stimulated cellular function can then be attributed to CrkII enhancement of PI 3-kinase stimulation by these hormones. Thus, CrkII-enhanced PI 3-kinase activity is used to enhance actin filament reorganization in response to both hGH and hIGF-1, to enhance stress activated protein kinase (SAPK) activity in response to hGH, and to diminish STAT5-mediated transcription in response to hGH. It is apparent, however, that CrkII also regulates cellular function independent of its ability to stimulate PI 3-kinase activity. This is evidenced by the ability of CrkII, in a PI 3-kinase-independent manner, to diminish the activation of p44/42 mitogen-activated protein kinase in response to both hGH and hIGF-1 and to inhibit the activation of SAPK by hIGF-1. Therefore, despite the common use of CrkII to activate PI 3-kinase, CrkII also allows hGH or hIGF-1 to selectively switch the activation of SAPK. Thus, common utilization of CrkII by hGH and hIGF-1 allows the execution of common cellular effects of these hormones, concomitant with the retention of hormonal specificity.
      GH
      growth hormone
      hGH
      human growth hormone
      IGF-1
      insulin-like growth factor-1
      hIGF-1
      human IGF-1
      FAK
      focal adhesion kinase
      PMSF
      phenylmethylsulfonyl fluoride
      TRITC
      tetramethylrhodamine isothiocyanate
      FITC
      fluorescein isothiocyanate
      PBS
      phosphate-buffered saline
      MAP
      mitogen-activated protein
      SAPK
      stress-activated protein kinase
      CAT
      chloramphenicol acetyltransferase
      PI
      phosphatidylinositol
      STAT
      signal transducer and activator of transcription
      Growth hormone (GH)1 is the major regulator of postnatal somatic growth (
      • Isaksson O.G.P.
      • Eden S.
      • Jansson J.O.
      ). The anabolic and growth-promoting effects of GH are largely thought to be mediated via stimulation of insulin-like growth factor-1 expression in hepatic and extrahepatic tissues (
      • Butler A.A.
      • Ambler G.R.
      • Breier B.H.
      • LeRoith D.
      • Roberts Jr., C.T.
      • Gluckman P.D.
      ). Although it is now apparent that GH may act independently of insulin-like growth factor-1 (IGF-1), the two hormones possess multiple common effects on cellular function. The GH receptor is a member of the cytokine receptor superfamily and therefore mediates tyrosine phosphorylation of cellular proteins by its association with the JAK family of nonreceptor tyrosine kinases (
      • Carter-Su C.
      • Schwartz J.
      • Smit L.S.
      ). In contrast, the IGF-1 receptor is a receptor tyrosine kinase, and ligand stimulation results in direct phosphorylation of signaling molecules by the receptor itself. Despite the difference in which the hormones initiate signal transduction, there exists a common utilization of multiple signal-transducing molecules such as FAK, CrkII, p130 cas, IRS-1, IRS-2, p44/42 MAP kinase, and PI 3-kinase, which may provide the basis for the shared cellular function (
      • Zhu T.
      • Goh E.L.K.
      • Lobie P.E.
      ,
      • Beitner-Johnson D.
      • LeRoith D.
      ,
      • Zhu T.
      • Goh E.L.K.
      • LeRoith D.
      • Lobie P.E.
      ,
      • Sorokin A.
      • Reed E.
      ,
      • Souza S.C.
      • Frick G.P.
      • Yip R.
      • Lobo R.B.
      • Tai L.R.
      • Goodman H.M.
      ,
      • Sun X.J.
      • Pons S.
      • Wang L.M.
      • Zhang Y.
      • Yenush L.
      • Burks D.
      • Nyers Jr., M.G.
      • Glasheen E.
      • Copeland N.G.
      • Jenkins N.A.
      • Pierce J.H.
      • White M.F.
      ,
      • Parrizas M.
      • Saltiel A.R.
      • LeRoith D.
      ).
      We have previously demonstrated that human growth hormone (hGH) stimulates the formation of a large multiprotein signaling complex centered around CrkII and p130 cas. CrkII is a member of a family of adaptor proteins predominantly composed of Src homology 2 and 3 domains whose role in signaling pathways is presently unclear, although it has been implicated in various cellular functions such as cytoskeletal reorganization and mitogenesis (
      • Klemke R.L.
      • Leng J.
      • Molamder R.
      • Brooks P.C.
      • Vuori K.
      • Cheresh D.A.
      ,
      • Nakashima N.
      • Rose D.W.
      • Xiao S.
      • Egawa K.
      • Martin S.S.
      • Haruta T.
      • Saltiel A.R.
      • Olefsky J.M.
      ). Similarly, the structure of p130 cas suggests that it is a docking protein with a role in multiprotein signaling complexes (
      • Sakai R.
      • Iwamatsu A.
      • Hirano N.
      • Ogawa S.
      • Tanaka T.
      • Mano H.
      • Yazaki Y.
      • Hirai H.
      ). Other components of the hGH-stimulated complex include c-Src, c-Fyn, c-Cbl, Nck, FAK, paxillin, IRS-1, C3G, SHC, Grb-2, and Sos-1 (
      • Zhu T.
      • Goh E.L.K.
      • LeRoith D.
      • Lobie P.E.
      ). Here we have examined the role of CrkII in the cellular responses to both GH and IGF-1 and demonstrate that the adaptor molecule acts as both a point of convergence and divergence in their cellular effects. It appears that many of the effects of CrkII on the cellular functions of hGH and hIGF-1 lie with its ability to dramatically enhance PI 3-kinase activity stimulated by these hormones. Despite the common use of CrkII to activate PI 3-kinase, CrkII also allows these hormones to selectively switch the activation of SAPK. Thus, common utilization of CrkII by hGH and hIGF-1 allows the execution of the common cellular effects of these hormones, concomitant with the retention of hormonal specificity.

      DISCUSSION

      We have demonstrated here that the CrkII adaptor molecule regulates various hGH and hIGF-1 signaling pathways. We have identified CrkII as a powerful positive regulator of PI 3-kinase activity stimulated by both hGH and hIGF-1. The mechanism by which CrkII regulates PI 3-kinase activity is not clear, although we have previously demonstrated that both CrkII and the p85 regulatory subunit of PI 3-kinase co-exist in a multiprotein signaling complex stimulated by hGH (
      • Zhu T.
      • Goh E.L.K.
      • LeRoith D.
      • Lobie P.E.
      ). Other components of this complex include p130 cas, c-Src, c-Fyn, c-Cbl, Nck, FAK, paxillin, IRS-1, C3G, SHC, Grb-2, and Sos-1. One possibility is that CrkII simply acts as an adaptor molecule to facilitate the interactions between components of the hGH-stimulated complex regulating PI 3-kinase activity. In this regard, it is interesting that c-Fyn has been reported to phosphorylate tyrosine 731 of c-Cbl, which is required for the binding of the p85 subunit of PI 3-kinase to c-Cbl (
      • Hunter S.
      • Burton E.A.
      • Wu S.C.
      • Anderson S.M.
      ). Similarly, IRS-1 has been reported to be a substrate for FAK, and FAK overexpression has been reported to increase IRS-1 tyrosine phosphorylation and the association between IRS-1 and the p85 subunit of PI 3-kinase (
      • Lebrun P.
      • Mothe-Satney I.
      • Delahaye L.
      • Van Obberghen E.
      • Baron V.
      ). Activation of PI 3-kinase by the related hormone prolactin has been demonstrated to require c-Fyn (
      • al-Sakkaf K.A.
      • Dobson P.R.
      • Brown B.L.
      ), although c-Fyn and the p85 subunit of PI 3-kinase may associate directly (
      • Mak P.
      • He Z.
      • Kurosaki T.
      ). The p85 subunit of PI 3-kinase has also been reported to associate with FAK either directly or indirectly, and FAK has been demonstrated to phosphorylate p85 in vitro (
      • Chen H.C.
      • Appeddu P.A.
      • Isoda H.
      • Guan J.L.
      ). In any case, the majority of the effects of CrkII overexpression on hGH- and hIGF-1-stimulated cellular function can be attributed to CrkII enhancement of PI 3-kinase stimulation by these hormones. It is apparent, however, that CrkII also regulates cellular function independent of its ability to stimulate PI 3-kinase activity as evidenced by the ability of CrkII to diminish the activation of p44/42 MAP kinase in response to both hGH and hIGF-1 in a PI 3-kinase-independent manner.
      We have previously demonstrated that actin cytoskeletal reorganization stimulated by both hGH and hIGF-1 is PI 3- kinase-dependent (
      • Goh E.L.K.
      • Pircher T.J.
      • Wood T.J.J.
      • Norstedt G.
      • Graichen R.
      • Lobie P.E.
      ). Thus, CrkII-enhanced stimulation of PI 3-kinase activity by both hormones resulted in increased formation of membrane ruffles in these cells (this study); since the effect of CrkII overexpression on cytoskeletal reorganization could be inhibited with PI 3-kinase inhibitors. These results are in agreement with a recent report in which microinjection of CrkII antibody into cells prevented membrane ruffle formation induced by IGF-1 (
      • Nakashima N.
      • Rose D.W.
      • Xiao S.
      • Egawa K.
      • Martin S.S.
      • Haruta T.
      • Saltiel A.R.
      • Olefsky J.M.
      ). CrkII overexpression in fibroblasts has also been demonstrated to enhance p130 cas phosphorylation and Rac-dependent cell migration (
      • Klemke R.L.
      • Leng J.
      • Molamder R.
      • Brooks P.C.
      • Vuori K.
      • Cheresh D.A.
      ), and the formation of a p130 cas -CrkII complex has been demonstrated to be sufficient for cell migration. We have also demonstrated that CrkII possessed the appropriate spatial distribution within the cell to mediate membrane ruffle formation, with both CrkII and the p85 regulatory subunit of PI 3-kinase localized to the membrane ruffles. It has also been previously demonstrated that CrkII is localized to the membrane ruffles of cells induced by attachment of the cells to vitronectin matrix or upon insulin treatment (
      • Klemke R.L.
      • Leng J.
      • Molamder R.
      • Brooks P.C.
      • Vuori K.
      • Cheresh D.A.
      ). The association and functional interactions between PI 3-kinase and the mediators of actin rearrangements, the small GTPases Rho and Rac, is well established (
      • Keely P.J.
      • Westwick J.K.
      • Whitehead I.P.
      • Der C.J.
      • Parise L.V.
      ). Recently, CrkII has been shown to regulate the Rho signaling pathway (
      • Klemke R.L.
      • Leng J.
      • Molamder R.
      • Brooks P.C.
      • Vuori K.
      • Cheresh D.A.
      ,
      • Li E.
      • Stupack D.
      • Bokoch G.M.
      • Nemerow G.R.
      ,
      • Nievers M.G.
      • Birge R.B.
      • Greulich H.
      • Verkleij A.J.
      • Hanafusa H.
      • van Bergen en Henegouwen P.M.
      ,
      • Altun-Gultekin Z.F.
      • Chandriani S.
      • Bougeret C.
      • Ishizaki T.
      • Narumiya S.
      • De Graaf P.
      • van Bergen en Henegouwen P.M.
      ,
      • Feller S.M.
      • Knudsen B.
      • Hanafusa H.
      ,
      • Erickson M.R.
      • Galletta B.J.
      • Abmayr S.M.
      ,
      • Yamaguchi A.
      • Urano T.
      • Goi T.
      • Feig L.A.
      ,
      • Wu Y-C.
      • Horvitz H.R.
      ). In addition, DOCK180, a CrkII Src homology 3-binding protein, was shown to participate in the activation of Rac1 in integrin signaling (
      • Kiyokawa E.
      • Hashimoto Y.
      • Kobayashi S.
      • Sugimura H.
      • Kurata T.
      • Matsuda M.
      ).
      We have demonstrated here that overexpression of CrkII enhances the ability of hGH to stimulate SAPK activity as previously published (
      • Zhu T.
      • Goh E.L.K.
      • LeRoith D.
      • Lobie P.E.
      ) and in accord with the demonstration that a CrkII-C3G complex activates SAPK through a pathway involving the mixed lineage kinase family of proteins (
      • Tanaka S.
      • Hanafusa H.
      ). Interestingly, however, we observe that CrkII overexpression diminishes the hGH stimulation of p44/42 MAP kinase activity. We have previously reported that C3G is present in the hGH-stimulated multiprotein signaling complex centered around CrkII, and we have also observed hGH-stimulated tyrosine phosphorylation of C3G.
      T. Zhu and P. E. Lobie, unpublished observations.
      C3G appears to function as a specific guanine nucleotide exchange factor for Rap1 (
      • Gotoh T.
      • Hattori S.
      • Nakamura S.
      • Kitayama H.
      • Noda M.
      • Takai Y.
      • Kaibuchi K.
      • Matsui H.
      • Hatase O.
      • Takahashi H.
      ), and membrane targeting of Crk enhances the Rap1 guanine nucleotide exchange activity of C3G (
      • Ichiba T.
      • Kuraishi Y.
      • Sakai O.
      • Nagata S.
      • Groffen J.
      • Kurata T.
      • Hattori S.
      • Matsuda M.
      ). It has been reported that insulin stimulation of cells results in a rapid disassociation of the CrkII-C3G complex (
      • Okada S.
      • Matsuda M.
      • Anafi M.
      • Pawson T.
      • Pessin J.E.
      ) with subsequent inhibition of the Rap1-Raf1 interaction. These authors postulate that uncoupling of the CrkII-C3G complex by insulin de-represses Rap1 function, thereby releasing Raf1 for activation by Ras, with resultant MEK activation (
      • Okada S.
      • Matsuda M.
      • Anafi M.
      • Pawson T.
      • Pessin J.E.
      ). In contrast, since CrkII overexpression inhibited hGH stimulation of p44/42 MAP kinase, hGH stimulation of cells would be expected to activate Rap1 in a CrkII-dependent manner, and this is indeed what we find.
      T. Zhu, and P. E. Lobie, manuscript in preparation.
      The effect of hIGF-1 on the CrkII-C3G complex has not been reported, but it should not be expected to be similar to insulin, since IGF-1 and insulin differentially regulate CrkII-associated proteins. One example is that insulin stimulates the dephosphorylation of p130 cas, whereas cellular stimulation with IGF-1 results in increased p130 cas phosphorylation (
      • Sorokin A.
      • Reed E.
      ). One difference that has been reported for hGH and hIGF-1 is that hGH stimulates the association between CrkII and IRS-1 (
      • Zhu T.
      • Goh E.L.K.
      • LeRoith D.
      • Lobie P.E.
      ), whereas IGF-1 stimulates the disassociation between CrkII and IRS-1 (
      • Beitner-Johnson D.
      • Blakesley V.A.
      • Shen-Orr Z.
      • Jimenez M.
      • Stannard B.
      • Wang L.M.
      • Pierce J.
      • LeRoith D.
      ). In any case, although both hGH and IGF-1 stimulate the phosphorylation of CrkII, it is differentially utilized for regulation of SAPK but not p44/42 MAP kinase activities. Further studies are required to identify the mechanisms involved in the selective activation of p44/42 MAP kinase or SAPK by these hormones.
      We have demonstrated in this paper that overexpression of CrkII diminishes hGH stimulation of STAT5-mediated transcription in a PI 3-kinase-dependent manner without alteration of hGH-stimulated STAT5 tyrosine phosphorylation. This suggests that CrkII regulation of STAT5 transcription occurs distally. It has been demonstrated that type I interferons induced the formation of a CrkL-STAT5 complex that translocates to the nucleus, and CrkL, in this case, modulates STAT5-mediated transcription directly at the level of DNA binding (
      • Fish E.N.
      • Uddin S.
      • Korkmaz M.
      • Majchrzak B.
      • Druker B.J.
      • Platanias L.C.
      ). A similar direct association between phosphorylated STAT5 and CrkL has been demonstrated upon stimulation of the EPO receptor (
      • Ota J.
      • Kimura F.
      • Sato K.
      • Wakimoto N.
      • Nakamura Y.
      • Nagata N.
      • Suzu S.
      • Yamada M.
      • Shimamura S.
      • Motoyoshi K.
      ). Thus, it is likely that CrkII also associates with phosphorylated STAT5 and prevents its binding to DNA and therefore transcriptional activation. It is interesting that c-Cbl, which is also found in the multiprotein signaling complex stimulated by hGH, decreases hGH stimulated STAT5-mediated transcription by inhibition of STAT5 phosphorylation.
      E. L. K. Goh, T. Zhu, and P. E. Lobie, unpublished observations.
      Thus, two adaptor molecules present in the hGH stimulated multiprotein complex act to inhibit STAT5-mediated transcription at either proximal or distal points in the signal transduction pathway. At the present time, it is not clear why CrkII inhibition of STAT5-mediated transcription is PI 3-kinase-dependent. It is interesting to note that the activation of phospholipase C is PI 3-kinase dependent and pharmacological inhibition of phospholipase C also increases GH-stimulated STAT5-mediated transcription (
      • Fernandez L.
      • Flores-Morales A.
      • Lahuna O.
      • Sliva D.
      • Norstedt G.
      • Haldosen L.A.
      • Mode A.
      • Gustafsson J.A.
      ) by maintaining the activation (or delaying the deactivation) of STAT5. It remains to be determined how PI 3-kinase negatively regulates STAT5-mediated transcription.
      In conclusion, we have examined the role of CrkII in the cellular response to both GH and IGF-1 and demonstrate that the adaptor molecule acts as both a point of convergence and divergence in their cellular effects. It appears that many of the effects of CrkII on the cellular function of hGH and hIGF-1 lie with its ability to dramatically enhance PI 3-kinase activity stimulated by these hormones. Despite the common use of CrkII to activate PI 3-kinase, CrkII also allows these hormones to selectively switch the activation of SAPK. Thus, common utilization of CrkII by hGH and hIGF-1 allows the execution of the common cellular effects of these hormones, concomitant with the retention of hormonal specificity.

      REFERENCES

        • Isaksson O.G.P.
        • Eden S.
        • Jansson J.O.
        Annu. Rev. Physiol. 1985; 47: 433-489
        • Butler A.A.
        • Ambler G.R.
        • Breier B.H.
        • LeRoith D.
        • Roberts Jr., C.T.
        • Gluckman P.D.
        Mol. Cell. Endocrinol. 1994; 101: 321-330
        • Carter-Su C.
        • Schwartz J.
        • Smit L.S.
        Annu. Rev. Physiol. 1996; 58: 187-207
        • Zhu T.
        • Goh E.L.K.
        • Lobie P.E.
        J. Biol. Chem. 1998; 273: 10682-10689
        • Beitner-Johnson D.
        • LeRoith D.
        J. Biol. Chem. 1995; 270: 5187-5190
        • Zhu T.
        • Goh E.L.K.
        • LeRoith D.
        • Lobie P.E.
        J. Biol. Chem. 1998; 273: 33864-33875
        • Sorokin A.
        • Reed E.
        Biochem. J. 1998; 334: 595-600
        • Souza S.C.
        • Frick G.P.
        • Yip R.
        • Lobo R.B.
        • Tai L.R.
        • Goodman H.M.
        J. Biol. Chem. 1994; 269: 30085-30088
        • Sun X.J.
        • Pons S.
        • Wang L.M.
        • Zhang Y.
        • Yenush L.
        • Burks D.
        • Nyers Jr., M.G.
        • Glasheen E.
        • Copeland N.G.
        • Jenkins N.A.
        • Pierce J.H.
        • White M.F.
        Mol. Endocrinol. 1997; 11: 251-262
        • Parrizas M.
        • Saltiel A.R.
        • LeRoith D.
        J. Biol. Chem. 1997; 272: 154-161
        • Klemke R.L.
        • Leng J.
        • Molamder R.
        • Brooks P.C.
        • Vuori K.
        • Cheresh D.A.
        J. Cell Biol. 1998; 140: 961-972
        • Nakashima N.
        • Rose D.W.
        • Xiao S.
        • Egawa K.
        • Martin S.S.
        • Haruta T.
        • Saltiel A.R.
        • Olefsky J.M.
        J. Biol. Chem. 1999; 274: 3001-3008
        • Sakai R.
        • Iwamatsu A.
        • Hirano N.
        • Ogawa S.
        • Tanaka T.
        • Mano H.
        • Yazaki Y.
        • Hirai H.
        EMBO J. 1994; 13: 3748-3756
        • Chen H.C.
        • Guan J.L.
        Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10148-10152
        • Auger K.R.
        • Songyang Z.
        • Lo S.H.
        • Roberts T.M.
        • Chen L.B.
        J. Biol. Chem. 1996; 271: 23452-23457
        • Hartley D.
        • Meisner H.
        • Corvera S.
        J. Biol. Chem. 1995; 270: 18260-18263
        • Yamauchi T.
        • Kaburagi Y.
        • Ueki K.
        • Tsuji Y.
        • Stark G.R.
        • Kerr I.M.
        • Tsushima T.
        • Akanuma Y.
        • Komuro I.
        • Tobe K.
        • Yazaki Y.
        • Kadowaki T.
        J. Biol. Chem. 1998; 273: 15719-15726
        • Goh E.L.K.
        • Pircher T.J.
        • Wood T.J.J.
        • Norstedt G.
        • Graichen R.
        • Lobie P.E.
        Endocrinology. 1997; 138: 3207-3215
        • Hodge C.
        • Liao J.
        • Stofega M.
        • Guan K.
        • Carter-Su C.
        • Schwartz J.
        J. Biol. Chem. 1998; 273: 31327-31336
        • Smit L.S.
        • Meyer D.J.
        • Billestrup N.
        • Norstedt G.
        • Schwartz J.
        • Carter-Su C.
        Mol. Endocrinol. 1996; 10: 519-533
        • Hunter S.
        • Burton E.A.
        • Wu S.C.
        • Anderson S.M.
        J. Biol. Chem. 1999; 274: 2097-2106
        • Lebrun P.
        • Mothe-Satney I.
        • Delahaye L.
        • Van Obberghen E.
        • Baron V.
        J. Biol. Chem. 1998; 273: 32244-32253
        • al-Sakkaf K.A.
        • Dobson P.R.
        • Brown B.L.
        J. Mol. Endocrinol. 1997; 19: 347-350
        • Mak P.
        • He Z.
        • Kurosaki T.
        FEBS Lett. 1996; 397: 183-185
        • Chen H.C.
        • Appeddu P.A.
        • Isoda H.
        • Guan J.L.
        J. Biol. Chem. 1996; 271: 26329-26334
        • Keely P.J.
        • Westwick J.K.
        • Whitehead I.P.
        • Der C.J.
        • Parise L.V.
        Nature. 1997; 11: 632-636
        • Li E.
        • Stupack D.
        • Bokoch G.M.
        • Nemerow G.R.
        J. Virol. 1998; 72: 8806-8812
        • Nievers M.G.
        • Birge R.B.
        • Greulich H.
        • Verkleij A.J.
        • Hanafusa H.
        • van Bergen en Henegouwen P.M.
        J. Cell Sci. 1997; 110: 389-399
        • Altun-Gultekin Z.F.
        • Chandriani S.
        • Bougeret C.
        • Ishizaki T.
        • Narumiya S.
        • De Graaf P.
        • van Bergen en Henegouwen P.M.
        Mol. Cell. Biol. 1998; 18: 3044-3058
        • Feller S.M.
        • Knudsen B.
        • Hanafusa H.
        EMBO J. 1994; 13: 2341-2351
        • Erickson M.R.
        • Galletta B.J.
        • Abmayr S.M.
        J. Cell Biol. 1997; 138: 589-603
        • Yamaguchi A.
        • Urano T.
        • Goi T.
        • Feig L.A.
        J. Biol. Chem. 1997; 272: 31230-31234
        • Wu Y-C.
        • Horvitz H.R.
        Nature. 1998; 392: 501-504
        • Kiyokawa E.
        • Hashimoto Y.
        • Kobayashi S.
        • Sugimura H.
        • Kurata T.
        • Matsuda M.
        Genes Dev. 1998; 12: 3331-3336
        • Tanaka S.
        • Hanafusa H.
        J. Biol. Chem. 1998; 273: 1281-1284
        • Gotoh T.
        • Hattori S.
        • Nakamura S.
        • Kitayama H.
        • Noda M.
        • Takai Y.
        • Kaibuchi K.
        • Matsui H.
        • Hatase O.
        • Takahashi H.
        Mol. Cell. Biol. 1995; 15: 6746-6753
        • Ichiba T.
        • Kuraishi Y.
        • Sakai O.
        • Nagata S.
        • Groffen J.
        • Kurata T.
        • Hattori S.
        • Matsuda M.
        J. Biol. Chem. 1997; 272: 22215-22220
        • Okada S.
        • Matsuda M.
        • Anafi M.
        • Pawson T.
        • Pessin J.E.
        EMBO J. 1998; 17: 2554-2565
        • Beitner-Johnson D.
        • Blakesley V.A.
        • Shen-Orr Z.
        • Jimenez M.
        • Stannard B.
        • Wang L.M.
        • Pierce J.
        • LeRoith D.
        J. Biol. Chem. 1996; 271: 9287-9290
        • Fish E.N.
        • Uddin S.
        • Korkmaz M.
        • Majchrzak B.
        • Druker B.J.
        • Platanias L.C.
        J. Biol. Chem. 1999; 274: 571-573
        • Ota J.
        • Kimura F.
        • Sato K.
        • Wakimoto N.
        • Nakamura Y.
        • Nagata N.
        • Suzu S.
        • Yamada M.
        • Shimamura S.
        • Motoyoshi K.
        Biochem. Biophys. Res. Commun. 1998; 252: 779-786
        • Fernandez L.
        • Flores-Morales A.
        • Lahuna O.
        • Sliva D.
        • Norstedt G.
        • Haldosen L.A.
        • Mode A.
        • Gustafsson J.A.
        Endocrinology. 1998; 139: 1815-1824