Insulin Like Growth Factor 1 Receptor Signal Transduction to the Nucleus

  • Steven A. Rosenzweig
  • Barry S. Oemar
  • Norman M. Law
  • Uma T. Shankavaram
  • Bradley S. Miller
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 343)


The IGF-1 receptor (IGF-1R) is a member of the tyrosine kinase class of cell surface receptors which become autophosphorylated on tyrosyl residues upon ligand binding (Czech, 1989). It has striking homology to the insulin receptor; however, each receptor maintains a unique specificity for its own ligand (Schumacher et al., 1991). The mechanism by which the binding of IGF-1 to its receptor elicits a cellular effect has been the subject of considerable research with a singular cohesive model having yet to be defined. The autophosphorylation of the IGF-1R via subunit transphosphorylation is clearly a necessary requisite for transmission of an intracellular signal, as found for the insulin receptor (Sweet et al., 1987; Ullrich and Schlessinger, 1990). In the case of other growth factor receptors with tyrosine kinase domains such as the EGF and PDGF receptors, receptor activation results in phospholipase C activation leading to 1,2-diacylglycerol and inositol 1,4,5-trisphosphate production and a corresponding increase in protein kinase C (pkC) and calcium mobilization, respectively (Berridge, 1993). Recently, evidence for a direct association between the EGF and PDGF receptors and a number of key substrates such as phospholipase C-γ, PI-3 kinase and GAP (p21ras GTPase activating protein, Cantley et al., 1991) has been demonstrated. This direct link has also been established for the IGF-1R and PI-3 kinase interactions (Cantley et al., 1991; Yamamoto et al., 1992; Lavan et al., 1992). It was recently reported that in cells stimulated with insulin in the presence of the protein tyrosine phosphatase inhibitor, phenylarsine oxide, 5–10% of the cellular GAP associates with the insulin receptor (Pronk et al., 1992).


Insulin Receptor Nuclear Extract PDGF Receptor CaSki Cell Tyrosyl Residue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adler, V., Polotskaya, A., Wagner, F. and Kraft, A.S. (1992). Affinity-purified c-Jun amino-terminal protein kinase requires serine/threonine phosphorylation for activity. J. Biol. Chem. 267,17001–17005.PubMedGoogle Scholar
  2. Andrews, N.C. and Faller, D.V. (1991). A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nuc. Acids Res. 19, 2499.CrossRefGoogle Scholar
  3. Angel, P., Imagawa, M., Chiu, R., Stein, B., Imbra, R.J., Rahmsdorf, H.J., Jonat, C., Herrlich, P. and Karin, M. (1987). Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-activating factor. Cell 49, 729–739.PubMedCrossRefGoogle Scholar
  4. Bell, J.C., Mahadevan, L.C., Colledge, W.H., Frackleton Jr., A.R., Sargent, M.G. and Foulkes, J.G. (1987). Abelson-transformed fibroblasts contain nuclear phosphotyrosyl proteins which preferentially bind to murine DNA. Nature 325, 552–554.PubMedCrossRefGoogle Scholar
  5. Berridge, M.J. (1993). Inositol trisphosphate and calcium signalling. Nature 361, 315–325.PubMedCrossRefGoogle Scholar
  6. Bos, T.J., Bohmann, D., Tsuchle, H., Tjian, R. and Vogt, P.K. (1988). v-jun encodes a nuclear protein with enhancer binding properties of AP-1. Cell 52, 705–712.PubMedCrossRefGoogle Scholar
  7. Cantley, L.C., Auger, K.R., Carpenter, C., Duckworth, B., Graziani, A., Kapeller, R. and Soltoff, S. (1991). Oncogenes and signal transduction. Cell 64, 281–302.PubMedCrossRefGoogle Scholar
  8. Chen, R.H., Sarnecki, C. and Blenis, J. (1992). Nuclear localization and regulation of erk-encoded and rskencoded protein kinases. Mol. Cell. Biol. 12, 915–927.PubMedGoogle Scholar
  9. Czech, M.P. (1989). Signal transmission by the insulin-like growth factors. Cell 59, 235–238.PubMedCrossRefGoogle Scholar
  10. Kaleko, M., Rutter, W.J. and Miller, A.D. (1990). Overexpression of the human insulinlike growth factor I receptor promotes ligand-dependent neoplastic transformation. Mol. Cell. Biol. 10, 464–73.PubMedGoogle Scholar
  11. Koch, C.A., Anderson, D., Moran, M.F., Ellis, C. and Pawson, T. (1991). SH2 and SH3 domains -Elements that control interactions of cytoplasmic signaling proteins. Science 252, 668–674.PubMedCrossRefGoogle Scholar
  12. Lavan, B.E., Kuhne, M.R., Garner, C.W., Anderson, D., Reedijk, M., Pawson, T. and Lienhard, G.E. (1992). The association of insulin-elicited phosphotyrosine proteins with sre homology 2 domains. J. Biol Chem. 267, 11631–6.PubMedGoogle Scholar
  13. Nakabeppu, Y., Ryder, K. and Nathans, D. (1988). DNA binding activities of three murine jun proteins: Stimulation by fos. Cell 55, 907–915.PubMedCrossRefGoogle Scholar
  14. Oemar, B.S., Foellmer, H.G., Hodgdon-Anandan, L. and Rosenzweig, S.A. (1991a). Regulation of Insulin-Like Growth Factor-I Receptors in diabetic mesangial cells. J. Biol. Chem. 266, 2369–2373.PubMedGoogle Scholar
  15. Oemar, B.S., Law, N.M. and Rosenzweig, S.A. (1991b). Insulin-Like Growth Factor-I induces tyrosyl phosphorylation of nuclear proteins. J. Biol. Chem. 266, 24241–24244.PubMedGoogle Scholar
  16. Pronk, G.J., Polakis, P., Wong, G., Devriessmits, A.M.M., Bos, J.L. and Mccormick, F. (1992). Association of a tyrosine kinase activity with gap complexes in v-src transformed fibroblasts. Oncogene 7, 389– 394.PubMedGoogle Scholar
  17. Ray, L.B. and Sturgill, T.W. (1988). Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo. Proc. Natl. Acad. Sci. USA 85, 3753–3757.PubMedCrossRefGoogle Scholar
  18. Rosenzweig, S.A., Zetterstròm, C. and Benjamin, A. Identification of retinal insulin receptors using sitespecific antibodies to a carboxyl-terminal peptide of the human insulin receptor α-subunit: Up-regulation of neuronal insulin receptors in diabetes. J. Biol. Chem. 265:18030–18034, 1990.PubMedGoogle Scholar
  19. Rothenberg, P.L., Lane, W.S., Karasik, A., Backer, J., White, M. and Kahn, C.R. (1991). Purification and partial sequence analysis of pp185, the major cellular substrate of the insulin receptor tyrosine kinase. J. Biol. Chem. 266, 8302–8311.PubMedGoogle Scholar
  20. Schumacher, R., Mosthaf, L., Schlessinger, J., Brandenburg, D. and Ullrich, A. (1991). Insulin and Insulin-Like Growth Factor-1 binding specificity is determined by distinct regions of their cognate receptors. J. Biol. Chem. 266, 19288–19295.PubMedGoogle Scholar
  21. Sheng, M. and Greenberg, M.E. (1990). The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 4, 477–485.PubMedCrossRefGoogle Scholar
  22. Singh, H., Sen, R., Baltimore, D. and Sharp, P.A. (1986). A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes. Nature 319, 154–158.PubMedCrossRefGoogle Scholar
  23. Smeal, T., Binetruy, B., Mercola, D., Groverbardwick, A., Heidecker, G., Rapp, U.R. and Karin, M. (1992). Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serine-63 and serine-73. Mol. Cell. Biol. 12, 3507–3513.PubMedGoogle Scholar
  24. Sun, X.J., Rothenberg, P., Kahn, C.R., Backer, J.M., Araki, E., Wilden, P.A., Cahill, D.A., Goldstein, B.J. and White, M.F. (1991). Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73–77.PubMedCrossRefGoogle Scholar
  25. Sweet, L.J., Morrison, B.D., Wilden, P.A. and Pessin, J.E. (1987). Insulin-dependent intermolecular subunit communication between isolated αß heterodimeric insulin receptor complexes. J. Biol. Chem. 262, 16730–16738.PubMedGoogle Scholar
  26. Trejo, J., Chambard, J-C., Karin, M. and Brown, J.H. (1992). Biphasic increase in c-jun mRNA is required for induction of AP-1-mediated gene transcription: Differential effects of muscarinic and thrombin receptor activation. Mol. Cell Biol. 12, 4742–4750.PubMedGoogle Scholar
  27. Ullrich, A. and Schlessinger, J. (1990). Signal transduction by receptors with tyrosine kinase activity. Cell 61,203–212.PubMedCrossRefGoogle Scholar
  28. Werner, H., Shenorr, Z., Stannard, B., Burguera, B., Roberts, C.T. and Leroith, D. (1990). Experimental diabetes increases Insulinlike Growth Factor-I and Factor-II receptor concentration and gene expression in kidney. Diabetes 39, 1490–1497.PubMedCrossRefGoogle Scholar
  29. White, M.F., Maron, R. and Kahn, C.R. (1985). Insulin rapidly stimulates tyrosine phosphorylation of a Mr 185,000 protein in intact cells. Nature 318, 183–186.PubMedCrossRefGoogle Scholar
  30. Yamamoto, K., Altschuler, D., Wood, E., Horlick, K., Jacobs, S. and Lapetina, E.G. (1992). Association of phosphorylated Insulin-like Growth Factor-I receptor with the SH2 domains of phosphatidylinositol 3-kinase p85. J. Biol. Chem. 267 ,11337–43.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Steven A. Rosenzweig
    • 1
  • Barry S. Oemar
    • 2
  • Norman M. Law
    • 3
  • Uma T. Shankavaram
    • 1
  • Bradley S. Miller
    • 1
  1. 1.Department of Cell and Molecular Pharmacology and Experimental TherapeuticsMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Research Kantonsspital BaselUniversity of BaselBaselSwitzerland
  3. 3.Oncology and Virology Research Department, Pharmaceuticals DivisionCIBA-GEIGY, Ltd.BaselSwitzerland

Personalised recommendations