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Research Article| Volume 45, ISSUE 12, P1474-1482, December 1996

The dominant negative effect of a kinase-defective insulin receptor on insulin-like growth factor-I-stimulated signaling in Rat-1 fibroblasts

DOI:https://doi.org/10.1016/S0026-0495(96)90175-4
The dominant negative effect of a kinase-defective insulin receptor on insulin-like growth factor-I-stimulated signaling in Rat-1 fibroblasts
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      Abstract

      To study the interaction between insulin receptor (IR) and insulin-like growth factor-I (IGF-I) receptor (IGF-IR) tyrosine kinases, we examined IGF-I action in Rat-1 cells expressing a naturally occurring tyrosine kinase-deficient mutant IR (Asp 1048 IR). IGF-I normally stimulated receptor autophosphorylation, IRS-I phosphorylation, and glycogen synthesis in cells expressing Asp 1048 IR. However, the Asp 1048 IR inhibited IGF-I-stimulated thymidine uptake by 45% to 52% and amino acid uptake (aminoisobutyric acid [AIB]) by 58% in Asp 1048 IR cells. Furthermore, IGF-I-stimulated tyrosine kinase activity toward synthetic polymers, Shc phosphorylation, and mitogen-activated protein (MAP) kinase activity was inhibited. The inhibition of mitogenesis and AIB uptake was restored with the amelioration of the impaired tyrosine kinase activity and Shc phosphorylation by the introduction of abundant wild-type IGF-IR in Asp 1048 IR cells. These results suggest that the Asp 1048 IR causes a dominant negative effect on IGF-IR in transmitting signals to Shc and MAP kinase activation, which leads to decreased IGF-I-stimulated DNA synthesis, and that the kinase-defective insulin receptor does not affect IGF-I-stimulated IRS-I phosphorylation, which leads to the normal IGF-I-stimulated glycogen synthesis.
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      References

        • Froesch ER
        • Schmid C
        • Schwander J
        • et al.
        Actions of insulin-like growth factors.
        Annu Rev Physiol. 1985; 47: 443-467
        • Ebina Y
        • Ellisu L
        • Jarnagin K
        • et al.
        The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signaling.
        Cell. 1985; 40: 747-758
        • Ullich A
        • Gray A
        • Tam AW
        • et al.
        Insulin-like growth factor I receptor primary structure: Comparison with insulin receptor suggests structural determinants that define functional specificity.
        EMBO J. 1986; 5: 2503-2512
        • Ullrich A
        • Schlessinger J
        Signal transduction by the receptors with tyrosine kinase activity.
        Cell. 1990; 61: 203-212
        • Obberghen EV
        Signaling through the insulin receptor and the insulin-like growth factor-I receptor.
        Diabetologia. 1994; 37: S125-S134
        • Giorgetti S
        • Pelicci PG
        • Pelicci G
        • et al.
        Involvement of Src-homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor.
        Eur J Biochem. 1994; 223: 195-202
        • Beguinot F
        • Smith RJ
        • Kahn CR
        • et al.
        Phosphorylation of insulin-like growth factor I receptor by insulin receptor tyrosine kinase in intact cultured skeletal muscle cells.
        Biochemistry. 1988; 27: 3222-3228
        • Tartare S
        • Ballotti R
        • Obberghen EV
        Interaction between heterologous receptor tyrosine kinases.
        in: Hormone-stimulated insulin receptors activate unoccupied IGF-I receptors. ed 4. FEBS Lett. 295. 1991: 219-222
        • Kuzuya H
        • Matsuura N
        • Sakamoto M
        • et al.
        Trial of insulin like growth factor I therapy for patients with extreme insulin resistance syndromes.
        Diabetes. 1993; 42: 696-705
        • Turkalj I
        • Keller U
        • Ninnis R
        • et al.
        Effect of increasing doses of recombinant human insulin-like growth factor I on glucose, lipid, and leucine metabolism in man.
        J Clin Endocrinol Metab. 1992; 75: 1186-1197
        • Dohm GL
        • Elton CW
        • Raji MS
        • et al.
        IGF-I-stimulated glucose transport in human skeletal muscle and IGF-I resistance in obesity and NIDDM.
        Diabetes. 1990; 39: 1028-1032
        • Dills DG
        • Moss SE
        • Klein R
        • et al.
        Association of elevated IGF-I levels with increased retinopathy in late-onset diabetes.
        Diabetes. 1991; 40: 1725-1730
        • Haruta T
        • Takata Y
        • Iwanishi M
        • et al.
        Ala 1048-Asp mutation in the kinase domain of insulin receptor causes defective kinase activity and insulin resistance.
        Diabetes. 1993; 42: 1837-1844
        • Kaplowits PB
        • D'ercole AJ
        Fibroblasts from a patient with leprechaunism are resistant to insulin, epidermal growth factor, and somatomedin C.
        J Clin Endocrinol Metab. 1982; 55: 741-748
        • Craig JW
        • Larner J
        • Locker EF
        • et al.
        Mechanism of insulin resistance in cultured fibroblasts from a patient with leprechaunism: Impaired post-binding actions of insulin and multiplication-stimulating activity.
        Metabolism. 1984; 33: 1084-1096
        • Levy-Toledano R
        • Caro LH
        • Accili D
        • et al.
        Investigation of the mechanism of the dominant negative effect of mutations in the tyrosine kinase domain of the insulin receptor.
        EMBO J. 1994; 13: 835-842
        • Takata Y
        • Kobayashi M
        Insulin-like growth factor I signaling through heterodimers of insulin and insulin-like growth factor I receptors.
        Diabete Metab. 1994; 20: 31-36
        • Takata Y
        • Webster NJ
        • Olefsky JM
        Mutation of the carboxyl-terminal tyrosines results in an insulin receptor with normal metabolic signaling but enhanced mitogenic signaling properties.
        J Biol Chem. 1991; 266: 9135-9139
        • Takata Y
        • Webster NJ
        • Olefsky JM
        Intracellular signaling by a mutant human insulin receptor lacking the carboxyl-terminal tyrosine autophosphorylation sites.
        J Biol Chem. 1992; 267: 9065-9070
        • Langloins WJ
        • Sasaoka T
        • Yip CC
        • et al.
        Functional characterization of hybrid receptors composed of a truncated insulin receptor and wild type insulin-like growth factor I or insulin receptors.
        Endocrinology. 1995; 136: 1978-1986
        • Sasaoka T
        • Draznin B
        • Leitner JW
        • et al.
        Shc is the predominant signaling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation.
        J Biol Chem. 1994; 269: 10734-10738
        • Prager D
        • Yamasaki H
        • Weber MM
        • et al.
        Human insulin-like growth factor I receptor function in pituitary cells in suppressed by a dominant negative mutant.
        J Clin Invest. 1992; 90: 2117-2122
        • Gronborg M
        • Wulff BS
        • Rasmussen JS
        • et al.
        Structure-function relationship of the insulin-like growth factor-I receptor tyrosine kinase.
        J Biol Chem. 1993; 268: 23435-23440
        • Li S
        • Ferber A
        • Miura M
        • et al.
        Mitogenicity and transforming activity of the insulin-like growth factor-I receptor with mutations in the tyrosine kinase domain.
        J Biol Chem. 1994; 269: 32558-32564
        • Ueno H
        • Corbert H
        • Escobedo JA
        • et al.
        Inhibition of PDGF β receptor signal transduction by coexpression of a truncated receptor.
        Science. 1991; 252: 844-848
        • Steele-Pwekins G
        • Turner J
        • Edman JC
        • et al.
        Expression and characterization of a functional human insulin-like growth factor I receptor.
        J Biol Chem. 1988; 263: 11486-11492
        • Hofmann C
        • Goldfine ID
        • Whittaker J
        The metabolic and mitogenic effects of both insulin and insulin-like growth factor are enhanced by transfection of insulin receptors into NIH3T3 fibroblasts.
        J Biol Chem. 1989; 264: 8606-8611
        • Moxham CP
        • Duronio V
        • Jacobs S
        Insulin-like growth factor I receptor β-subunit heterogeneity.
        J Biol Chem. 1989; 264: 13238-13244
        • Chin JE
        • Tabaré JM
        • Ellis L
        • et al.
        Evidence for hybrid rodent and human insulin receptors in transfected cells.
        J Biol Chem. 1991; 266: 15587-15590
        • Soos MA
        • Field CE
        • Siddle K
        Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity.
        Biochem J. 1993; 290: 419-426
        • Treadway JL
        • Morrison BD
        • Soos MA
        • et al.
        Transdominant inhibition of tyrosine kinase activity in mutant insulin/insulin-like growth factor I hybrid receptors.
        in: ed 4. Proc Natl Acad Sci USA. 88. 1991: 214-218
        • Frattali AL
        • Treadway JL
        • Pessin JE
        Transmembrane signaling by the human insulin receptor kinase.
        J Biol Chem. 1992; 267: 19521-19528
        • Sasaoka T
        • Rose DW
        • Jhun BH
        • et al.
        Evidence for a functional role of Shc protein in mitogenic signaling induced by insulin, insulin-like growth factor-I and epidermal growth factor.
        J Biol Chem. 1994; 269: 13689-13694
        • McClain DA
        • Maegawa H
        • Thies SR
        • et al.
        Dissection of the growth versus metabolic effects of insulin and insulin-like growth factor-I in transfected cells expressing kinase-defective human insulin receptors.
        J Biol Chem. 1990; 265: 1678-1682
        • Kahn CR
        • White MF
        • Shoelson SE
        • et al.
        The insulin receptor and its substrate: Molecular determinants of early events in insulin action.
        Recent Prog Horm Res. 1993; 48: 291-339
        • Hubbard SR
        • Wei L
        • Ellis L
        • et al.
        Crystal structure of the tyrosine kinase domain of the human insulin receptor.
        Nature. 1994; 372: 746-754
        • Sasaoka T
        • Langlois WJ
        • Rose DW
        • et al.
        Mechanism of enhanced transmembrane signaling by an insulin receptor lacking a cytoplasmic β-subunit domain.
        J Biol Chem. 1995; 270: 10885-10892
        • Yamamoto-Honda R
        • Kadowaki T
        • Momonura K
        • et al.
        Normal insulin substrate-I phosphorylation in autophosphorylation-defective truncated insulin receptor.
        J Biol Chem. 1993; 268: 16859-16865
      39. ed 4. The Diabetes Annual. vol 3. Elsevier Science, Amsterdam, The Netherlands1987: 433-488
        • Kublaoui B
        • Lee J
        • Pilch PE
        Dynamics of signaling during insulin-stimulated endocytosis of its receptor in adipocytes.
        J Biol Chem. 1995; 270: 59-65
        • Lazor DF
        • Wiese RJ
        • Brady MJ
        • et al.
        Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin.
        J Biol Chem. 1995; 270: 20801-20807
        • Segar R
        • Biener Y
        • Feinstein R
        • et al.
        Differential activation of mitogen-activated protein kinase and S6 kinase signaling pathways by 12-O-tetradecanoylphorbol-1-acetate (TPA) and insulin.
        J Biol Chem. 1995; 270: 28235-28330
        • Taouis M
        • Levy-Toledano R
        • Caro LHP
        • et al.
        Rescue and activation of a binding-deficient insulin receptor.
        J Biol Chem. 1994; 269: 27762-27766
        • Taouis M
        • Levy-Toledano R
        • Roach P
        • et al.
        Structural basis by which a recessive mutation in the alpha-subunit of the insulin receptor affects insulin binding.
        J Biol Chem. 1994; 269: 14192-14198
        • Seely BL
        • Reichart DR
        • Takata Y
        • et al.
        A functional assessment of insulin/insulin-like growth factor-I hybrid receptors.
        Endocrinology. 1995; 136: 1635-1641
        • Chang PY
        • Goodyear LJ
        • Benecke H
        • et al.
        Impaired insulin signaling in skeletal muscles from transgenic mice expressing kinase-deficient insulin receptors.
        J Biol Chem. 1995; 270: 12593-12600

      Article info

      Publication history

      Accepted: June 4, 1996
      Received: October 22, 1995

      Footnotes

      ☆Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan, a Grant-in-Aid for Intractable Diseases from the Ministry of Welfare, Japan, a Grant-in-Aid from Otsuka Pharmaceutical, Japan, and a Grant-in-Aid from the Japan Diabetes Society.

      Identification

      DOI: https://doi.org/10.1016/S0026-0495(96)90175-4

      Copyright

      © 1996 Published by Elsevier Inc.

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