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Tissue-specific expression of two alternatively spliced isoforms of the human insulin receptor protein

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Abstract

Two insulin receptor mRNA species are expressed in human tissues as a result of alternative splicing of exon 11. This event is regulated in a tissue-specific manner. To date, there is little information about the relative abundance of the two receptor protein isoforms on the cell surface. The aim of the present investigation was to assess whether the tissue-specific expression of the two insulin receptor mRNA species is paralleled by a similar pattern of expression of the two receptor protein isoforms. To this end, we assessed the relative distribution of the two receptor variants in various human tissues at the mRNA and protein levels. A PCR-based technique was used to measure the relative abundance of the two mRNA species, and two immunological assays were used to measure the relative steady-state expression of the two receptor protein isoforms. The expression of the two insulin receptor protein isoforms followed the tissue-specific pattern of expression of the two mRNA species.

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References

  1. Olefsky JM, The insulin receptor: a multifunctional protein. Diabetes 39:1009–1016, 1990

    Google Scholar 

  2. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Moson A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J, Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761, 1985

    Google Scholar 

  3. Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ, The structural basis for hormone-activated transmembrane signalling. Cell 40:747–758, 1985

    Google Scholar 

  4. Seino S, Seino M, Nishi S, Bell GI, Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci USA 86:114–118, 1989

    Google Scholar 

  5. Seino S, Bell GI, Alternative splicing of human insulin receptor messenger RNA. Biochem Biophys Res Commun 159: 312–316, 1989

    Google Scholar 

  6. Moller DE, Yokota A, Caro JF, Flier JE, Tissue-specific expression of two alternative spliced insulin receptor mRNA in man. Mol Endocrinol 3:1263–1269, 1989

    Google Scholar 

  7. Goldstein BJ, Dudley AL, The rat insulin receptor: primary structure and conservation of tissue-specific alternative messenger RNA splicing. Mol Endocrinol 4:235–244, 1990

    Google Scholar 

  8. Mosthaf L, Grako D, Dull TJ, Coussens L, Ullrich A, McClain DA, Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J 9:2409–2413, 1990

    Google Scholar 

  9. Vogt B, Carrascosa JM, Ermel B, Ullrich A, Haring HU, The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics. Biochem Biophys Res Commun 177:1013–1018, 1991

    Google Scholar 

  10. Yamaguchi Y, Flier JS, Yokota A, Benecke H, Backer JM, Moller DE, Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells. Endocrinology 129:2058–2066, 1991

    Google Scholar 

  11. McClain DA, Different ligand affinities of two human insulin receptor splice variants are reflected in parallel changes in sensitivity for insulin action. Mol Endocrinol 5:734–739, 1991

    Google Scholar 

  12. Kellerer M, Lammers R, Ermel B, Tippmer B, Vogt B, Obermaier-Kusser B, Ullrich A, Haring HU, Distinct α-subunit structure of human insulin receptor A and B variants determine differences in tyrosine kinase activities. Biochemistry 31: 4588–4596, 1992

    Google Scholar 

  13. Sesti G, Marini MA, Montemurro A, Condorelli L, Borboni P, Haring HU, Ullrich A, Goldfine ID, De Pirro R, Lauro R, Evidence that two naturally occurring human insulin receptor α-subunit variants are immunologically distinct. Diabetes 41: 6–11, 1992

    Google Scholar 

  14. Yamaguchi Y, Flier JS, Benecke H, Rnasil BJ, Moller DE, Ligand-binding properties of the two isoforms of the human insulin receptor. Endocrinology 132:1132–1138, 1993

    Google Scholar 

  15. Mosthaf L, Vogt B, Haring HU, Ullrich A, Altered expression of insulin receptor types A and B in the skeletal muscle of noninsulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 88:4728–4730, 1991

    Google Scholar 

  16. Sesti G, Marini MA, Tullio AN, Montemurro A, Borboni P, Fusco A, Accili D, Lauro R, Altered expression of the two naturally occurring human insulin receptor variants in isolated adipocytes of non-insulin-dependent diabetes mellitus patients. Biochem Biophys Res Commun 181:1419–1424, 1991

    Google Scholar 

  17. Benecke H, Flier JS, Moller DE, Alternatively spliced variants of the human insulin receptor protein. J Clin Invest 89: 2066–2070, 1992

    Google Scholar 

  18. Mosthaf L, Eriksson J, Haring HU, Groop L, Widen E, Ullrich A, Insulin receptor isotypes expression correlates with risk of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 90:2633–2635, 1993

    Google Scholar 

  19. Norgren S, Zierath J, Galuska D, Walleberg-Henriksson H, Luthman H, Differences in the ratio of RNA encoding two isoforms of the insulin receptor between control and NIDDM patients. Diabetes 42:675–681, 1993

    Google Scholar 

  20. Anderson CM, Henry RR, Knudson PE, Olesky JM, Webster NJG, Relative expression of insulin receptor isoforms does not differ in lean, obese, and noninsulin-dependent diabetes mellitus subjects. J Clin Endocrinol Metab 72:1380–1383, 1993

    Google Scholar 

  21. Kellerer M, Sesti G, Seffer E, Obermaier-Kusser B, Pongratz DE, Mosthaf L, Haring HU, Altered pattern of insulin receptor isotypes in skeletal muscle membranes of type II (non-insulin-dependent) diabetic subjects. Diabetologia 36:628–632, 1993

    Google Scholar 

  22. Benzi L, Pezzino V, Marchetti P, Gullo D, Cecchetti P, Masoni A, Vigneri R, Navalesi R, A-14-125I monoiodoinsulin purified by different high-performance liquid chromatographic procedures and by polyacrylamide gel electrophoresis: preparation, immunochemical properties and receptor binding affinity. J Chromatogr 378:337–347, 1986

    Google Scholar 

  23. Pessino A, Gherzi R, Damiani G, Longhi R, Adezati L, Cordera R, Antipeptide antibodies toward the extracellular domain of insulin receptor beta-subunit. Biochem Biophys Res Commun 162:1236–1243, 1989

    Google Scholar 

  24. Sesti G, Marini MA, Briata P, Tullio AN, Montemurro A, Borboni P, De Pirro R, Gherzi R, Lauro R, Androgens increase insulin receptor gene expression and insulin responsiveness in Hep-2 larynx carcinoma cells. Mol Cell Endocrinol 86: 111–118, 1992

    Google Scholar 

  25. Gherzi P, Sesti G, Andraghetti G, De Pirro R, Lauro R, Adezati L, Cordera R, An extracellular domain of the insulin receptor β-subunit with regulatory function on protein-tyrosine kinase. J Biol Chem 264:8627–8635, 1989

    Google Scholar 

  26. Borboni P, Di Cola G, Sesti G, Marini MA, Del Porto P, Gilardini Montani MS, Lauro R, De Pirro, β-endorphin receptors on cultured and freshly isolated lymphocytes from normal subjects. Biochem Biophys Res Commun 163:642–648, 1989

    Google Scholar 

  27. National Diabetes Data Group, Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039–1057, 1979

    Google Scholar 

  28. Lesko L, Donlon M, Marinetti GV, Hare JD, A rapid method for the isolation of rat plasma membranes using an aqueous twophases polymer system. Biochem Biophys Acta 311:173–179, 1973

    Google Scholar 

  29. Whittaker J, Okamoto AK, Thys R, Bell GI, Steiner DF, Hofmann CA, High-level expression of human receptor cDNA in mouse NIH 3T3 cells. Natl Acad Sci USA 84:5237–5241, 1987

    Google Scholar 

  30. Accili D, Frapier C, Mosthaf L, McKeon M, Elbein SC, Permutt MA, Ramos E, Lander E, Ullrich A, Taylor SI, A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes. EMBO J 8:2509–2517, 1989

    Google Scholar 

  31. Maniatis T, Fritsch EF, Sambrook J, Molecular cloning, a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, 1982

    Google Scholar 

  32. Grossman PD, Soane DS, Capillary electrophoresis of DNA in entangled polymer solutions. J Chromatogr 559:257–266, 1991

    Google Scholar 

  33. Forsayeth JR, Montemurro A, Maddux B, De Pirro R, Goldfine ID, Effects of monoclonal antibodies on human insulin receptor autophosphorylation, negative cooperativity and down-regulation. J Biol Chem 262:4134–4139, 1987

    Google Scholar 

  34. De Pirro R, Borboni P, Lauro R, Festa A, Testa I, De Martinis C, Maddux BA, Goldfine ID, Tissue-specific antibodies against the fibroblast insulin receptor in a patient with lupus nephritis in the brain and hypoglycemia. Diabetes 34:1088–1091, 1985

    Google Scholar 

  35. Heidenreich KA, Zahniser NR, Berhanu P, Brandenburg D, Olesky JM, Structural differences between insulin receptors in the brain and peripheral target tissues. J Biol Chem 258:8527–8530, 1983

    Google Scholar 

  36. Roth RA, Morgan DO, Beaudoin J, Sara V, Purification and characterization of the human brain insulin receptor. J Biol Chem 261:3753–3757, 1986

    Google Scholar 

  37. Burant CF, Treutelaar MK, Block NE, Buse MG, Structural differences between liver- and muscle-derived insulin receptors in rats. J Biol Chem 259:14361–14364, 1986

    Google Scholar 

  38. Caro JF, Raju SM, Sinha MK, Goldfine ID, Dohm GL, Heterogeneity of human liver, muscle and adipose tissue insulin receptor. Biochem Biophys Res Commun 151:123–129, 1988

    Google Scholar 

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Sesti, G., Tullio, A.N., D'Alfonso, R. et al. Tissue-specific expression of two alternatively spliced isoforms of the human insulin receptor protein. Acta Diabetol 31, 59–65 (1994). https://doi.org/10.1007/BF00570536

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  • DOI: https://doi.org/10.1007/BF00570536

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