Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 6 May 1988:
Vol. 240. no. 4853, pp. 784 - 787
DOI: 10.1126/science.3283938
Prev | Table of Contents | Next

Articles

Science, Vol 240, Issue 4853, 784-787
Copyright © 1988 by American Association for the Advancement of Science

articles

Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing

Y Yoshimasa, S Seino, J Whittaker, T Kakehi, A Kosaki, H Kuzuya, H Imura, GI Bell, and DF Steiner

Department of Biochemistry and Molecular Biology, University of Chicago, IL 60637.

A point mutation in the human insulin receptor gene in a patient with type A insulin resistance alters the amino acid sequence within the tetrabasic processing site of the proreceptor molecule from Arg-Lys-Arg-Arg to Arg-Lys-Arg-Ser. Epstein-Barr virus-transformed lymphocytes from this patient synthesize an insulin receptor precursor that is normally glycosylated and inserted into the plasma membrane but is not cleaved to mature alpha and beta subunits. Insulin binding to these cells is severely reduced but can be increased about fivefold by gentle treatment with trypsin, accompanied by the appearance of normal alpha subunits. These results indicate that proteolysis of the proreceptor is necessary for its normal full insulin-binding sensitivity and signal-transducing activity and that a cellular protease that is more stringent in its specificity than trypsin is required to process the receptor precursor.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A: FUNCTIONAL CONSEQUENCES OF NATURAL MUTATIONS AND POST-TRANSLATIONAL MODIFICATIONS.
S. Benjannet, D. Rhainds, J. Hamelin, N. Nassoury, and N. G. Seidah (2006)
J. Biol. Chem. 281, 30561-30572
   Abstract »    Full Text »    PDF »
Mutation at Cleavage Site of Insulin-Like Growth Factor Receptor in a Short-Stature Child Born with Intrauterine Growth Retardation.
Y. Kawashima, S. Kanzaki, F. Yang, T. Kinoshita, K. Hanaki, J.-i. Nagaishi, Y. Ohtsuka, I. Hisatome, H. Ninomoya, E. Nanba, et al. (2005)
J. Clin. Endocrinol. Metab. 90, 4679-4687
   Abstract »    Full Text »    PDF »
Transcriptional regulation of glucose-6-phosphatase catalytic subunit promoter by insulin and glucose in the carnivorous fish, Sparus aurata.
M C Salgado, I Meton, M Egea, and I V Baanante (2004)
J. Mol. Endocrinol. 33, 783-795
   Abstract »    Full Text »    PDF »
Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations.
F. Qian, A. Boletta, A. K. Bhunia, H. Xu, L. Liu, A. K. Ahrabi, T. J. Watnick, F. Zhou, and G. G. Germino (2002)
PNAS 99, 16981-16986
   Abstract »    Full Text »    PDF »
Alternative Proteolytic Processing of Mouse Mammary Tumor Virus Superantigens.
F. Denis, N. H. Shoukry, M. Delcourt, J. Thibodeau, N. Labrecque, H. McGrath, J. S. Munzer, N. G. Seidah, and R.-P. Sékaly (2000)
J. Virol. 74, 3067-3073
   Abstract »    Full Text »
Truncated Human Leptin ({Delta}133) Associated with Extreme Obesity Undergoes Proteasomal Degradation after Defective Intracellular Transport.
H. Rau, B. J. Reaves, S. O’Rahilly, and J. P. Whitehead (1999)
Endocrinology 140, 1718-1723
   Abstract »    Full Text »
Mutation at the Processing Site of Chicken Low Density Lipoprotein Receptor-related Protein Impairs Efficient Endoplasmic Reticulum Exit, but Proteolytic Cleavage Is Not Essential for Its Endocytic Functions.
K. W. S. Ko, R. S. McLeod, R. K. Avramoglu, J. Nimpf, D. J. FitzGerald, J. Vukmirica, and Z. Yao (1998)
J. Biol. Chem. 273, 27779-27785
   Abstract »    Full Text »    PDF »
Deficient Processing and Activity of Type I Insulin-Like Growth Factor Receptor in the Furin-Deficient LoVo-C5 Cells.
M. Lehmann, F. Andre, C. Bellan, M. Remacle-Bonnet, F. Garrouste, F. Parat, J.-C. Lissitsky, J. Marvaldi, and G. Pommier (1998)
Endocrinology 139, 3763-3771
   Abstract »    Full Text »    PDF »
Folding of Insulin Receptor Monomers Is Facilitated by the Molecular Chaperones Calnexin and Calreticulin and Impaired by Rapid Dimerization.
J. Bass, G. Chiu, Y. Argon, and D. F. Steiner (1998)
J. Cell Biol. 141, 637-646
   Abstract »    Full Text »    PDF »
Interaction Between BTBR and C57BL/6J Genomes Produces an Insulin Resistance Syndrome in (BTBR x C57BL/6J) F1 Mice.
T. Ranheim, C. Dumke, K. L. Schueler, G. D. Cartee, and A. D. Attie (1997)
Arterioscler. Thromb. Vasc. Biol. 17, 3286-3293
   Abstract »    Full Text »
Fusion of Insulin Receptor Ectodomains to Immunoglobulin Constant Domains Reproduces High-affinity Insulin Binding in Vitro.
J. Bass, T. Kurose, M. Pashmforoush, and D. F. Steiner (1996)
J. Biol. Chem. 271, 19367-19375
   Abstract »    Full Text »    PDF »
An Insulin Receptor Mutant (Asp707 right-arrow Ala), Involved in Leprechaunism, Is Processed and Transported to the Cell Surface but Unable to Bind Insulin.
L. M.'t Hart, D. Lindhout, G. C.M. V. d. Zon, H. Kayserilli, M. Y. Apak, W. J. Kleijer, E. R.V. d. Vorm, and J. A. Maassen (1996)
J. Biol. Chem. 271, 18719-18724
   Abstract »    Full Text »    PDF »
Alanine-scanning Mutagenesis of a C-terminal Ligand Binding Domain of the Insulin Receptor alpha Subunit.
D. C. Mynarcik, G. Q. Yu, and J. Whittaker (1996)
J. Biol. Chem. 271, 2439-2442
   Abstract »    Full Text »    PDF »
Insulin Resistance Is Mediated by a Proteolytic Fragment of the Insulin Receptor.
V. P. Knutson, P. V. Donnelly, Y. Balba, and M. Lopez-Reyes (1995)
J. Biol. Chem. 270, 24972-24981
   Abstract »    Full Text »    PDF »
Molecular Characterization of the Human Transmembrane Protein-tyrosine Phosphatase [IMAGE].
R. Pulido, N. X. Krueger, C. Serra-Pagès, H. Saito, and M. Streuli (1995)
J. Biol. Chem. 270, 6722-6728
   Abstract »    Full Text »    PDF »
Molecular defects in insulin action.
C. Kahn and B. Goldstein (1989)
Science 245, 13
   PDF »
Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor.
M Taira, M Taira, N Hashimoto, F Shimada, Y Suzuki, A Kanatsuka, F Nakamura, Y Ebina, M Tatibana, H Makino, et al. (1989)
Science 245, 63-66
   Abstract »    PDF »
Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor.
M Odawara, T Kadowaki, R Yamamoto, Y Shibasaki, K Tobe, D Accili, C Bevins, Y Mikami, N Matsuura, Y Akanuma, et al. (1989)
Science 245, 66-68
   Abstract »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)