NDLI: Mutation in a conserved motif next to the insulin receptor key autophosphorylation sites de-regulates kinase activity and impairs insulin action.

Content Provider	Journal of Biological Chemistry (JBC)
Author	Formisano, P. Sohn, K. J. Miele, C. Finizio, B. Di Petruzziello, A. Riccardi, G. Beguinot, L. Beguinot, F.
Abstract	We have recently reported two non-insulin-dependent diabetic patients exhibiting a heterozygous point mutation (R1152-Q) next to the key tyrosine autophosphorylation sites (Y1146, Y1150, Y1151) of the insulin receptor. In the present study, we demonstrate that the Q1152 mutation alters a previously unrecognized consensus sequence in the insulin receptor family of tyrosine kinases. To define the effect of this alteration on insulin receptor function, the mutant insulin receptor (Q1152) was constructed and overexpressed in NIH-3T3 cells. In spite of normal insulin binding, "in vivo" and "in vitro" autophosphorylation as well as transphosphorylation by the wild-type receptor (WT) were deficient in Q1152 as compared with the transfected WT receptors. Insulin-stimulated kinase activity toward poly(Glu, Tyr) 4:1 and the endogenous substrates p120 and p175 were also impaired in Q1152. However, insulin-independent kinase activity of Q1152 was 2-5-fold higher than that of WT. While insulin stimulated 2-deoxyglucose uptake and glycogen synthase activity in WT-transfected cells with a sensitivity proportional to receptor number, no insulin stimulation was observed in Q1152 cells. Similar to the kinase, insulin-independent glycogen synthase activity and 2-deoxyglucose uptake were 2-fold higher in Q1152 than in either WT or parental cells. We conclude that the Q1152 mutation deregulates insulin receptor kinase and generates insulin insensitivity in cells. Alterations in this highly conserved region of the insulin receptor may contribute to non-insulin dependent diabetes mellitin pathogenesis in humans.
Related Links	http://www.jbc.org/content/268/7/5241.abstract
Ending Page	5248
Starting Page	5241
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	7
Volume Number	268
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1993-03-05
Access Restriction	Open
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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A mutation in the extracellular domain of the insulin receptor impairs the ability of insulin to stimulate receptor autophosphorylation.

Substitution of isoleucine for methionine at position 1153 in the beta-subunit of the human insulin receptor. A mutation that impairs receptor tyrosine kinase activity, receptor endocytosis, and insulin action.

Insulin receptor kinase domain autophosphorylation regulates receptor enzymatic function.

Autophosphorylation of the insulin receptor in vitro. Designation of phosphorylation sites and correlation with receptor kinase activation.

Substrate phosphorylation catalyzed by the insulin receptor tyrosine kinase. Kinetic correlation to autophosphorylation of specific sites in the beta subunit.

Relationship of site-specific beta subunit tyrosine autophosphorylation to insulin activation of the insulin receptor (tyrosine) protein kinase activity.

Insulin receptors prepared with iodoacetamide show enhanced autophosphorylation and receptor kinase activity.

Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats.

Antibodies to insulin receptor tyrosine kinase stimulate its activity towards exogenous substrates without inducing receptor autophosphorylation.

Mutation in a conserved motif next to the insulin receptor key autophosphorylation sites de-regulates kinase activity and impairs insulin action.

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A mutation in the extracellular domain of the insulin receptor impairs the ability of insulin to stimulate receptor autophosphorylation.

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Insulin receptor kinase domain autophosphorylation regulates receptor enzymatic function.

Autophosphorylation of the insulin receptor in vitro. Designation of phosphorylation sites and correlation with receptor kinase activation.

Substrate phosphorylation catalyzed by the insulin receptor tyrosine kinase. Kinetic correlation to autophosphorylation of specific sites in the beta subunit.

Relationship of site-specific beta subunit tyrosine autophosphorylation to insulin activation of the insulin receptor (tyrosine) protein kinase activity.

Insulin receptors prepared with iodoacetamide show enhanced autophosphorylation and receptor kinase activity.

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Mutation in a conserved motif next to the insulin receptor key autophosphorylation sites de-regulates kinase activity and impairs insulin action.