Mutation of arginine 86 to proline in the insulin receptor alpha subunit causes lack of transport of the receptor to the plasma membrane, loss of binding affinity and a constitutively activated tyrosine kinase in transfected cells.
We have investigated the role of Ser 85 and Arg 86 of the human insulin receptor (HIR) in insulin binding and tyrosine kinase activity by mutational analysis. Four mutant cDNAs were created (R86P, R86N, S85T+R86N, S85W+R86K) and stably transfected into BHK cells. R86P-HIR was also transiently expressed in 293 cells. Only the R86P receptor had substantially altered properties: lack of transport to the plasma membrane, loss of insulin binding, a constitutively activated autophosphorylation and tyrosine kinase, and an incomplete processing. Some of these alterations mimic those reported for the insulin receptor of the leprechaun Atl, which has a homozygous R86P mutation (Longo, N., et al, Biochem. Biophys. Res. Commun., 167, 1229, 1990; Clin. Res., 40, 2, 329, 1992).
Grønskov
K
K
Hagedorn Research Institute, Gentofte, Denmark.
Vissing
H
H
Shymko
R M
RM
Tornqvist
H
H
De Meyts
P
P
D000818:Animals; D001120:Arginine / Q000235:genetics*; D001665:Binding Sites; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010766:Phosphorylation; D011392:Proline / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D001120:Arginine; D011392:Proline; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin