The inhibition of the insulin receptor by the receptor protein PC-1 is not specific and results from the hydrolysis of ATP.
The membrane protein plasma cell differentiation antigen 1 (PC-1) has been purified as an inhibitor of insulin receptor tyrosine kinase activity and has been implicated in the pathogenesis of NIDDM. However, we show here that PC-1 is a general protein kinase inhibitor in vitro and that this inhibition results from the hydrolysis of ATP by the intrinsic nucleotide pyrophosphatase activity of PC-1. Thus, the inhibition diminished with increasing ATP concentrations, and it was nullified when the ATP concentration was kept constant with a regenerating system or when ATP was added repetitively. When care was taken to avoid ATP depletion, PC-1 did not affect the insulin sensitivity of insulin receptor autophosphorylation. We conclude that the reported inhibition of insulin signaling by PC-1 does not result from a direct inhibition of the insulin receptor kinase activity.
Stefan
C
C
Division of Biochemistry, Faculty of Medicine, Catholic University of Leuven, Belgium.
Wera
S
S
Stalmans
W
W
Bollen
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D047388:Casein Kinases; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000302:isolation & purification / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D010744:Phosphoric Monoester Hydrolases; D010764:Phosphorylase Kinase / Q000302:isolation & purification / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011494:Protein Kinases / Q000302:isolation & purification / Q000378:metabolism; D011755:Pyrophosphatases; D011817:Rabbits; D051381:Rats; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013154:Spleen / Q000201:enzymology; D013552:Swine
D004791:Enzyme Inhibitors; D007328:Insulin; D008562:Membrane Glycoproteins; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D010764:Phosphorylase Kinase; D011972:Receptor, Insulin; D047388:Casein Kinases; D010744:Phosphoric Monoester Hydrolases; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases