title: Inhibition of insulin receptor phosphorylation by PC-1 is not mediated by the hydrolysis of adenosine triphosphate or the generation of adenosine.
abstract: Individuals with insulin resistance show increased levels of PC-1 expression in skeletal muscle and fibroblasts, and in transfected cell lines that overexpress PC-1 there is a reduction in the insulin-stimulated insulin receptor tyrosine phosphorylation. As PC-1 is a type II transmembrane protein with extracellular phosphodiesterase and pyrophosphatase activity, increased expression of PC-1 at the cell surface will decrease extracellular adenosine triphosphate levels and increase extracellular adenosine levels. Consequently it is possible that PC-1-mediated insulin resistance could be caused either by a decrease in adenosine triphosphate or an indirect increase in adenosine levels. We have tested this hypothesis and find that the PC-1-mediated inhibition of insulin-stimulated insulin receptor autophosphorylation is not altered by agents that alter the level or action of adenosine. Further, a mutated PC-1 with a single amino acid change that abolishes the phosphodiesterase and pyrophosphatase activities is still able to inhibit insulin-stimulated insulin receptor phosphorylation. The results of these experiments indicate that the phosphodiesterase activity of PC-1 is not involved in the inhibition of insulin receptor autophosphorylation.
authors.affiliation: Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: A
authors.initials: A
authors.lastname: Grupe
authors.forename: J
authors.initials: J
authors.lastname: Alleman
authors.forename: I D
authors.initials: ID
authors.lastname: Goldfine
authors.forename: M
authors.initials: M
authors.lastname: Sadick
authors.forename: T A
authors.initials: TA
authors.lastname: Stewart
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D001483:Base Sequence; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D051741:Kruppel-Like Transcription Factors; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D058915:Purinergic P1 Receptor Antagonists; D011755:Pyrophosphatases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000302:isolation & purification*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D007328:Insulin; D051741:Kruppel-Like Transcription Factors; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D012097:Repressor Proteins; C095634:ZNF174 protein, human; D000255:Adenosine Triphosphate; D011972:Receptor, Insulin; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase; D000241:Adenosine