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The Q Allele Variant (GLN¹²¹) of Membrane Glycoprotein PC-1 Interacts With the Insulin Receptor and Inhibits Insulin Signaling More Effectively Than the Common K Allele Variant (LYS¹²¹)

¹ Institute of Internal Medicine, Endocrine and Metabolic Diseases, University of Catania, Ospedale Garibaldi, Catania
² Division and Research Unit of Endocrinology, Scientific Institute, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia)
³ Institute of Neurological Diseases, Ospedale Policlinico Istituto Ricovero e Cura a Carattere Scientifico, Milan, Italy

When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. A PC-1 variant (K¹²¹Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. To better understand the effects of the Q allele on IR function and downstream signaling, we transfected cultured cells with cDNAs for either the Q or the K alleles. In human MCF-7 cells, the Q allele was severalfold more effective (P < 0.05–0.01) than the K allele in reducing insulin stimulation of IR autophosphorylation, insulin receptor substrate-1 phosphorylation, phosphatidylinositol 3-kinase activity, glycogen synthesis, and cell proliferation. Similar data on IR autophosphorylation inhibition were also obtained in mouse R^-/hIR and human HEK 293 cell lines. In transfected MCF-7 cells, ¹²⁵I-labeled insulin binding and IR content were unchanged, and PC-1 overexpression did not influence IGF-1 stimulation of IGF-1 receptor autophosphorylation. Both the Q and K alleles directly interacted with the IR, as documented by coimmunoprecipitation assays. This interaction was greater for the Q allele than for the K allele (P < 0.01), suggesting that direct PC-1–IR interactions are important for the PC-1 inhibitory effect on insulin signaling. In conclusion, the Q allele has stronger inhibitory activity on IR function and insulin action than the more common K allele, and this is likely a consequence of the intrinsic characteristics of the molecule, which more strongly interacts with the IR.

Abbreviations: a-pY, antiphosphotyrosine; ECL, enhanced chemiluminescence; ELISA, enzyme-linked immunosorbent assay; IGF-1-R, IGF-1 receptor; IR, insulin receptor; IRS-1, IR substrate-1; PI 3-kinase, phosphatidylinositol 3-kinase; PNTP, p-nitrophenyl thymidine 5'-monophosphate; TK, tyrosine kinase

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