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).
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.
Costanzo
B V
BV
Institute of Internal Medicine, Endocrine and Metabolic Diseases, University of Catania, Ospedale Garibaldi, Italy.
Trischitta
V
V
Di Paola
R
R
Spampinato
D
D
Pizzuti
A
A
Vigneri
R
R
Frittitta
L
L
D000483:Alleles; D000595:Amino Acid Sequence / Q000235:genetics; D002460:Cell Line; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation; D011755:Pyrophosphatases; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D008562:Membrane Glycoproteins; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases