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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).
- Source :
-
Diabetes [Diabetes] 2001 Apr; Vol. 50 (4), pp. 831-6. - Publication Year :
- 2001
-
Abstract
- 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.
- Subjects :
- Amino Acid Sequence genetics
Cell Line
Humans
Membrane Glycoproteins metabolism
Phosphorylation
Receptor, IGF Type 1 metabolism
Receptor, Insulin metabolism
Alleles
Genetic Variation
Insulin physiology
Membrane Glycoproteins genetics
Membrane Glycoproteins physiology
Phosphoric Diester Hydrolases
Pyrophosphatases
Receptor, Insulin physiology
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0012-1797
- Volume :
- 50
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 11289049
- Full Text :
- https://doi.org/10.2337/diabetes.50.4.831