Targeting of PED/PEA-15 Molecular Interaction with Phospholipase D1 Enhances Insulin Sensitivity in Skeletal Muscle Cells
Copyright policy )Targeting of PED/PEA-15 Molecular Interaction with Phospholipase D1 Enhances Insulin Sensitivity in Skeletal Muscle Cells
Phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) is overexpressed in several tissues of individuals affected by type 2 diabetes. In intact cells and in transgenic animal models, PED/PEA-15 overexpression impairs insulin regulation of glucose transport, and this is mediated by its interaction with the C-terminal D4 domain of phospholipase D1 (PLD1) and the consequent increase of protein kinase C-alpha activity. Here we show that interfering with the interaction of PED/PEA-15 with PLD1 in L6 skeletal muscle cells overexpressing PED/PEA-15 (L6(PED/PEA-15)) restores insulin sensitivity. Surface plasmon resonance and ELISA-like assays show that PED/PEA-15 binds in vitro the D4 domain with high affinity (K(D) = 0.37 +/- 0.13 mum), and a PED/PEA-15 peptide, spanning residues 1-24, PED-(1-24), is able to compete with the PED/PEA-15-D4 recognition. When loaded into L6(PED/PEA-15) cells and in myocytes derived from PED/PEA-15-overexpressing transgenic mice, PED-(1-24) abrogates the PED/PEA-15-PLD1 interaction and reduces protein kinase C-alpha activity to levels similar to controls. Importantly, the peptide restores insulin-stimulated glucose uptake by approximately 70%. Similar results are obtained by expression of D4 in L6(PED/PEA-15). All these findings suggest that disruption of the PED/PEA-15-PLD1 molecular interaction enhances insulin sensitivity in skeletal muscle cells and indicate that PED/PEA-15 as an important target for type 2 diabetes.
EXPRESSION, Protein Kinase C-alpha, Genetic Vectors, Mice, Transgenic, Biochemistry, ASTROCYTES, Models, Biological, Mice, Phospholipase D, Animals, PROTEIN-KINASE-C, PHOSPHORYLATION, Muscle, Skeletal, Molecular Biology, Aurora Universities Network, DEATH, GLUCOSE-METABOLISM, Biological Transport, Cell Biology, PEA-15, Phosphoproteins, GENE, PROTEIN-KINASE-C; GLUCOSE-METABOLISM; PEA-15; EXPRESSION; PHOSPHORYLATION; ASTROCYTES; APOPTOSIS; DEATH; GENE; SECRETION, APOPTOSIS, Rats, Glucose, Astrocytes, SECRETION, Apoptosis Regulatory Proteins, Peptides, Gene Deletion
EXPRESSION, Protein Kinase C-alpha, Genetic Vectors, Mice, Transgenic, Biochemistry, ASTROCYTES, Models, Biological, Mice, Phospholipase D, Animals, PROTEIN-KINASE-C, PHOSPHORYLATION, Muscle, Skeletal, Molecular Biology, Aurora Universities Network, DEATH, GLUCOSE-METABOLISM, Biological Transport, Cell Biology, PEA-15, Phosphoproteins, GENE, PROTEIN-KINASE-C; GLUCOSE-METABOLISM; PEA-15; EXPRESSION; PHOSPHORYLATION; ASTROCYTES; APOPTOSIS; DEATH; GENE; SECRETION, APOPTOSIS, Rats, Glucose, Astrocytes, SECRETION, Apoptosis Regulatory Proteins, Peptides, Gene Deletion
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