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  • Title: Inhibition of the transmembrane protein tyrosine phosphatase lar by 3S-peptide-I enhances insulin receptor phosphorylation in intact cells.
    Author: Kole HK, Kole S, Mallory BP, Li PM, Goldstein BJ, Bernier M.
    Journal: J Basic Clin Physiol Pharmacol; 1998; 9(2-4):111-26. PubMed ID: 10212829.
    Abstract:
    3S-peptide-I, a tris-sulfotyrosyl dodecapeptide that corresponds to the major autophosphorylation domain within the insulin receptor beta-subunit, selectively enhances insulin signal transduction by specifically inhibiting dephosphorylation of the insulin receptor catalyzed by protein tyrosine phosphatases (PTPases). Because of the potential role of the transmembrane PTPase LAR in the regulation of insulin signaling, we assessed the effect of 3S-peptide-I on recombinant LAR PTPase activity and in McA-RH7777 rat hepatoma cells overexpressing full-length LAR protein (McA4B/LAR). 3S-peptide-I significantly reduced insulin receptor dephosphorylation by recombinant LAR (p < 0.001) while blocking dephosphorylation of the insulin receptor by approximately 72% in semi-permeabilized McA4B/LAR cells (p < 0.001). Increased LAR expression resulted in 40% reduction in ligand-mediated phosphorylation of the insulin receptor compared with null vector control (p < 0.001). However, treatment of intact McA4B/LAR cells with a fatty acid derivative of 3S-peptide-I (50 microM) led to an enhancement of insulin-stimulated receptor phosphorylation by 89% (p < 0.001). As a result, control and McA4B/LAR cells showed comparable steady-state levels of insulin receptor phosphorylation in the presence of insulin. These findings provide evidence that 3S-peptide-I may improve insulin responsiveness in intact cells by inhibiting LAR, an enzyme whose activity has been implicated in the pathogenesis of insulin resistance.
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