This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Band, C. J. Articles by Contreres, J.-O. Search for Related Content PubMed PubMed Citation Articles by Band, C. J. Articles by Contreres, J.-O.

Early Signaling Events Triggered by Peroxovanadium [bpV(phen)] Are Insulin Receptor Kinase (IRK)-Dependent: Specificity of Inhibition of IRK-Associated Protein Tyrosine Phosphatase(s) by bpV(phen)

The Polypeptide Hormone Laboratory and the Departments of Medicine and Physiology McGill University Montreal, Quebec, Canada H3A 2B2

Peroxovanadiums (pVs) are potent protein tyrosine phosphatase (PTP) inhibitors with insulin-mimetic properties in vivo and in vitro. We have established the existence of an insulin receptor kinase (IRK)-associated PTP whose inhibition by pVs correlates closely with IRK tyrosine phosphorylation, activation, and downstream signaling. pVs have also been shown to activate various tyrosine kinases (TKs) that could participate in activation of the insulin-signaling pathway. In the present study we have sought to determine whether pV-induced IRK tyrosine phosphorylation requires the intrinsic kinase activity of the IRK, and whether IRK activation is necessary to realize the early steps in the insulin-signaling cascade. To address this we evaluated the effect of a pure pV compound, bis peroxovanadium 1,10-phenanthroline [bpV(phen)], in HTC rat hepatoma cells overexpressing normal (HTC-IR) or kinase-deficient (HTC-M1030) mutant IRKs. We showed that at a dose of 0.1 mM, but not 1 mM, bpV(phen) induced IRK-dependent events. Thus, 0.1 mM bpV(phen) increased tyrosine phosphorylation and IRK activity in HTC-IR but not HTC-M1030 cells. Tyrosine phosphorylation of insulin signal-transducing molecules was promoted in HTC-IR but not HTC-M1030 cells by bpV(phen). The association of p185 and p60 with the src homology-2 (SH2) domains of Syp and the p85-regulatory subunit of phosphatidylinositol 3'-kinase was induced by bpV(phen) in HTC-IR, but not in HTC-M1030 cells, as was insulin receptor substrate-1-associated phosphatidylinositol 3'-kinase activity. Thus autophosphorylation and activation of the IRK by bpV(phen) is effected by the IRK itself, and the early events in the insulin- signaling cascade follow from this activation event. This establishes a critical role for PTP(s) in the regulation of IRK activity. bpV(phen) could be distinguished from insulin only in its ability to activate ERK1 in HTC-M1030 cells, thus indicating that this event is IRK independent, consistent with our previous hypothesis that bpV(phen) inhibits a PTP involved in the negative regulation of mitogen-activated protein kinases.

This article has been cited by other articles:

				M. D. Perry and G. I. Sandle Regulation of colonic apical potassium (BK) channels by cAMP and somatostatin Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G159 - G167. [Abstract] [Full Text] [PDF]

				S. Nakashima, S. A. Arnold, E. T. Mahoney, S. D. Sithu, Y. P. Zhang, S. E. D'Souza, C. B. Shields, and T. Hagg Small-Molecule Protein Tyrosine Phosphatase Inhibition as a Neuroprotective Treatment after Spinal Cord Injury in Adult Rats J. Neurosci., July 16, 2008; 28(29): 7293 - 7303. [Abstract] [Full Text] [PDF]

				A. Kakazu, G. Sharma, and H. E. P. Bazan Association of Protein Tyrosine Phosphatases (PTPs)-1B with c-Met Receptor and Modulation of Corneal Epithelial Wound Healing Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 2927 - 2935. [Abstract] [Full Text] [PDF]

				S. Bose, M A. Farah, H.-C. Jung, J.-H. Lee, and Y. Kim Molecular mechanism of bis(maltolato)oxovanadium(IV)-induced insulin signaling in 3T3-L1 and IM9 cells: impact of dexamethasone J. Mol. Endocrinol., June 1, 2007; 38(6): 627 - 649. [Abstract] [Full Text] [PDF]

				J. Blanchette, P. Pouliot, and M. Olivier Role of protein tyrosine phosphatases in the regulation of interferon-{gamma}-induced macrophage nitric oxide generation: implication of ERK pathway and AP-1 activation J. Leukoc. Biol., March 1, 2007; 81(3): 835 - 844. [Abstract] [Full Text] [PDF]

				C. Mounier, V. Dumas, and B. I. Posner Regulation of Hepatic Insulin-Like Growth Factor-Binding Protein-1 Gene Expression by Insulin: Central Role for Mammalian Target of Rapamycin Independent of Forkhead Box O Proteins Endocrinology, May 1, 2006; 147(5): 2383 - 2391. [Abstract] [Full Text] [PDF]

				L. A. Nolte, D.-H. Han, P. A. Hansen, K. A. Hucker, and J. O. Holloszy A Peroxovanadium Compound Stimulates Muscle Glucose Transport as Powerfully as Insulin and Contractions Combined Diabetes, August 1, 2003; 52(8): 1918 - 1925. [Abstract] [Full Text] [PDF]

				P. G. Drake, A. Balbis, J. Wu, J. J. M. Bergeron, and B. I. Posner Association of phosphatidylinositol 3-kinase with the insulin receptor: compartmentation in rat liver Am J Physiol Endocrinol Metab, August 1, 2000; 279(2): E266 - E274. [Abstract] [Full Text] [PDF]

				L. Lavoie, C. J. Band, M. Kong, J. J. M. Bergeron, and B. I. Posner Regulation of Glycogen Synthase in Rat Hepatocytes. EVIDENCE FOR MULTIPLE SIGNALING PATHWAYS J. Biol. Chem., October 1, 1999; 274(40): 28279 - 28285. [Abstract] [Full Text] [PDF]