Vanadium Complexes Induce Cellular Phosphorylation Through The Inhibition Of PTP1B

Protein tyrosine phosphatases (PTPs) are a large family of signaling enzymes that play an important role in signal transduetion and regulation of cellular processes. Many human diseases, such as diabetes, obesity, cancer and immune disorders, are involved in the dysregulation of PTP activities. PTP1B has been demonstrated to play key roles in the negative regulation of signaling pathways mediated by insulin and leptin receptors. The PTPIB gene-null mice have increased insulin sensitivity and obesity resistance, even on a high-fat diet and has therefore emerged as a potential pharmaceutical target for the treatment of type II diabetes and obesity. Vanadium compounds have insulin mimic effect and are potent PTPs inhibitors. Our recent study revealed that several vanadium complexes exhibited certain selectivity against PTP1B in vitro. Here, two vanadium complexes [VIVO(nbbb)(H2O)2] (1) and [VIVO(bpmp)2] (2) are investigated for their influence on cellular phosphorylation and PTP1B selectivity.Both complexes increased the phosphorylation of P-Src(Y529), (IR/IGF1R)(PYPYPY1158/1162/1163) and P-EGFR(Y 1092) that are substrates of PTP1B in MCF-7,HepG-2 and Hela cells but they did not evidently improve the phosphorylation of P-Src(Y418) that is dephosphorylated by TCPTP, suggesting the complexes kept their selectivity against the inhibition of PTP1B in the cells. Complex (1) displayed obviously stronger potency in improving cellular phosphorylation than complex (2) and VOSO4, especially in MCF-7 cells.In addition, the PTP inhibition of vanadium complexes with bioligands are investigated. The results indicate most vanadium complexes with bioligands are potent PTPIB inhibitors. [VO(Phe)2] system displays strongest inhibition while [VO(Arg)2], [VO(Oxalate)], [VO(Nitrilotriacetate] and [VO(Citrate)] systems show weaker inhibition. The selectivity of [VO(Arg)2], [VO(Tyr)2], [VO(Phe)2], [VO(Malate)], [VO(Lactate)] and [VO(Citrate)] systems over PTP1B, TCPTP, HePTP and SHP-1 shows the inhibitions against four PTPs are varied with the change of the bioligands, suggesting the structures of the bioligands influence the potency of the PTP inhibition and the selectivity.