The protein tyrosine phosphatases（PTPs） comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-I has been regarded as one of the best validated intracellular tyrosine phosph...The protein tyrosine phosphatases（PTPs） comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-I has been regarded as one of the best validated intracellular tyrosine phospha- tases. Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway. In this study, we found the role of Candesartan cilexetil targeting at SHP-1. The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1（IC50=85.6 ~tmol/L and Ki=24 ~tmol/L）. We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs. Through the consequence of Western blotting, it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor（IR）, insulin receptor substrate（IRS） and ERK] in insulin signaling pathway in HepG2 cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1. These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great applica- tion potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.展开更多
基金Supported by the National Natural Science Foundation of China（Nos.81102859, 81000202, 31000358） and the Research Fund for the Doctoral Program of Higher Education of China（No.20090061110019）.
文摘The protein tyrosine phosphatases（PTPs） comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-I has been regarded as one of the best validated intracellular tyrosine phospha- tases. Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway. In this study, we found the role of Candesartan cilexetil targeting at SHP-1. The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1（IC50=85.6 ~tmol/L and Ki=24 ~tmol/L）. We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs. Through the consequence of Western blotting, it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor（IR）, insulin receptor substrate（IRS） and ERK] in insulin signaling pathway in HepG2 cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1. These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great applica- tion potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.
