Effect of protein kinase inhibitors on activity of mammalian small heat shock protein (HSP25) kinase

被引:31
|
作者
Hayess, K [1 ]
Benndorf, R [1 ]
机构
[1] MAX DELBRUCK CTR MOL MED, D-13122 BERLIN, GERMANY
关键词
protein serine threonine kinase; inhibitors; Ehrlich ascites tumor cells; heat-shock protein; HSP25; phosphorylation;
D O I
10.1016/S0006-2952(96)00877-5
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The aim of this study was to investigate different protein kinase inhibitors (secondary metabolite derived substances, synthetic compounds, and substrate-based peptides) for their potency to inhibit the mammalian small heat shock protein (HSP25) kinase (E.C. 2.7.1.37) isolated from Ehrlich ascites tumor cells. Among the secondary metabolite-derived inhibitors (staurosporine, K-252a, K-252b, KT5926, KT5720, erbstatin analog, and quercetin) and synthetic compounds (H-9, H-89, HA 1004, KN-62, ML-7, tyrphostin A25, and tyrphostin B42), KT5926, staurosporine, and K-252a inhibited HSP25 kinase most efficiently. Kinetic analysis revealed that inhibition by staurosporine (K-i = 32.4 nM) and K-252a (K-i = 13.7 nM) was competitive with ATP. Inhibition by KT5926 was competitive with the substrate peptide KKKALNRQLSVAA (K-i = 27.2 nM) and noncompetitive with respect to ATP (K-i = 38.8 nM). In comparison with other protein kinases, HSP25 kinase was relatively resistant to most of the inhibitors. KT5926 was the only tested inhibitor with certain preference for HSP25 kinase when compared with protein kinases A, C, and G. Among the tested substrate-based peptides, we identified one peptide (KKKALNRQLGVAA), which preferentially inhibited HSP25 kinase in comparison with protein kinases A and C and mitogen-activated protein kinase. This peptide inhibited HSP25 kinase competitively with the substrate peptide (K-i = 8.1 mu M) and noncompetitively with ATP (K-i = 134 mu M). A peptide (SRVLKEDKERWEDVK) derived from the putative autoinhibitory domain of the closely related human mitogen-activated protein kinase-activated protein kinase-2 did not inhibit HSP25 kinase activity, suggesting the existence of several species of HSP25 kinases. Furthermore, the data identified structural requirements for inhibitors of HSP25-kinase. (C) 1997 Elsevier Science Inc.
引用
收藏
页码:1239 / 1247
页数:9
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