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Regulation of the Src Family Kinase Lck by Hsp90 and Ubiquitination

机译：Hsp90和泛素化对Src家族激酶Lck的调控

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Regulation of the Src-related tyrosine kinase Lck is crucial to the outcome of T-cell receptor (TCR) stimulation. It was previously shown that the stability of the constitutively active mutant LckY505F is controlled by Hsp90 (M. J. Bijlmakers and M. Marsh, Mol. Biol. Cell. >11:1585-1595, 2000). Here we establish that following TCR stimulation, endogenous activated Lck in T cells is also degraded in the presence of the Hsp90 inhibitor geldanamycin. Using Lck constructs expressed in COS-7 cells, we show that the presence of activating Lck mutations results not only in the enhanced dependence on Hsp90 but also in enhanced ubiquitination of Lck. Although both processes were induced by mutations Y505F and W97A that release the SH2 and SH3 inhibitory intramolecular interactions, respectively, neither process required Lck kinase activity or activation-dependent phosphorylation at serines 42 and 59 or tyrosine 394. By binding to the ATP-binding site, the Src family inhibitor PP2 reduced ubiquitination and overcame the need for Hsp90 monitoring of active Lck. We conclude that the levels of active Lck are influenced by two opposing processes, targeting for degradation by ubiquitination and rescue from degradation by Hsp90 monitoring. Based on the PP2 result, we propose that activation-induced conformational changes of the Lck kinase domain instigate both regulatory processes.
机译：Src相关酪氨酸激酶Lck的调节对于T细胞受体（TCR）刺激的结果至关重要。先前已经证明，组成型活性突变体LckY505F的稳定性由Hsp90控制（M.J.Bijlmakers和M.Marsh，Mol.Biol.Cell。> 11： 1585-1595，2000）。在这里，我们确定在TCR刺激后，在Hsp90抑制剂格尔德霉素的存在下，T细胞中的内源性激活Lck也被降解。使用在COS-7细胞中表达的Lck构建体，我们表明激活Lck突变的存在不仅导致对Hsp90的依赖性增强，而且导致Lck的泛素化增强。尽管这两个过程都是分别由释放SH2和SH3抑制性分子内相互作用的突变Y505F和W97A诱导的，但两个过程都不​​需要Lck激酶活性或丝氨酸42和59或酪氨酸394的活化依赖性磷酸化。通过与ATP结合位点结合，Src家族抑制剂PP2减少了泛素化，从而克服了对Hsp90监测活性Lck的需求。我们得出的结论是，活性Lck的水平受两个相反过程的影响，两个过程分别是通过泛素化降解和通过Hsp90监测从降解中恢复。基于PP2的结果，我们建议激活诱导Lck激酶域的构象变化引发两个调节过程。

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