CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4
CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4
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DOI：
10.1038/sj.emboj.7601267
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发表时间：
2006-08-23
期刊：
影响因子：
11.4
通讯作者：
Stenmark, Harald
中科院分区：
文献类型：
--
作者：
Slagsvold, Thomas;Marchese, Adriano;Stenmark, Harald
癌症中的HER 2过表达导致PI 3-激酶途径的过度活化和趋化因子受体CXCR 4水平的升高，这与转移潜能的增加密切相关。在这里，我们提供的证据表明，非依赖于精氨酸的生存激酶CISK被激活下游的PI 3-激酶依赖性激酶PDK 1的内体和负调控溶酶体降解CXCR 4。我们证明了CISK通过抑制受体从早期内体到溶酶体的分选来防止CXCR 4降解。相反，CISK不干扰配体诱导的表皮生长因子受体降解。CISK与E3泛素连接酶AIP 4强烈相互作用并共定位，AIP 4对于CXCR 4的泛素依赖性溶酶体降解很重要。此外，所观察到的抑制既依赖于CISK和AIP 4之间的相互作用，也依赖于CISK的激活状态。与此相一致，CISK的活化形式而不是相关激酶SGK 1在体外磷酸化AIP 4的特定位点。总之，这些结果揭示了CISK在特异性减弱CXCR 4的泛素依赖性降解中的关键功能，并提供了PI 3-激酶途径和CXCR 4稳定性之间的机制联系。
HER2 overexpression in cancers causes hyperactivation of the PI 3-kinase pathway and elevated levels of the chemokine receptor CXCR4, which is strongly associated with increased metastatic potential. Here, we provide evidence that the cytokine-independent survival kinase CISK is activated downstream of the PI 3-kinase-dependent kinase PDK1 on endosomes and negatively regulates the lysosomal degradation of CXCR4. We demonstrate that CISK prevents CXCR4 degradation by inhibiting sorting of the receptor from early endosomes to lysosomes. In contrast, CISK does not interfere with ligand-induced degradation of epidermal growth factor receptors. CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro. Taken together, these results reveal a critical function of CISK in specifically attenuating ubiquitin- dependent degradation of CXCR4, and provide a mechanistic link between the PI 3-kinase pathway and CXCR4 stability.