Autoregulatory control of microtubule binding in doublecortin-like kinase 1.
Autoregulatory control of microtubule binding in doublecortin-like kinase 1.
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DOI：
10.7554/elife.60126
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发表时间：
2021-07-26
期刊：
影响因子：
7.7
通讯作者：
Ori-McKenney KM
中科院分区：
文献类型：
--
作者：
Agulto RL;Rogers MM;Tan TC;Ramkumar A;Downing AM;Bodin H;Castro J;Nowakowski DW;Ori-McKenney KM
微管相关蛋白，双皮质素样激酶1（DCLK 1），在一系列癌症中高度表达，是激酶抑制剂的主要治疗靶点。DCLK 1激酶活性的生理作用及其调节方式仍然难以捉摸。在这里，我们分析哺乳动物DCLK 1激酶活性在调节微管结合的作用。我们发现DCLK 1自身磷酸化其C-末端尾内的残基以限制其激酶活性并防止其微管结合结构域内的异常过度磷酸化。去除C-末端尾部或该残基的突变导致双皮质素结构域内磷酸化的增加，这消除了微管结合。因此，DCLK 1内特定位点的自磷酸化对该分子与微管的结合具有直接影响。我们的研究结果表明，DCLK 1调节其激酶活性，以调整其微管结合亲和力的机制。这些结果为未来与DCLK 1在癌症发展和进展中的作用相关的治疗工作提供了分子见解。
The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We found that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 has diametric effects on the molecule’s association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1’s role in cancer development and progression.
影响因子：
7.3
作者：
Hornick JE;Karanjeet K;Collins ES;Hinchcliffe EH
通讯作者：
Hinchcliffe EH