Department of Neuroscience P037, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.
Oncogene. 2012 May 31;31(22):2773-82. doi: 10.1038/onc.2011.437. Epub 2011 Sep 26.
A recent genome-wide association study identified the gene encoding lemur tyrosine kinase-2 (LMTK2) as a susceptibility gene for prostate cancer. The identified genetic alteration is within intron 9, but the mechanisms by which LMTK2 may impact upon prostate cancer are not clear because the functions of LMTK2 are poorly understood. Here, we show that LMTK2 regulates a known pathway that controls phosphorylation of kinesin-1 light chain-2 (KLC2) by glycogen synthase kinase-3β (GSK3β). KLC2 phosphorylation by GSK3β induces the release of cargo from KLC2. LMTK2 signals via protein phosphatase-1C (PP1C) to increase inhibitory phosphorylation of GSK3β on serine-9 that reduces KLC2 phosphorylation and promotes binding of the known KLC2 cargo Smad2. Smad2 signals to the nucleus in response to transforming growth factor-β (TGFβ) receptor stimulation and transport of Smad2 by kinesin-1 is required for this signalling. We show that small interfering RNA loss of LMTK2 not only reduces binding of Smad2 to KLC2, but also inhibits TGFβ-induced Smad2 signalling. Thus, LMTK2 may regulate the activity of kinesin-1 motor function and Smad2 signalling.
最近的全基因组关联研究确定编码狐猴酪氨酸激酶-2（LMTK2）的基因是前列腺癌的易感基因。鉴定出的遗传改变位于内含子 9 内，但 LMTK2 可能影响前列腺癌的机制尚不清楚，因为 LMTK2 的功能知之甚少。在这里，我们表明 LMTK2 调节了已知的途径，该途径控制糖原合酶激酶-3β（GSK3β）对驱动蛋白轻链-2（KLC2）的磷酸化。GSK3β 磷酸化 KLC2 诱导货物从 KLC2 释放。LMTK2 通过蛋白磷酸酶-1C（PP1C）发出信号，增加 GSK3β 在丝氨酸-9 上的抑制性磷酸化，从而减少 KLC2 的磷酸化，并促进已知的 KLC2 货物 Smad2 的结合。Smad2 在响应转化生长因子-β（TGFβ）受体刺激时向核内发出信号，并且需要驱动蛋白-1 将 Smad2 运输到核内以进行这种信号转导。我们表明，LMTK2 的小干扰 RNA 缺失不仅减少了 Smad2 与 KLC2 的结合，而且还抑制了 TGFβ 诱导的 Smad2 信号转导。因此，LMTK2 可能调节驱动蛋白-1 运动功能和 Smad2 信号转导的活性。
