摘要
很多细胞内的信号传导通路是由受体型酪氨酸蛋白激酶(RPTK)调控的,这些通路可以控制细胞的生长、分化和新陈代谢等不同功能。RPTK的异常表达通常会导致机体发育的紊乱或者肿瘤的发生。最近,一个新的RPTK类似分子被识别鉴定并且被命名为NOK(Novel Oncogene with Kinase-domain)。
过量表达的NOK会导致细胞转化和诱发裸鼠体内的肿瘤生成和转移。我们构建了两个NOK基因胞内结构域的保守酪氨酸位点突变Y327F和Y356F,它们是潜在的控制细胞内主要信号通路的位点。随后,我们利用BaF3细胞建立了稳定表达细胞系,分别表达小鼠促红细胞生成素受体(mEPOR)胞外区和NOK基因跨膜/胞内区及两个突变体的融合蛋白。通过观察上述细胞系的集落生成、细胞增殖(3H-TdR掺入)和流式细胞术检测细胞周期实验的结果,我们可知这两个突变可以使NOK基因丧失诱发细胞转化的能力。通过裸鼠成瘤实验和病理分析以及免疫染色实验,我们发现两个突变中的任何一个都可以消除BaF3/EN稳定表达细胞系注射后诱发的裸鼠体内成瘤和原发性的转移。更重要的是,信号通路研究显示ERK的磷酸化可以被Y356F突变完全阻断或者被Y327F突变显著降低。而且两个突变均可以显著的降低Akt和STAT5的磷酸化水平。此外,这两个突变还可以减弱NOK对E-cadherin的影响,而后者是细胞转移功能的重要标志基因。综合这些结果可知,NOK可能是通过促使信号通路的过度活化而诱发肿瘤生成的。通过蛋白序列的比对和突变不影响NOK激酶活性的事实,我们可以推论突变可能是依靠阻止下游信号分子和NOK的结合从而阻止磷酸化级联信号通路的激活。
综上所述,体外和体内水平的实验结果均表明NOK的保守酪氨酸位点Y327和Y356可能在其诱发成瘤的功能中发挥关键作用。并且由于这两个位点在整个PTK家族中的高度保守性,我们的研究结果可能预示了该家族成员的一种共同的诱发成瘤机制及可能的抑制调控方法。
Receptor protein-tyrosine kinases (RPTKs) are tightly regulated during normal cellular signal transduction processes including cell growth, differentiation, and metabolism. Aberrant expression of RPTK usually results in developmental disorders and cancer. Recently, a RPTK like molecule named Novel Oncogene with Kinase-domain (NOK) has been identified and characterized. Over-expression of NOK gene severely caused cellular transformation as well as tumorigenesis and metastasis in nude mice.
In current study, we generated two point mutations (Y327F and Y356F) within the endodomain of NOK that are the potential tyrosine phosphorylation sites controlling major intracellular signaling. Using BaF3 cells stably expressing the fusion protein with ectodomain of mouse erythropoietin receptor (mEPOR) and transmembrane/endodomain of NOK (BaF3-E/N), we were able to show that point mutations at Y327F and Y356F completely blockaded cellular transformation by NOK gene as examined by colony formation, cellular DNA synthesis and FACS. Moreover, tumorigenesis and metastasis induced by BaF3-E/N were completely abrogated upon the introduction of either single mutation. Importantly, signaling studies revealed that the activation of ERK pathway was completely inhibited by Y356F and significantly reduced by Y327F. Both mutations significantly prevented Akt and STAT5 activation. In addition that NOK inhibiting E-cadherin, which is an important metastasis marker gene, was also renewed by the two mutations.
Taken together, our studies both in vitro and in vivo demonstrate that these two tyrosine phosphorylation sites Y327F and Y356F may play critical role in NOK mediated tumorigenesis. Our study suggested a potential mechanism of tumorigenesis induced by PTKs, resulting from the conservation of these two tyrosine residues in most of the PTKs subfamilies.
引文
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