Identification of downstream regulatory factor in RET signaling pathway and its application to cancer treatment

Ret酪氨酸激酶（Ret）在胚胎发育和肿瘤发生中起着关键作用。RET主要以RET51和RET9两种异构体表达，这两种异构体通过选择性剪接产生了不同的c末端，而以往的研究表明RET9在肾发生和肠神经发生中是不可或缺的。我们发现在MEF3T3细胞诱导表达RET9后，细胞中酪氨酸磷酸化蛋白显著增加。通过基因表达谱分析，我们发现在RET51或RET9诱导表达下，261个基因存在差异表达。独创性途径分析显示，基因表达相关基因，包括转录因子，在这些差异表达基因中富集。接下来我们尝试用LC/MS鉴定RET51和RET9与RET之间的差异结合蛋白，但我们没有找到这样的候选蛋白，解释了RET51和RET9之间不同的功能。

Ret tyrosine kinase (RET) plays critical roles in embryonic development as well as oncogenesis. RET is mainly expressed as two isoforms, RET51 and RET9, which have different C-terminal ends generated through alternative splicing , whereas previous studies show that RET9 is indispensable for nephrogenesis and enteric neurogenesis. We found remarkable increase of tyrosine- phosphorylated proteins in the cells after inducible expression of RET9 in MEF3T3 cells. We demonstrated that 261 genes were differentially expressed under inducible expression of either RET51 or RET9 by gene expression profiling. Ingenuity pathway analysis revealed that gene expression-related genes, including transcription factors, were enriched in these differentially expressed genes. Next we tried to identify differentially binding protein to RET between RET51 and RET9 using LC/MS, but we failed to find such candidate proteins, accounting for different function between RET51 and RET9.