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主要表达为两种亚型，RET 51和RET 9，它们具有通过选择性剪接产生的不同C末端，而先前的研究表明RET 9对于肾发生和肠神经发生是不可或缺的。我们发现在MEF 3 T3细胞中诱导表达RET 9后，细胞中酪氨酸磷酸化蛋白质显著增加。我们通过基因表达谱分析证明了261个基因在RET 51或RET 9的诱导表达下差异表达。免疫途径分析显示，基因表达相关基因，包括转录因子，富集在这些差异表达的基因。接下来，我们试图使用LC/MS鉴定RET 51和RET 9之间与RET的差异结合蛋白，但我们未能找到这样的候选蛋白，这解释了RET 51和RET 9之间的不同功能。

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.