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

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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.