Transforming Ability of MEN2A-RET Requires Activation of the Phosphatidylinositol 3-Kinase/AKT Signaling Pathway

摘要: The RET gene codes for a receptor tyrosine kinase that plays crucial role during the development of both enteric nervous system and kidney. Germ line missense mutations at one six codons specifying extracytoplasmic cysteines are responsible two related cancer disorders as follows: multiple endocrine neoplasia type2A (MEN2A) familial medullary thyroid carcinoma (FMTC). MEN2A FMTC result in constitutive catalytic activity consequence convert into dominantly acting transforming gene. Although it has been shown RET-MEN2 mutants activate several transduction pathways, their respective contribution to neoplastic phenotype remains poorly understood. Over past few years, become increasingly clear ability viral cellular oncoproteins depends on capacity phosphatidylinositol 3-kinase (PI3K). We now report carrying representative mutation Cys-634 (termed RET-MEN2A) activates PI3K its downstream effector, serine/threonine AKT/protein B. Previous studies have demonstrated Tyr-1062, which is intracellular docking site Shc Enigma RET, abolishes RET-MEN2A activity. provide evidence Tyr-1062 abrogates binding p85 regulatory subunit subsequent stimulation PI3K/AKT pathway. Furthermore, infection rat fibroblasts with retrovirus expressing dominant-interfering form suppresses RET-MEN2A-dependent transformation, whereas overexpression AKT enhances oncogenic potential. In summary, these data consistent notion RET-mediated cell-transforming effect critically dependent activation