多发性内分泌腺瘤病.ppt

* This year marked the 20th anniversary of linking the MEN2 genetic defect to chromosome 10. Six years later two independent groups, Bruce Ponder at Cambridge and Helen Donis-Keller at WashU linked MEN2A to the RET proto-oncogene. The RET proto-oncogene encodes a trans-membrane receptor tyrosine kinase. * So what is RET? It is a type of receptor tyrosine kinase, just like c-kit and EGFR. The protein is mainly expressed in the neural crest and is essential for the development of enteric nervous system and kidney. Mutation of RET can either cause Hirshsprung disease or tumors, most importantly, MTC. * Like any other RTK, normally, RET functions as transducing signals in response to extracellular stimuli. This is the receptor, after binding of the ligand, GDNF, and the coreceptors GFR, the RET receptor is activated, leading to dimerization by the cysteine-rich region. And then the dimerized receptor induce the conformational change in the intracellular tyrosine kinase domains and lead to autophosphorylation and further activation of the downstream signaling pathways related to cell growth and survival. * If there is an introduction of mutation in the extracellular domain, the dimerization of the receptor could be achieved in the absence of ligand binding. If the mutation occurs in the intracellular domain, you get direct autophosphorylation without ligand binding or dimerizaiton of the receptors. In both cases, the RET signalling pathway will be activated, which can cause unregulated cell survival and MTC. * The cancer phenotype is associated with activating RET mutation. This table summarize the missense mutation and the related tumor type. FMTC is familiar MTC without other cancer syndrome; MEN2A is a syndrome with MTC, pheochromocytoma and hyperparathyroidism; MEN2B is MTC plus mucosal neuroma. Codon 634 is located in the extracellular Cysteine rich region, which is important for the dimerization of the RET receptor, mutation in this codon account for over 90%