Putting the bits and pieces of the RET proto-oncogene puzzle together

The RET proto-oncogene has been implicated in the causation of papillary thyroid carcinoma, multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B), and Hirschsprungʹs disease. The mutation in these syndromes can be categorized into activating or inactivating mutations. Activating mutations of a cysteine-rich extracellular region cause enhanced dimerization of the RET tyrosine kinase receptor and autophosphorylation, and are causative for MEN 2A and familial medullary thyroid carcinoma (FMTC). An activating mutation of the tyrosine kinase domain causes increased autophosphorylation but does not affect the state of dimerization. A variety of inactivating mutations of the RET protooncogene, which result in defective protein formation, are causative for Hirschsprungʹs disease.