File:Cln-67-s1-77-g002.jpg

English: Molecular mechanisms of pathogenic RET activation. Schematic diagrams showing mechanisms of RET activation in the presence of various multiple endocrine neoplasia type 2 (MEN 2) mutations. (A) Substitutions of extracellular cysteines lead to formation of intermolecular disulfide bonds and to constitutive RET dimerization and activation. (B) The MEN 2B mutation, M918T (star) in the kinase domain, leads to a conformational change with multiple effects including an increase in RET kinase activity and activation of receptors in either dimeric or monomeric form. (C) Intracellular kinase domain mutations asterisk implicated in familial medullary thyroid carcinoma (FMTC) (e.g. residues 791 and 891), permit activation of monomeric RET, allowing for a partially active conformation.