Figure 2 Mechanisms of RET activation in cancer

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Figure 2 Mechanisms of RET activation in cancer Figure 2 | Mechanisms of RET activation in cancer. a | In-frame RET rearrangements that result in fusion proteins containing the RET kinase domain can lead to the activation of oncogenic RET signalling. Activating RET fusions maintain the tyrosine kinase domain of the 3′ RET gene; breakpoints commonly occur within intron 11; however, introns 10 and 7 (not shown) are occasionally involved, resulting in the inclusion of the RET transmembrane (TM) domain. A variety of upstream, 5′ gene partners contribute different domains, such as coiled-coil, LIS1 homology (LisH), tryptophan–aspartate repeat (WDR), and sterile alpha motif (SAM) domains, to RET fusion proteins. These motifs mediate ligand-independent dimerization of the chimeric oncoprotein and, thus, autophosphorylation of the RET kinase domain, resulting in the activation of downstream signalling pathways that drive tumour-cell proliferation. 5′ gene partners that contain two different dimerization domains, such as TBL1XR1, are listed twice in the figure. In general, 5′ partners are not thought to exclusively pair with specific 3′ partners with defined breakpoints at introns 7, 10, and 11. RET rearrangements are largely thought to be somatic events, as opposed to RET mutations that can occur in the germ line or be acquired somatically. b | Activating RET mutations can result in substitutions of extracellular cysteine residues for alternate amino acids, which disrupt intramolecular disulfide bridges, enabling the formation of novel intermolecular covalent disulfide bonds that lead to ligand-independent dimerization. Such mutations are identified in the germ line of patients with multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid cancer (FMTC), which are associated with cancer predisposition. Mutations in the intracellular kinase domain of RET occur in multiple endocrine neoplasia type 2B (MEN 2B), and occasionally in FMTC, leading to monomeric (depicted) and/or dimeric (not depicted) activation of RET. In cases of ligand-independent RET dimerization and activation, downstream signalling might be enhanced by ligand binding. Select extracellular and intracellular domain substitution mutations are listed, along with the exon in which the mutation occurs. Drilon, A. et al. (2017) Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2017.175