RET and NTRK1 proto‐oncogenes in human diseases

Abstract

RET and NTRK1 are receptor tyrosine kinase (RTK) proteins which play a role in the development and maturation of specific component of the nervous system. Their alterations have been associated to several human diseases, including some forms of cancer and developmental abnormalities. These features have contributed to the concept that one gene can be responsible for more than one disease. Moreover, both genes encoding for the two RTKs show genetic alterations that belong to either "gain of function" or "loss of function" class of mutations. In fact, receptor rearrangements or point mutations convert RET and NTRK1 in dominantly acting transforming genes leading to thyroid tumors, whereas inactivating mutations, associated with Hirschsprung's disease (HSCR) and congenital insensitivity to pain with anhidrosis (CIPA), impair RET and NTRK1 functions, respectively. In this review we have summarized the main features of the two receptors, their physiological and pathological roles. In addition, we attempted to identify the correlations between the different genetic alterations and the related pathogenetic mechanisms.

Myeloproliferative disorders: the centrosome connection

“…21 H4/CCDC6 is a coiled-coil protein that is also fused to the RET TK in thyroid carcinomas. 40 Rabaptin 5 and HCMOGT1 have also coiled-coil domains; Rabaptin 5 is found in the endosomes. TP53BP1 controls the G2/M checkpoint.…”

“…57 Centrosome alteration might also occur in epithelial cancers, in which some examples of translocations leading to chimeric TK activation have been described. 40,58,59 However, all fusion proteins will not target the centrosome. Still, some of the oncogenic kinases that are not addressed to the centrosome may target subcellular sites that are involved in the control of cell division in coordination with this organelle, for example, the Golgi apparatus or the nucleolus, or may use some relays at the centrosome, as suggested for BCR-FGFR1.…”

Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene

“…Rearrangements of the RET receptor tyrosine kinase (RTK) gene, caused by chromosomal inversions or translocations, is a frequent genetic event (Ϸ30%) in PTC (12). These rearrangements mediate fusion of the tyrosine kinase-encoding domain of RET with heterologous genes, leading to the generation of chimeric RET͞PTC oncogenes.…”

“…The multidocking site Tyr-1062 (Tyr-451 in RET͞PTC1) in the C-terminal region of RET, interacting with a number of transduction molecules and involved in almost all downstream pathways activated by RET (14), was demonstrated necessary for the transforming activity of RET͞PTC oncogenes (15). Alternative pathogenetic events have been found in PTC and include chromosomic rearrangement involving TRKA (12) or BRAF point mutations or rearrangement (16)(17)(18).…”

Primary RET-mutated lung neuroendocrine carcinoma in MEN2B: response to RET-targeted therapy

“…MEN is first suspected when an index patient presents with one or more tumors specific to that syndrome. Of all MEN2B cases, 95% are represented by a germline point mutation affecting codon 918 (exon 16) resulting in a methionine to threonine alteration (M918T), inducing constitutive activation of the intracellular tyrosine kinase domain of the encoded RET receptor tyrosine kinase (RTK) (Alberti et al 2003). Tumor formation occurs in the neuroendocrine organs where constitutively activated RET is expressed.…”