RET

RET
Name	RET
Organism	Homo sapiens
Chromosome	10
Location	10q11.21
Aliases	REarranged during Transfection

RET

RET is a receptor tyrosine kinase encoded on chromosome 10q11.21 that plays critical roles in the development and function of neural crest–derived tissues and organs. Initially characterized through studies of oncogenic rearrangements and developmental genetics, RET integrates extracellular signals to influence cell survival, differentiation, migration, and organogenesis. Dysregulation of RET through germline mutations, somatic point mutations, or gene fusions contributes to a spectrum of hereditary syndromes and sporadic malignancies, prompting extensive research into targeted diagnostics and therapies.

Overview

RET was first implicated in human disease through analyses of familial syndromes and chromosomal rearrangements identified in thyroid carcinomas, with key early contributions from researchers at institutions such as the National Institutes of Health and the University of California, San Francisco. The protein functions as a transmembrane tyrosine kinase activated by members of the glial cell line–derived neurotrophic factor family, which were characterized by laboratories including those at the Howard Hughes Medical Institute. RET signaling intersects with pathways studied at centers like Cold Spring Harbor Laboratory and influences processes investigated in model organisms such as Mus musculus, Danio rerio, and Drosophila melanogaster. Clinically, RET alterations are central to conditions investigated at specialty centers including Memorial Sloan Kettering Cancer Center and Mayo Clinic.

Structure and Function

The RET protein comprises an extracellular cadherin-like domain, a transmembrane segment, and an intracellular tyrosine kinase domain; structural elucidation owes much to methods developed at Max Planck Society laboratories and cryo-EM work from groups at EMBL. Extracellular activation requires co-receptors from the GFRα family, characterized by teams at institutions such as Salk Institute and Institut Pasteur, and ligands including members of the GDNF family, identified by researchers at Columbia University and the University of Michigan. Upon ligand-co-receptor binding, RET dimerizes and autophosphorylates conserved tyrosines in its kinase domain, recruiting adaptors and effectors that overlap with signaling modules described in studies at Dana-Farber Cancer Institute and Johns Hopkins University, thereby modulating pathways first detailed in work at Massachusetts Institute of Technology and Stanford University.

Clinical Significance and Diseases

Germline activating mutations in RET cause multiple endocrine neoplasia type 2 syndromes, with genotype–phenotype correlations defined in cohorts from Cleveland Clinic and Royal Marsden Hospital. Loss-of-function RET variants contribute to Hirschsprung disease as documented in consortia including European Society of Human Genetics and clinical groups at Great Ormond Street Hospital. Somatic RET fusions and point mutations drive subsets of non–small-cell lung carcinoma, papillary thyroid carcinoma, and medullary thyroid carcinoma, with epidemiologic patterns reported by public health agencies such as the Centers for Disease Control and Prevention and registries maintained at SEER Program. RET-related tumors are subjects of clinical trials conducted by cooperative groups including EORTC and SWOG.

Genetic Alterations and Mechanisms

RET alterations span germline missense substitutions discovered in familial studies at institutions like Mayo Clinic to somatic chromosomal rearrangements producing fusion oncoproteins identified by teams at Memorial Sloan Kettering Cancer Center and Vanderbilt University Medical Center. Mechanistically, activating point mutations cluster in the extracellular cysteine-rich region or the kinase domain, altering disulfide bonding or ATP binding—a mechanistic framework informed by crystallography from laboratories at University of Cambridge and Yale University. Fusion partners such as KIF5B and CCDC6 were first reported in genomic screens from centers including Broad Institute and University of Texas MD Anderson Cancer Center; these fusions drive constitutive dimerization and kinase activation, a paradigm shared with other oncogenic tyrosine kinases characterized at Institut Curie.

Diagnosis and Testing

Diagnostic approaches incorporate sequencing modalities developed at facilities like the Wellcome Sanger Institute and clinical genomics laboratories at Invitae. Germline testing for familial RET mutations follows guidelines published by professional bodies such as the American Thyroid Association and genetic counseling programs at centers like St. Jude Children’s Research Hospital. Tumor testing employs targeted next-generation sequencing panels, fluorescence in situ hybridization, and reverse-transcriptase PCR techniques standardized in laboratories affiliated with European Molecular Genetics Quality Network and College of American Pathologists. Multidisciplinary tumor boards at comprehensive cancer centers such as Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center integrate RET results into management plans.

Therapeutic Approaches and Drug Development

Targeted inhibition of aberrant RET signaling has been advanced by pharmaceutical collaborations involving companies such as Novartis, Bayer, and Roche, which supported clinical development of selective inhibitors. Approved and investigational agents that target RET-driven cancers have emerged from multicenter trials coordinated by groups including ASCO and ESMO, demonstrating responses in RET-rearranged lung and thyroid cancers. Resistance mechanisms—secondary mutations in the kinase domain or bypass pathway activation—are areas of active research in laboratories at University of Chicago and Fred Hutchinson Cancer Research Center, guiding next-generation inhibitor design and combination strategies tested in trials at National Cancer Institute and academic sites worldwide.

Category:Human genes