Ret Proto OncogeneEdit
The RET proto-oncogene encodes a receptor tyrosine kinase that sits at a crossroads of developmental signaling and cancer biology. In normal physiology, RET integrates signals from the glial cell line-derived neurotrophic factor (GDNF) family ligands through partnerships with GFR co-receptors to regulate the growth, survival, and migration of neural crest–derived cells, as well as the formation of the kidneys and urinary tract. When RET signaling goes awry, it can contribute to disease in two broad ways: loss-of-function changes that impair normal development, and gain-of-function alterations that drive uncontrolled cell growth in various cancers. The gene resides on chromosome 10q11.2 and produces a receptor protein with an extracellular domain, a transmembrane segment, and an intracellular tyrosine kinase domain that becomes activated upon ligand-induced dimerization.
In the germline, RET mutations can shape developmental trajectories in a way that predisposes individuals to distinct clinical syndromes. In cancer, the landscape is more heterogeneous: somatic rearrangements and amplifications can create fusion kinases or constitutively active receptors that sustain malignant signaling. Across these contexts, RET has become a focal point for precision medicine, with therapies tailored to specific RET alterations and ongoing debates about how best to deploy testing and treatment in diverse patient populations. gene oncogene GDNF GFR MAPK signaling PI3K/AKT signaling
Structure and function
Gene and protein architecture - The RET gene encodes a single-pass transmembrane protein with an extracellular region rich in cadherin-like domains, a transmembrane helix, and an intracellular tyrosine kinase domain. Alternative splicing yields isoforms, such as RET9 and RET51, that differ at the carboxyl terminus and may influence downstream signaling patterns. For an overview of how this architecture supports signaling, see RET proto-oncogene and tyrosine kinase receptor.
Ligand recognition and signaling - Activation requires ligands from the GDNF family (GDNF, neurturin, artemin, persephin) presented to RET in conjunction with GFRα co-receptors. This ternary complex promotes RET dimerization and autophosphorylation of key tyrosine residues, which in turn recruits adaptor proteins and triggers multiple signaling cascades, including the MAPK signaling cascade and the PI3K/AKT signaling pathway. These pathways regulate cell fate decisions such as proliferation, survival, differentiation, and migration. See also GDNF and GFRα for related components.
Physiological roles - RET signaling is essential for neural crest–derived lineages, especially in the enteric nervous system and the development of the kidneys and urinary tract. Disruption can lead to developmental conditions, while precise tuning of RET activity influences tissue patterning and organogenesis. For a broader view of neural crest biology, see neural crest and for organogenesis, see kidney development.
Developmental and physiological roles
Neural crest and organ development - During embryogenesis, RET activity guides the migration and differentiation of neural crest cells, contributing to autonomic and enteric nervous system formation. In the kidney, RET signaling promotes branching morphogenesis of the ureteric bud, shaping the collecting system. These developmental roles explain why germline RET mutations can produce congenital disorders and why RET remains a therapeutic target in certain cancers.
Hirschsprung disease and related conditions - Loss-of-function RET mutations can contribute to Hirschsprung disease, an aganglionic segment of the colon that impairs intestinal motility. The condition illustrates how reduced RET signaling translates into absent or defective neural crest derivatives in the gut. See Hirschsprung disease for a fuller discussion of the syndrome and its genetic architecture.
Cancer and somatic alterations - In cancer biology, RET is frequently altered by chromosomal rearrangements that generate oncogenic fusions or by point mutations that stabilize the kinase in an active state. In papillary thyroid carcinoma, somatic RET rearrangements such as RET/PTC contribute to tumorigenesis by constitutively activating RET signaling. In lung adenocarcinoma and other malignancies, RET fusions such as KIF5B-RET and CCDC6-RET act as potent oncogenic drivers. For a broader context on RET-driven cancers, see papillary thyroid carcinoma and lung adenocarcinoma.
Pathology and clinical significance
Inherited syndromes - Multiple endocrine neoplasia type 2 (MEN2) is a familial cancer syndrome caused by activating germline RET mutations. MEN2A and MEN2B differ in mutation spectra and clinical manifestations, with medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism among the core features. The most notorious MEN2B mutation, M918T, is associated with a particularly aggressive course. Prophylactic screening and early intervention, including thyroid management, are central to patient care. See MEN2 and medullary thyroid carcinoma for linked topics.
- In contrast, germline RET loss-of-function variants can predispose to Hirschsprung disease, underscoring the gene’s critical developmental role. See Hirschsprung disease for more.
Cancers and targeted therapy - Somatic RET rearrangements drive a subset of papillary thyroid carcinomas and a smaller fraction of non-small cell lung cancers. Identification of RET alterations has shifted treatment toward targeted tyrosine kinase inhibitors (TKIs). Early broad-spectrum TKIs such as vandetanib and cabozantinib demonstrated activity against RET-driven tumors but come with off-target toxicities. More recent, selective RET inhibitors—such as pralsetinib and selpercatinib—offer high response rates with improved tolerability for patients with RET fusions. See vandetanib and cabozantinib for context on first-generation RET targeting, and KIF5B-RET for example fusion partners.
- In thyroid cancer, RET/PTC rearrangements are a recognized driver in a subset of cases and have informed diagnostic and therapeutic strategies. In lung cancer, RET fusions identify a molecularly defined subset of tumors that respond to RET-selective therapy. For broader cancer-genomics context, see papillary thyroid carcinoma and lung adenocarcinoma.
Therapeutics and management - The therapeutic landscape for RET alterations has evolved toward precision medicine. Selective RET inhibitors provide targeted suppression of aberrant signaling with a side-effect profile that is often more favorable than older multikinase inhibitors. The clinical decision to employ RET-targeted therapy involves molecular testing to confirm RET alterations, assessment of disease burden, prior therapies, and patient comorbidities. See targeted therapy and precision oncology for related themes.
- Molecular testing is supported by methods such as fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) panels that can detect RET fusions and point mutations. See FISH and NGS for methodological context.
Controversies and debates
Testing and access
- A central debate concerns how broadly to screen tumors and at-risk individuals for RET alterations, balancing the benefits of targeted therapy against costs and the practical realities of healthcare systems. Proponents argue that identifying RET drivers enables highly effective, less toxic treatments, while critics worry about overtesting and the resource implications of expanding access to expensive therapies.
Therapeutic strategies
- The shift from multikinase inhibitors to highly selective RET inhibitors has improved tolerability and outcomes for many patients, but debates continue over optimal sequencing, combination approaches, and management of resistance. Some clinicians emphasize biomarker-driven, first-line RET inhibitors, while others advocate for personalized plans that consider coexisting mutations and tumor heterogeneity. Against this, discussions on real-world effectiveness and long-term toxicity inform guidelines and reimbursement decisions.
Early detection and family screening
- In hereditary RET syndromes such as MEN2, the tension between aggressive early intervention (e.g., prophylactic thyroidectomy in infants) and quality-of-life considerations for the patient raises ethical and clinical questions. Stakeholders weigh the benefits of cancer prevention against potential surgical and developmental risks, with patient autonomy and family counseling playing key roles.