RET Gene (Ret Proto-Oncogene): Structure, Function, and Clinical Significance
A comprehensive biomedical overview of the RET gene, its associated diseases, expression patterns, mutations, and molecular functions.
Gene Information Card
| Symbol | RET |
|---|---|
| Full Name | ret proto-oncogene |
| Gene Type | protein-coding |
| Chromosomal Location | 10q11.21 |
| NCBI Gene ID | 5979 ncbi.nlm.nih.gov/gene/5979 |
| Ensembl ID | ENSG00000165731 |
| UniProt ID | P07949 |
| OMIM ID | 164761 |
| HGNC ID | 9967 |
| Aliases | CDHF12, CDHR16, PTC, RET-ELE1, RET51 |
Description
The RET gene encodes a receptor tyrosine kinase that is involved in cell survival, proliferation, differentiation, and migration. It is essential for the development of the enteric nervous system and the kidney. Mutations in RET are associated with multiple endocrine neoplasia type 2 (MEN2), medullary thyroid carcinoma (MTC), pheochromocytoma, and Hirschsprung disease. RET is also implicated in papillary thyroid carcinoma through chromosomal rearrangements (RET/PTC).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Multiple Endocrine Neoplasia Type 2A (MEN2A) | Activating missense mutations in the extracellular cysteine-rich domain (e.g., Cys634Arg) cause ligand-independent dimerization and constitutive activation of RET kinase. | OMIM #171400; ClinVar; COSMIC |
| Multiple Endocrine Neoplasia Type 2B (MEN2B) | Activating mutation in the kinase domain (e.g., Met918Thr) alters substrate specificity and increases catalytic activity, leading to aggressive tumorigenesis. | OMIM #162300; ClinVar; COSMIC |
| Medullary Thyroid Carcinoma (MTC) | Germline or somatic activating mutations in RET (e.g., Cys634, Met918) drive tumorigenesis in thyroid C cells. | OMIM #155240; ClinVar; COSMIC |
| Hirschsprung Disease | Loss-of-function mutations (e.g., frameshift, nonsense, or missense) impair RET signaling, leading to aganglionosis of the distal colon. | OMIM #142623; ClinVar; HGNC |
| Papillary Thyroid Carcinoma (PTC) | Chromosomal rearrangements (e.g., RET/PTC1, RET/PTC3) fuse RET kinase domain with partner genes, causing constitutive activation. | COSMIC; NCBI Gene; OMIM #188470 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Thyroid | High | High expression in thyroid C cells (parafollicular cells). |
| Adrenal Gland | Moderate | Expression in adrenal medulla (chromaffin cells). |
| Nervous System | Low | Expression in developing enteric neurons and some adult neural tissues. |
| Kidney | Low | Expression during embryonic development; low in adult. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| TT (thyroid carcinoma) | High | Medullary thyroid carcinoma cell line with RET mutation (Cys634Trp). |
| MZ-CRC-1 (thyroid carcinoma) | High | Medullary thyroid carcinoma cell line with RET mutation (Met918Thr). |
| SH-SY5Y (neuroblastoma) | Moderate | Neuroblastoma cell line expressing RET. |
| PC12 (pheochromocytoma) | Moderate | Rat pheochromocytoma cell line; used for RET signaling studies. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Cys634Arg | Missense | Common in MEN2A | Constitutive dimerization and activation of RET kinase. |
| Met918Thr | Missense | Common in MEN2B | Alters kinase substrate specificity; increased catalytic activity. |
| Cys620Arg | Missense | Associated with MEN2A and Hirschsprung disease | Dual effect: gain-of-function in MEN2A, loss-of-function in Hirschsprung. |
| Val804Met | Missense | Associated with familial MTC | Activating mutation in kinase domain; moderate oncogenic potential. |
| Arg982Cys | Missense | Rare; associated with Hirschsprung disease | Loss-of-function; impairs RET signaling. |
| RET/PTC1 rearrangement | Chromosomal rearrangement | Somatic in papillary thyroid carcinoma | Fusion of RET kinase domain with CCDC6; constitutive activation. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in RET (e.g., frameshift, nonsense, or missense in critical domains) impair receptor signaling, leading to Hirschsprung disease. These mutations often reduce protein expression, disrupt ligand binding, or impair kinase activity.
Gain of Function (GOF)
Gain-of-function mutations (e.g., Cys634Arg, Met918Thr) cause constitutive activation of RET kinase, leading to MEN2 syndromes and medullary thyroid carcinoma. These mutations promote cell proliferation and survival.
Dominant Negative (DN)
Some RET mutations, particularly those associated with Hirschsprung disease, may exert dominant-negative effects by forming non-functional heterodimers with wild-type RET, reducing overall signaling output.
View complete mutation data：
Gene Ontology (GO)
Pathways
• RET signaling pathway (KEGG: hsa04360)
• MAPK/ERK signaling pathway
• PI3K/AKT signaling pathway
• JAK/STAT signaling pathway
• GDNF/GFRα signaling pathway
Protein Summary
The RET protein is a single-pass type I transmembrane receptor tyrosine kinase. It consists of an extracellular domain with four cadherin-like repeats and a cysteine-rich region, a transmembrane domain, and an intracellular tyrosine kinase domain. Upon binding to ligands such as GDNF (glial cell-derived neurotrophic factor) in complex with co-receptors (GFRα1-4), RET undergoes dimerization and autophosphorylation, activating downstream signaling cascades (e.g., RAS/MAPK, PI3K/AKT). RET is critical for development of the enteric nervous system and kidney. Aberrant RET signaling due to mutations leads to various cancers and developmental disorders.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| RETREG1 Knockout HEK293 Cell Line | EDJ-KQ978 | Human | 54463 | Details Get a Quote |
| RETNLB Knockout HEK293 Cell Line | EDJ-KQ10156 | Human | 84666 | Details Get a Quote |
| RETN Knockout HEK293 Cell Line | EDJ-KQ11881 | Human | 56729 | Details Get a Quote |
| RETSAT Knockout HEK293 Cell Line | EDJ-KQ14286 | Human | 54884 | Details Get a Quote |
| RETREG2 Knockout HEK293 Cell Line | EDJ-KQ15037 | Human | 79137 | Details Get a Quote |
| RETREG3 Knockout HEK293 Cell Line | EDJ-KQ15038 | Human | 162427 | Details Get a Quote |
| RET Knockout HEK293 Cell Line | EDJ-KQ17840 | Human | 5979 | Details Get a Quote |
| RETREG1 Knockout HCT 116 Cell Line | EDJ-KQ19999 | Human | 54463 | Details Get a Quote |
| RETREG1 Knockout HeLa Cell Line | EDJ-KQ20000 | Human | 54463 | Details Get a Quote |
| RETREG1 Knockout A-549 Cell Line | EDJ-KQ18677 | Human | 54463 | Details Get a Quote |
| RET Knockout HCT 116 Cell Line | EDJ-KQ21301 | Human | 5979 | Details Get a Quote |
| RETREG2 Knockout A-549 Cell Line | EDJ-KQ45577 | Human | 79137 | Details Get a Quote |
| RETREG2 Knockout HCT 116 Cell Line | EDJ-KQ45578 | Human | 79137 | Details Get a Quote |
| RETREG2 Knockout HeLa Cell Line | EDJ-KQ45579 | Human | 79137 | Details Get a Quote |
| RETREG3 Knockout A-549 Cell Line | EDJ-KQ45580 | Human | 162427 | Details Get a Quote |
