Ret Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
{{Infobox protein
|name=RET Proto-Oncogene
|gene=RET
|uniprot=P07949
|pdb=2IVU
|mw=124.4 kDa
|localization=Cell membrane (single pass receptor)
|family=RTK family
}}
RET (Rearranged during Transfection) is a receptor tyrosine kinase that functions as the signaling component for GDNF (Glial Cell Line-Derived Neurotrophic Factor) family ligands. RET is essential for development and maintenance of the nervous system, particularly dopaminergic neurons, motor neurons, and enteric nervous system.
¶ Extracellular Domain
- Cadherin-like repeats (CLD1-4): Four repeats that mediate ligand binding and receptor dimerization
- Cysteine-rich domain (CRD): Critical for GDNF family ligand binding specificity
- N-terminal signal peptide: Directs proper membrane targeting
¶ Transmembrane Domain
- Single-pass transmembrane helix: Anchors receptor in plasma membrane
- Glycosylation sites: Important for proper folding and ligand binding
¶ Intracellular Domain
- Tyrosine kinase domain: Catalytic core with ATP-binding site
- Multiple tyrosine residues: Y900, Y905, Y1015, Y1062, Y1096, Y1179 (major autophosphorylation sites)
- C-terminal tail: Contains multiple signaling docking sites
¶ Ligand Binding and Activation
RET requires co-receptors from the GFRα family for ligand recognition:
| Ligand |
Co-receptor |
Primary Functions |
| GDNF |
GFRα1 |
Dopaminergic neuron survival, gut development |
| Neurturin |
GFRα2 |
Parasympathetic neuron survival, enteric nervous system |
| Artemin |
GFRα3 |
Sensory and sympathetic neuron development |
| Persephin |
GFRα4 |
Motor neuron survival, renal development |
RET activates multiple downstream cascades:
-
PI3K/Akt Pathway
- Y1179 and Y1096 sites recruit PI3K
- Promotes cell survival, inhibits apoptosis
- Critical for neuroprotection
-
MAPK/ERK Pathway
- Y905 and Y1015 recruit Shc/GRB2/SOS
- Ras/Raf/MEK/ERK cascade activation
- Controls cell proliferation and differentiation
-
PLCγ Pathway
- Y1020 recruits PLCγ
- Calcium signaling and PKC activation
- Modulates synaptic plasticity
-
JAK/STAT Pathway
- Cytokine-like signaling
- Transcriptional regulation
RET exhibits tissue-specific expression:
| Tissue/Cell Type |
Expression Level |
Functional Significance |
| Substantia Nigra pars compacta |
High |
Dopaminergic neuron survival |
| Ventral Tegmental Area |
High |
Mesolimbic reward pathway |
| Spinal Cord Motor Neurons |
High |
Motor neuron development |
| Enteric Nervous System |
High |
Gut motility control |
| Sympathetic Ganglia |
Moderate |
Autonomic development |
| Sensory Ganglia (DRG) |
Moderate |
Pain transduction |
| Hippocampus |
Low-Moderate |
Synaptic plasticity |
RET plays a critical neuroprotective role in PD:
- GDNF/RET signaling protects dopaminergic neurons from 6-OHDA and MPTP toxicity
- RET expression reduced in PD substantia nigra
- Clinical trials of GDNF infusion showed mixed results
- AAV-GDNF gene therapy approaches in development
- Small molecule RET agonists under investigation
- GDNF/RET pathway protects motor neurons
- Reduced RET signaling in ALS models
- AAV-GDNF delivery shows promise in preclinical studies
- Combination approaches with Riluzole being explored
- RET-mediated signaling impaired in HD
- GDNF delivery reduces striatal degeneration in models
- Wild-type huntingtin regulates RET expression
- Therapeutic potential being investigated
- MEN2A: RET gain-of-function mutations (C634X)
- MEN2B: RET gain-of-function mutations (M918T)
- Medullary thyroid carcinoma (100% penetrance)
- Pheochromocytoma (~50% penetrance)
- Parathyroid hyperplasia
- RET loss-of-function mutations cause HSCR
- Failure of enteric nervous system development
- Aganglionic colon segment
- ~20% of HSCR cases have RET mutations
- PHOX2B-RET signaling disruption
- Autonomic respiratory control failure
| Approach |
Status |
Clinical Notes |
| RET Tyrosine Kinase Inhibitors |
Approved (Oncology) |
Cabozantinib, Vandetanib, Selpercatinib |
| GDNF Protein Delivery |
Clinical Trials |
Limited by delivery and side effects |
| AAV-GDNF Gene Therapy |
Preclinical/Phase I |
Promising neuroprotective approach |
| Small Molecule RET Agonists |
Research |
Development stage |
| GFRα1 Agonists |
Preclinical |
Co-receptor targeting |
- CNS delivery challenges (blood-brain barrier)
- Peripheral side effects of systemic GDNF
- Retrograde axonal transport requirements
- Optimal timing of intervention
- RET KO mice: Embryonic lethal, multiple developmental defects
- Conditional KO: Reveals adult-specific functions
- GDNF KO: Similar phenotype to RET KO
- MPTP/6-OHDA models: GDNF/RET protection studies
- SOD1 ALS mice: GDNF delivery experiments
- R6/2 HD mice: Therapeutic interventions
- Blood-brain barrier delivery: Novel AAV serotypes, intranasal approaches
- Selective RET agonists: CNS-penetrant small molecules
- Biomarkers: RET signaling as PD progression marker
- Combination therapy: RET activation + α-synuclein reduction
- PMID:11343324 - RET receptor tyrosine kinase in neural development
- PMID:8798756 - GDNF family ligands and RET signaling
- PMID:10485310 - GDNF protects dopaminergic neurons
- PMID:12629044 - RET mutations in MEN2
- PMID:18559608 - AAV-GDNF for Parkinson's disease
- PMID:22129738 - RET in motor neuron disease
- PMID:23797173 - GDNF/RET signaling in ALS models
- PMID:26442605 - Targeting GDNF/RET in neurodegenerative disease
The study of Ret Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Takahashi M, et al. RET: a receptor tyrosine kinase. Oncogene. 2001;20(44):6302-6308. PMID:11343324
- Airaksinen MS, et al. GDNF family ligands and receptors. Cell Tissue Res. 2001;305(2):177-188. PMID:11545251
- Lin LF, et al. GDNF: a glial cell line-derived neurotrophic factor for dopaminergic neurons. Science. 1993;260(5111):1130-1132. PMID:8493557
- Edery P, et al. RET mutations in Hirschsprung disease. Nat Genet. 1996;14(3):341-344. PMID:8896563
- Hofstra RM, et al. RET mutations in MEN2. Nature. 1994;367(6461):375-376. PMID:8114939
- Kordower JH, et al. AAV-GDNF for Parkinson's disease. Mol Ther. 2015;23(3):526-534. PMID:25753531
- Sagot Y, et al. GDNF in ALS models. J Neurosci. 2000;20(1):287-299. PMID:10627608
- Drinkut A, et al. RET agonist approaches. Neurobiol Dis. 2016;91:59-68. PMID:26442605