RET Protein
Introduction <table class="infobox infobox-protein">Substantia Nigra pars compacta </td>Ventral Tegmental Area </td>Spinal Cord Motor [Neurons](/entities/neurons) </td>Enteric Nervous System </td>Sympathetic Ganglia </td>Sensory Ganglia (DRG) </td>[Hippocampus](/brain-regions/hippocampus) </td>RET Tyrosine Kinase Inhibitors </td>GDNF Protein Delivery </td>AAV-GDNF Gene Therapy </td>
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RET Protein
Introduction <table class="infobox infobox-protein">Substantia Nigra pars compacta </td>Ventral Tegmental Area </td>Spinal Cord Motor [Neurons](/entities/neurons) </td>Enteric Nervous System </td>Sympathetic Ganglia </td>Sensory Ganglia (DRG) </td>[Hippocampus](/brain-regions/hippocampus) </td>RET Tyrosine Kinase Inhibitors </td>GDNF Protein Delivery </td>AAV-GDNF Gene Therapy </td>Small Molecule RET Agonists </td>GFRα1 Agonists </td>
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.
Overview 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.
Protein Structure
Extracellular Domain
Cadherin-like repeats (CLD1-4) : Four repeats that mediate ligand binding and receptor dimerizationCysteine-rich domain (CRD) : Critical for GDNF family ligand binding specificityN-terminal signal peptide : Directs proper membrane targetingTransmembrane Domain
Single-pass transmembrane helix : Anchors receptor in plasma membraneGlycosylation sites : Important for proper folding and ligand bindingIntracellular Domain
Tyrosine kinase domain : Catalytic core with ATP-binding siteMultiple tyrosine residues : Y900, Y905, Y1015, Y1062, Y1096, Y1179 (major autophosphorylation sites)C-terminal tail : Contains multiple signaling docking sitesMolecular Function
Ligand Binding and Activation RET requires co-receptors from the GFRα family for ligand recognition:
Signaling Pathways RET activates multiple downstream cascades:
PI3K/Akt Pathway Y1179 and Y1096 sites recruit PI3K
Promotes cell survival, inhibits [apoptosis](/entities/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
Expression Pattern RET exhibits tissue-specific expression:
Role in Disease
Parkinson's Disease 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
Amyotrophic Lateral Sclerosis (ALS)
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
Huntington's Disease
RET-mediated signaling impaired in HD
GDNF delivery reduces striatal degeneration in models
Wild-type [huntingtin](/proteins/huntingtin-protein) regulates RET expression
Therapeutic potential being investigated
Multiple Endocrine Neoplasia Type 2 (MEN2)
MEN2A : RET gain-of-function mutations (C634X)MEN2B : RET gain-of-function mutations (M918T)Medullary thyroid carcinoma (100% penetrance)
Pheochromocytoma (~50% penetrance)
Parathyroid hyperplasia
Hirschsprung Disease
RET loss-of-function mutations cause HSCR
Failure of enteric nervous system development
Aganglionic colon segment
~20% of HSCR cases have RET mutations
Congenital Central Hypoventilation Syndrome
PHOX2B-RET signaling disruption
Autonomic respiratory control failure
Therapeutic Targeting
Clinical Considerations
CNS delivery challenges (blood-brain barrier)
Peripheral side effects of systemic GDNF
Retrograde axonal transport requirements
Optimal timing of intervention
Animal Models
Knockout Studies
RET KO mice : Embryonic lethal, multiple developmental defectsConditional KO : Reveals adult-specific functionsGDNF KO : Similar phenotype to RET KODisease Models
MPTP/6-OHDA models : GDNF/RET protection studiesSOD1 ALS mice : GDNF delivery experimentsR6/2 HD mice : Therapeutic interventionsResearch Directions
[Blood-brain barrier](/entities/blood-brain-barrier) delivery : Novel AAV serotypes, intranasal approachesSelective RET agonists : CNS-penetrant small moleculesBiomarkers : RET signaling as PD progression markerCombination therapy : RET activation + [α-synuclein](/proteins/alpha-synuclein) reduction
Key Publications
PMID: 11343324 (https://pubmed.ncbi.nlm.nih.gov/11343324/) - RET receptor tyrosine kinase in neural developmentPMID: 8798756 (https://pubmed.ncbi.nlm.nih.gov/8798756/) - GDNF family ligands and RET signalingPMID: 10485310 (https://pubmed.ncbi.nlm.nih.gov/10485310/) - GDNF protects dopaminergic neuronsPMID: 12629044 (https://pubmed.ncbi.nlm.nih.gov/12629044/) - RET mutations in MEN2PMID: 18559608 (https://pubmed.ncbi.nlm.nih.gov/18559608/) - AAV-GDNF for Parkinson's diseasePMID: 22129738 (https://pubmed.ncbi.nlm.nih.gov/22129738/) - RET in motor neuron diseasePMID: 23797173 (https://pubmed.ncbi.nlm.nih.gov/23797173/) - GDNF/RET signaling in ALS modelsPMID: 26442605 (https://pubmed.ncbi.nlm.nih.gov/26442605/) - Targeting GDNF/RET in neurodegenerative disease
Background 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.
See Also
[RET Gene](/genes/ret)
[GDNF Gene](/clinical-trials/ab-1005-regenerate-pd-gdnf-gene-therapy)
[GFRα1 Protein](/proteins/gfra1-protein)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Neurotrophic Factor Signaling Pathway](/mechanisms/gdnf-neurotrophic-signaling-pathway)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Huntington's Disease](/diseases/huntingtons)
[Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
External Links
[UniProt: RET](https://www.uniprot.org/uniprot/P07949)
[PDB: 2IVU](https://www.rcsb.org/structure/2IVU)
[NCBI Gene: RET](https://www.ncbi.nlm.nih.gov/gene/5979)
[Human Protein Atlas: RET](https://www.proteinatlas.org/ENSG00000165731-RET)
References
[Takahashi M, et al, RET: a receptor tyrosine kinase (2001)](https://pubmed.ncbi.nlm.nih.gov/11343324/)
[Airaksinen MS, et al, GDNF family ligands and receptors (2001)](https://pubmed.ncbi.nlm.nih.gov/11545251/)
[Lin LF, et al, GDNF: a glial cell line-derived neurotrophic factor for dopaminergic neurons (1993)](https://pubmed.ncbi.nlm.nih.gov/8493557/)
[Edery P, et al, RET mutations in Hirschsprung disease (1996)](https://pubmed.ncbi.nlm.nih.gov/8896563/)
[Hofstra RM, et al, RET mutations in MEN2 (1994)](https://pubmed.ncbi.nlm.nih.gov/8114939/)
[Kordower JH, et al, AAV-GDNF for Parkinson's disease (2015)](https://pubmed.ncbi.nlm.nih.gov/25753531/)
[Sagot Y, et al, GDNF in ALS models (2000)](https://pubmed.ncbi.nlm.nih.gov/10627608/)
[Drinkut A, et al, RET agonist approaches (2016)](https://pubmed.ncbi.nlm.nih.gov/26442605/) Show full description