GFRA1 Human
Description
Role in Neural Development and Neurological Disorders
Neurogenesis and Synaptogenesis
GFRA1 is enriched in pre- and postsynaptic compartments of hippocampal neurons, promoting synapse formation and neuronal communication. GDNF-GFRA1 signaling enhances neurite outgrowth and protects against β-amyloid toxicity in Alzheimer’s disease (AD) models .
Hirschsprung Disease and Enteric Nervous System
-
GFRA1 mutations are linked to Hirschsprung disease, characterized by aganglionosis in the colon.
-
The receptor regulates enteric neuron proliferation and migration, with reduced expression causing intestinal motility disorders .
Neurodegenerative Diseases
-
Parkinson’s Disease (PD): GDNF-GFRA1 signaling supports dopaminergic neuron survival.
-
AD: GFRA1 overexpression may counteract amyloid-induced neuronal death .
Oncological Implications
Cancer Progression and Metastasis
GFRA1 is aberrantly expressed in cancers such as osteosarcoma, colon cancer, and pancreatic cancer, where it promotes:
-
Chemoresistance: GFRA1 mediates cisplatin-induced autophagy via SRC-AMPK signaling, enhancing osteosarcoma survival .
-
Metastasis: DNA demethylation of GFRA1 CpG islands correlates with poor differentiation and metastasis in colon cancer .
Targeted Therapies
-
Antibody-Drug Conjugates (ADCs): Preclinical studies explore anti-GFRA1 ADCs for breast and colon cancers .
-
Autophagy Inhibition: Chloroquine (autophagy inhibitor) synergizes with cisplatin to reduce tumor growth in osteosarcoma models .
Table 1: GFRA1 Expression and Clinical Correlations
Table 2: Signaling Pathways Activated by GFRA1
| Pathway | Key Molecules | Function | Disease Association |
|---|---|---|---|
| MAPK/ERK | RAS, ERK1/2 | Proliferation, survival | Cancer progression |
| PI3K/AKT | PI3K, AKT | Anti-apoptosis, metastasis | Chemoresistance |
| SRC-dependent | SRC, AMPK | Autophagy, neuronal adhesion | Osteosarcoma, AD |
Therapeutic Potential and Challenges
Targeted Interventions
-
Monoclonal Antibodies: Block GFRA1-GDNF interaction to inhibit cancer cell survival.
-
Epigenetic Modulation: Reactivate GFRA1 methylation to suppress metastasis in colon cancer .
Challenges
-
Off-Target Effects: GFRA1’s role in neural maintenance necessitates precise targeting to avoid neurotoxicity.
-
Heterogeneity: Tumor-specific GFRA1 expression levels require biomarker-driven therapies.
Product Specs
The GDNF family receptor alpha-1, also known as GFRA1, is a member of the GDNF receptor family. This receptor is attached to the cell surface by a glycosyl-phosphatidylinositol (GPI) anchor. GFRA1 acts as a receptor for both glial cell line-derived growth factor (GDNF) and neurturin (NTN), and it plays a crucial role in activating the RET tyrosine kinase receptor. As a potent survival factor for neurons in the central and peripheral nervous systems, GFRA1 is essential for the development of the kidneys and the enteric nervous system.
Recombinant human GFRA1, produced in HEK293 cells, is a single polypeptide chain that has undergone glycosylation. It spans amino acid residues 25 to 423 (a.a 25-423), resulting in a protein with 409 amino acids, including a 10 amino acid C-terminal His tag. The calculated molecular mass of this protein is 46.0 kDa.
The GFRA1 protein solution, at a concentration of 0.5 mg/ml in phosphate buffered saline (pH 7.5) containing 5% (w/v) trehalose, was filtered through a 0.4 μm filter before being lyophilized.
To create a working stock solution of roughly 0.5 mg/ml, it is advised to dissolve the lyophilized pellet in deionized water completely. It is important to note that GFRA1 is not sterile. Prior to using it in cell culture, the product must be filtered using a sterile filter that is suitable.
The purity of the protein is determined to be greater than 95.0% based on SDS-PAGE analysis.
GDNF receptor alpha-1, GDNFR-alpha-1, GFRalpha-1, RET ligand 1, TGF-beta-related neurotrophic factor receptor 1, GDNFRA1, RET1L2, RETL1, Glial Cell LineDerived Neurotrophic Factor Receptor Alpha, TRNR1, GPILinked Anchor Protein, PI-Linked Cell-Surface.
HEK293 cells.
DRLDCVKASD QCLKEQSCST KYRTLRQCVA GKETNFSLAS GLEAKDECRS AMEALKQKSL YNCRCKRGMK KEKNCLRIYW SMYQSLQGND LLEDSPYEPV NSRLSDIFRV VPFISVEHIP KGNNCLDAAK ACNLDDICKK YRSAYITPCT TSVSNDVCNR RKCHKALRQF FDKVPAKHSY GMLFCSCRDI ACTERRRQTI VPVCSYEERE KPNCLNLQDS CKTNYICRSR LADFFTNCQP ESRSVSSCLK ENYADCLLAY SGLIGTVMTP NYIDSSSLSV APWCDCSNSG NDLEECLKFL NFFKDNTCLK NAIQAFGNGS DVTVWQPAFP VQTTTATTTT ALRVKNKPLG PAGSENEIPT HVLPPCANLQ AQKLKSNVSG NTHLCISNGN YEKEGLGAS H HHHHHHHHH.
Product Science Overview
GDNF Family Receptor Alpha 1 (GFRA1) is a protein encoded by the GFRA1 gene in humans. It is a member of the GDNF receptor family and plays a crucial role in the nervous system by mediating the effects of neurotrophic factors such as Glial cell line-derived neurotrophic factor (GDNF) and Neurturin (NTN).
GFRA1 is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor. This means it is anchored to the cell membrane via a GPI anchor, which is a glycolipid that attaches proteins to the cell membrane. GFRA1 serves as a receptor for GDNF and NTN, facilitating their binding and subsequent activation of the RET tyrosine kinase receptor .
Mutations or dysregulation of the GFRA1 gene have been implicated in several disorders. Notably, GFRA1 is considered a candidate gene for Hirschsprung disease, a congenital condition characterized by the absence of ganglion cells in the intestines, leading to severe constipation or intestinal obstruction .
Recombinant human GFRA1 is produced using recombinant DNA technology, which involves inserting the GFRA1 gene into a suitable expression system, such as bacteria or mammalian cells, to produce the protein in large quantities. This recombinant protein is used in various research and therapeutic applications, including studies on neuronal survival, differentiation, and neurodegenerative diseases .
