GDNF Family
About GDNF Family
The GDNF (glial cell line-derived neurotrophic factor) family is a group of proteins that play important roles in the development, maintenance, and survival of different types of cells in the nervous system. This family includes the GDNF family ligands (GFLs) and the GDNF family receptors (GFRs).
The GDNF family ligands consist of four proteins: GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). These ligands are secreted proteins that act as growth factors and signal molecules in the nervous system. They are involved in the regulation of neuronal development, axon guidance, and the survival and maintenance of various cell types, including motor neurons, sensory neurons, enteric neurons, and dopaminergic neurons.
The GDNF family receptors are a group of cell surface receptors that interact with the GFLs to mediate their signaling. There are four types of GFRs: GFRα1, GFRα2, GFRα3, and GFRα4. These receptors have a high affinity for specific GFLs and are essential for their binding and activation. Additionally, all GFRs form complexes with the Ret receptor tyrosine kinase, which is required for signal transduction.
Upon binding of a GFL to its specific GFR, the GFL-GFR complex recruits and activates the Ret receptor. This leads to the activation of various signaling pathways, such as the MAPK/ERK and PI3K/Akt pathways, which regulate cell growth, survival, and differentiation. The GDNF family signaling is crucial for the development and function of the nervous system, and dysregulation of this signaling has been implicated in various neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS).
In summary, the GDNF family includes a group of ligands and receptors that play important roles in regulating cell survival, development, and maintenance in the nervous system. Understanding the mechanisms of GDNF family signaling can provide insights into the development and treatment of various neurological disorders.
Fig.1 The interaction of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) with their receptors. (Kim M, et al., 2018)
Four homodimeric GFLs (GDNF, NRTN, ARTN, and PSPN) recognize their corresponding GDNF family receptor α (GFRα/GFRA1-4). GDNF specifically binds to GFRA1, NRTN to GFRA2, ARTN to GFRA3, and PSPN to GFRA4. Dotted arrow indicates cross-interaction of GFLs with GFRA which has been observed. Binding of GFL with GFRA activates protein tyrosine kinase RET. Neural cell adhesion molecule (NCAM) has been identified as an alternative signaling receptor for GFLs. RET also has been known as the representative receptor tyrosine kinases (RTKs) for these neurotrophic factor receptors. Activation of RET or NCAM via the GFL/GFRA complex is involved in various physiological functions, such as neuronal cell growth, differentiation, migration, and osteosarcoma chemoresistance via autophagy. Gray-colored area of the membrane indicates lipid raft. NRTN, neurturin; ARTN, artemin; PSPN, persephin.
Mechanism of Action of GDNF Family
Mechanism of Action of GDNF Family Ligands:
1. Binding to GFRs: GDNF family ligands can bind to GFRα receptors, which are the high-affinity receptors for these ligands. For example, GDNF binds to GFRα1, NRTN to GFRα2, ARTN to GFRα3, and PSPN to GFRα4. This ligand-receptor binding is essential for downstream signaling events.
2. Formation of receptor complexes: After binding to GFRα receptors, GDNF family ligands further interact with the RET receptor, a receptor tyrosine kinase, to form ligand-receptor complexes. The GFRα-RET complex is necessary for the downstream activation of signaling pathways.
3. Activation of RET: Upon ligand binding, the RET receptor is activated, leading to the phosphorylation of tyrosine residues in the intracellular domain of RET. This autophosphorylation of RET triggers a cascade of intracellular signaling events.
4. Activation of downstream signaling pathways: The activated RET receptor recruits several intracellular proteins, such as Shc, Grb2, and Gab1, which in turn activate multiple signaling pathways, including the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways. These pathways regulate various cellular processes, including cell survival, proliferation, differentiation, and gene expression.
Mechanism of action of GDNF family receptors:
1. Ligand binding: GFRs are activated by binding to their specific ligands, which include glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN).
2. Receptor dimerization: Ligand binding induces the dimerization of GFRs, bringing together two receptor subunits. This dimerization is facilitated by the binding of the ligand to the semaphorin domain of the receptor.
3. Activation of receptor tyrosine kinase activity: Dimerization of GFRs leads to the activation of their intracellular tyrosine kinase domains. This activation is mediated by trans-phosphorylation, where one receptor subunit phosphorylates the tyrosine residues on the adjacent subunit.
4. Downstream signaling: Once activated, the tyrosine kinase domains of GFRs phosphorylate specific tyrosine residues on the cytoplasmic tail of the receptor. These phosphorylated tyrosine residues serve as docking sites for various downstream signaling molecules, such as adaptor proteins and enzymes.
5. Activation of signaling pathways: The binding of the downstream signaling molecules to the phosphorylated tyrosine residues initiates the activation of several intracellular signaling pathways, including the Ras-MAPK, PI3K-Akt, and JAK-STAT pathways. These pathways regulate various cellular processes, such as cell survival, proliferation, and differentiation.
6. Cellular effects: The activation of GFRs and their downstream signaling pathways leads to various cellular effects, depending on the specific cell type and context. These effects include promoting the survival and growth of neurons, regulating the development and maintenance of certain tissues, and facilitating tissue repair and regeneration.
The Significance of Studying GDNF Family
Neural Development and Survival: GDNF family ligands and receptors play crucial roles in the development and survival of various neuronal populations in the central and peripheral nervous systems. Understanding the mechanisms by which GDNF family members regulate neural development, including cell survival, axonal growth, and guidance, provides insights into the fundamental processes underlying the formation of functional neural circuits.
Neurodegenerative Diseases: Dysregulation of the GDNF family and its receptors has been implicated in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Investigating the expression, signaling pathways, and interactions of GDNF family ligands and receptors in these diseases can lead to a better understanding of disease mechanisms and potentially identify therapeutic targets for intervention.
Nerve Regeneration and Repair: GDNF family ligands and receptors have shown promise in promoting nerve regeneration and repair after injuries to the central and peripheral nervous systems. Elucidating the mechanisms by which they enhance neuronal survival, axonal growth, and synaptic plasticity can contribute to the development of strategies to facilitate functional recovery after nerve injuries, such as spinal cord injury and peripheral nerve damage.
Therapeutic Targets: GDNF family ligands and receptors have attracted attention as potential therapeutic targets for various neurological disorders. Modulating the activity of these factors through pharmacological interventions, gene therapy, or stem cell-based approaches may offer new avenues for treating neurodegenerative diseases, neuropathic pain, and other neurological conditions.
Development of Neurotrophic Factors: Understanding the structure-function relationships and signaling pathways of GDNF family ligands and receptors can aid in the development of novel neurotrophic factors. By engineering or modifying these molecules, researchers can potentially enhance their therapeutic efficacy, improve their stability, and optimize their delivery methods.
Tissue Engineering and Regenerative Medicine: The knowledge gained from studying the GDNF family can be applied to tissue engineering and regenerative medicine approaches. By harnessing the neurotrophic properties of GDNF family members, researchers can develop biomaterial-based platforms or cell-based therapies that facilitate the growth, differentiation, and survival of specific neuronal populations.
In summary, studying the GDNF family ligands and receptors is significant for unraveling the mechanisms underlying neural development, elucidating the pathogenesis of neurodegenerative diseases, facilitating nerve regeneration, identifying therapeutic targets, and advancing tissue engineering and regenerative medicine approaches in the field of neuroscience.
Available Resources for GDNF Family
Creative BioMart offers a variety of products and services to support research on GDNF family-related molecules. Here are some key products and services we provide:
Diverse Product Portfolio: The products we provide include but are not limited to the following types:
- Recombinant Proteins: We offer high-quality recombinant proteins, including members and ligands of the GDNF family. These recombinant proteins can be utilized for in vitro studies of their functions, interactions, and signaling pathways.
- Cell and Tissue Lysates: We provide a range of cell and tissue lysates, including lysates of molecules related to the GDNF family. These lysates can be applied in immunohistochemistry, immunoprecipitation, and other related experimental techniques.
- Protein Pre-coupled Beads: We supply various protein pre-coupled beads for studying interactions among molecules related to the GDNF family. These pre-coupled beads can be employed in experimental designs and applications such as immunoprecipitation, co-immunoprecipitation, and affinity purification.
Custom Services: Our scientific team possesses extensive experience and expertise to customize specific proteins, antibodies, or experimental protocols according to your specific requirements. We offer tailored services to meet your research's particular needs.
Resource Support: Beyond product supply, we provide extensive resource support. We offer technical information, literature references, and experimental protocols related to molecules of the GDNF family, helping you better understand and research the functions and regulatory mechanisms of these important molecules.
Feel free to view the GDNF family-related molecules below and click for more comprehensive resources.
We are dedicated to providing you with high-quality research tools and services to help you achieve successful scientific outcomes. If you have any further questions or require custom services, please feel free to contact us at any time.
References:
- Kim M, Kim DJ. GFRA1: A Novel Molecular Target for the Prevention of Osteosarcoma Chemoresistance. Int J Mol Sci. 2018;19(4):1078. Published 2018 Apr 4. doi:10.3390/ijms19041078
- Zhang Z, Sun GY, Ding S. Glial Cell Line-Derived Neurotrophic Factor and Focal Ischemic Stroke. Neurochem Res. 2021;46(10):2638-2650. doi:10.1007/s11064-021-03266-5.
