GDNF family of ligands

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The GDNF family of ligands (GFL) consists of four neurotrophic factors: glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN). GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. In particular signalling by GDNF promotes the survival of dopaminergic neurons. [1]

Contents

Signalling complex formation

At the cell surface of target cells, a signalling complex forms, composed of a particular GFL dimer, a receptor tyrosine kinase molecule RET, and a cell surface-bound co-receptor that is a member of the GFRα protein family. The primary ligands for the co-receptors GFRα1, GFRα2, GFRα3, and GFRα4 are GDNF, NRTN, ARTN, and PSPN, respectively. [2] Upon initial GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule. Phosphorylation of these tyrosines then initiates intracellular signal transduction processes.

It has been shown that in the case of GDNF, heparan sulfate glycosaminoglycans are also required to be present at the cell surface in order for RET mediated GDNF signalling to occur. [3] [4]

Clinical significance

GFLs are an important therapeutic target for several conditions:

Given a huge spectrum of possible therapeutic applications, the modulation of GFRα/RET receptor complex activity is of great interest. However, natural GDNF ligands are of a limited clinical use. As positively charged polypeptides GFLs are unable to penetrate the blood–brain barrier, and they have very small volume of distribution in the tissues. Therefore, the creation of small-molecule agonists is highly beneficial for the development of effective therapies against devastating neurological diseases. [15]

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A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

<span class="mw-page-title-main">Neurotrophin</span>

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

<span class="mw-page-title-main">Glial cell line-derived neurotrophic factor</span> Protein-coding gene in the species Homo sapiens

Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the GDNF gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particularly GFRα1. It is also responsible for the determination of spermatogonia into primary spermatocytes, i.e. it is received by RET proto-oncogene (RET) and by forming gradient with SCF it divides the spermatogonia into two cells. As the result there is retention of spermatogonia and formation of spermatocyte.

<span class="mw-page-title-main">Tropomyosin receptor kinase A</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.

<span class="mw-page-title-main">Tropomyosin receptor kinase B</span> Protein and coding gene in humans

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). Standard pronunciation is "track bee".

<span class="mw-page-title-main">Tropomyosin receptor kinase C</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

Neurturin (NRTN) is a protein that is encoded in humans by the NRTN gene. Neurturin belongs to the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the transforming growth factor beta (TGF-beta) subfamily along with its homologs persephin, artemin, and GDNF. It shares a 42% similarity in amino acid sequence with mature GDNF. It is also considered a trophic factor and critical in the development and growth of neurons in the brain. Neurotrophic factors like neurturin have been tested in several clinical trial settings for the potential treatment of neurodegenerative diseases, specifically Parkinson's disease.

Persephin is a neurotrophic factor in the glial cell line-derived neurotrophic factor (GDNF) family. Persephin shares around a 40% similarity in amino acid sequence compared to GDNF and neurturin, two members of the GDNF family.

<span class="mw-page-title-main">Artemin</span> Protein-coding gene in the species Homo sapiens

Artemin, also known as enovin or neublastin, is a protein that in humans is encoded by the ARTN gene.

<span class="mw-page-title-main">RET proto-oncogene</span> Mammalian protein

The RETproto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules. RET loss of function mutations are associated with the development of Hirschsprung's disease, while gain of function mutations are associated with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasias type 2A and 2B, pheochromocytoma and parathyroid hyperplasia.

<span class="mw-page-title-main">GFRA1</span> Protein-coding gene in the species Homo sapiens

GDNF family receptor alpha-1 (GFRα1), also known as the GDNF receptor, is a protein that in humans is encoded by the GFRA1 gene.

<span class="mw-page-title-main">GFRA3</span> Protein-coding gene in the species Homo sapiens

GDNF family receptor alpha-3 (GFRα3), also known as the artemin receptor, is a protein that in humans is encoded by the GFRA3 gene.

<span class="mw-page-title-main">GAS1</span> Protein-coding gene in the species Homo sapiens

Growth arrest-specific protein 1 is a protein that in humans is encoded by the GAS1 gene.

<span class="mw-page-title-main">GFRA2 (gene)</span> Protein-coding gene in the species Homo sapiens

GDNF family receptor alpha-2 (GFRα2), also known as the neurturin receptor, is a protein that in humans is encoded by the GFRA2 gene.

Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins.

Gliogenesis is the generation of non-neuronal glia populations derived from multipotent neural stem cells.

The GDNF family receptor-α (GFRα) proteins are a group of co-receptors which form complexes with GDNF-family ligands (GFLs) to activate RET, the receptor of the GFLs. The GFRα co-receptors include the following:

Malú G. Tansey is an American Physiologist and Neuroscientist as well as the Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. Tansey holds the titles of Evelyn F. and William L. McKnight Brain Investigator and Norman Fixel Institute for Neurological Diseases Investigator. As the principal investigator of the Tansey Lab, Tansey guides a research program centered around investigating the role of neuroimmune interactions in the development and progression of neurodegenerative and neuropsychiatric disease. Tansey's work is primarily focused on exploring the cellular and molecular basis of peripheral and central inflammation in the pathology of age-related neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis.

References

  1. ↑ Airaksinen M, Saarma M (2002). "The GDNF family: signalling, biological functions and therapeutic value". Nat Rev Neurosci. 3 (5): 383–94. doi:10.1038/nrn812. PMID   11988777. S2CID   2480120.
  2. ↑ Arighi E, Borrello MG, Sariola H (2005). "RET tyrosine kinase signaling in development and cancer". Cytokine Growth Factor Rev. 16 (4–5): 441–467. doi:10.1016/j.cytogfr.2005.05.010. PMID   15982921.
  3. ↑ Barnett MW, Fisher CE, et al. (2002). "Signalling by glial cell line-derived neurotrophic factor (GDNF) requires heparan sulfate glycosaminoglycan". J. Cell Sci. 115 (23): 4495–4503. doi:10.1242/jcs.00114. PMID   12414995. S2CID   5910562.
  4. ↑ "Increase BDNF Levels". Thursday, 5 November 2020
  5. ↑ Gill S, Patel N, Hotton G, O'Sullivan K, McCarter R, Bunnage M, Brooks D, Svendsen C, Heywood P (2003). "Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease". Nat Med. 9 (5): 589–95. doi:10.1038/nm850. PMID   12669033. S2CID   3331090.
  6. ↑ Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B (2005). "Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor". J. Neurosurg. 102 (2): 216–22. doi:10.3171/jns.2005.102.2.0216. PMID   15739547.
  7. ↑ Henderson C, Phillips H, Pollock R, Davies A, Lemeulle C, Armanini M, Simmons L, Moffet B, Vandlen R, Simpson L, et al. (1994). "GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle". Science. 266 (5187): 1062–1064. Bibcode:1994Sci...266.1062H. doi:10.1126/science.7973664. PMID   7973664.
  8. ↑ Airavaara M, Planken A, Gäddnäs H, Piepponen T, Saarma M, Ahtee L (2004). "Increased extracellular dopamine concentrations and FosB/DeltaFosB expression in striatal brain areas of heterozygous GDNF knockout mice". Eur J Neurosci. 20 (9): 2336–2344. doi:10.1111/j.1460-9568.2004.03700.x. PMID   15525275. S2CID   24973132.
  9. ↑ He D, McGough N, Ravindranathan A, Jeanblanc J, Logrip M, Phamluong K, Janak P, Ron D (2005). "Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption". J Neurosci. 25 (3): 619–28. doi:10.1523/JNEUROSCI.3959-04.2005. PMC   1193648 . PMID   15659598.
  10. ↑ Horger B, Nishimura M, Armanini M, Wang L, Poulsen K, Rosenblad C, Kirik D, Moffat B, Simmons L, Johnson E, Milbrandt J, Rosenthal A, Bjorklund A, Vandlen R, Hynes M, Phillips H (1998). "Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons". J Neurosci. 18 (13): 4929–4937. doi:10.1523/JNEUROSCI.18-13-04929.1998. PMC   6792569 . PMID   9634558.
  11. 1 2 Golden J, Milbrandt J, Johnson E (2003). "Neurturin and persephin promote the survival of embryonic basal forebrain cholinergic neurons in vitro". Exp Neurol. 184 (1): 447–55. doi:10.1016/j.expneurol.2003.07.999. PMID   14637114. S2CID   28406766.
  12. ↑ Garcès A, Livet J, Grillet N, Henderson C, Delapeyrière O (2001). "Responsiveness to neurturin of subpopulations of embryonic rat spinal motoneuron does not correlate with expression of GFR alpha 1 or GFR alpha 2". Dev Dyn. 220 (3): 189–97. doi: 10.1002/1097-0177(20010301)220:3<189::AID-DVDY1106>3.0.CO;2-I . PMID   11241828.
  13. ↑ Gardell L, Wang R, Ehrenfels C, Ossipov M, Rossomando A, Miller S, Buckley C, Cai A, Tse A, Foley S, Gong B, Walus L, Carmillo P, Worley D, Huang C, Engber T, Pepinsky B, Cate R, Vanderah T, Lai J, Sah D, Porreca F (2003). "Multiple actions of systemic artemin in experimental neuropathy". Nat Med. 9 (11): 1383–1389. doi:10.1038/nm944. PMID   14528299. S2CID   24449754.
  14. ↑ Tomac A, Agulnick A, Haughey N, Chang C, Zhang Y, Bäckman C, Morales M, Mattson M, Wang Y, Westphal H, Hoffer B (2002). "Effects of cerebral ischemia in mice deficient in Persephin". Proc Natl Acad Sci USA. 99 (14): 9521–9526. Bibcode:2002PNAS...99.9521T. doi: 10.1073/pnas.152535899 . PMC   123173 . PMID   12093930.
  15. ↑ Bespalov M.M.; Saarma M. (2007). "GDNF family receptor complexes are emerging drug targets". Trends Pharmacol. Sci. 28 (2): 68–74. doi:10.1016/j.tips.2006.12.005. PMID   17218019.
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