This group represents glial cell line-derived neurotrophic factor (GDNF). This is a neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake [, ]. Defects in GDNF are a cause of congenital central hypoventilation syndrome (also known as Ondine's curse) and are also linked with Hirschsprung disease [, ].
Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) receptors are potent survival factors for sympathetic, sensory and central nervous system neurons [, ]. GDNF and neurturin promote neuronal survival by signalling through similar multicomponent receptors that consist of a common receptor tyrosine kinase and a member of a GPI-linked family of receptors that determines ligand specificity [].Structurally, GDNF is composed of five helices with an irregular disulfide-linked array. It is topologically similar to the fungal elicitin fold ().
The GDNF family members (consists of GDNF, neurturin, artemin and persephin) are structurally similar to transforming growth factor-beta. Unlike other members of the TGF-beta superfamily, which signal through the receptor serine-threonine kinases, GDNF family ligands activate intracellular signalling cascades via the receptor tyrosine kinase Ret. GDNF family ligands binds to GDNF family receptor alpha (GFRalpha) and then the GDNF family ligand-GFRalpha complex binds to and stimulates autophosphorylation of Ret. For instance, GDNF binds to GFRalpha1, Neurturin binds to GFRalpha2, artemin to GFRalpha3 and persephin activates Ret by binding to GFRalpha4. The GDNF family members support the survival of dopamine neurons and motoneurons, and some of them also regulate the development of enteric, sympathetic and parasympathetic neurons []. GDNF also functions in the regeneration of sensory axons after spinal cord injury [], regulation of spermatogonia renewal and differentiation during male spermatogenesis []. It is also involved in kidney development [].
This cysteine rich domain is found in multiple copies in GNDF and GAS1 proteins. GDNF and neurturin (NTN) receptors are potent survival factors for sympathetic, sensory and central nervous system neurons [, ]. GDNF and neurturin promote neuronal survival by signalling through similar multicomponent receptors that consist of a common receptor tyrosine kinase and a member of a GPI-linked family of receptors that determines ligand specificity [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-1 receptor subtype have been cloned from mammalian and avian tissue. The receptor is activated by GDNF [], although there is evidence it can also bind neurturin, the principal ligand for GFRalpha-2 [].Activation of GFRalpha-1 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Ret is a single transmembrane-spanning receptor tyrosine kinase (RTK) that plays critical roles in the development of vertebrates. It contains four consecutive cadherin-like domains (CLD). This entry represents the first CLD at the N-terminal. Several regions within RET-CLD1 have been shown to be important for ligand-coreceptor binding. CLD1 and CLD2 have a distinctive clamshell shape and CLD1 is essential for CLD2 folding. CLD1 contains 2 sites for GDNF receptor alpha 1 binding [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma)dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-2 receptor subtype have been cloned from mammalian and avian tissue. The receptor is preferentially activated by neurturin, although there is evidence that GFRalpha-2 can also bindGDNF if pre-coupled to its effector molecule [].Activation of GFRalpha-2 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-3 has been cloned from mammalian tissue []. It represents the least conserved member of the GFR family in terms of amino acid sequence, and is activated by artemin [].Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
