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"Briefly, GDNF binds its receptor GFRA1 on SSCs, followed by a subsequent signaling of a co-receptor RET, a transmembrane receptor tyrosine kinase, within all undifferentiated spermatogonia, which leads to upregulation in Src family kinase (SFK) signaling and activation of genes encoding key transcription factors (e.g., B cell CLL and lymphoma6, member B (Bcl6b), brachyury, Id4, ets variant gene 5 (Etv5), and LIM homeobox protein 1 (Lhx1)), leading to self-renewal (XREF_FIG)."
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"In the classical signaling pathway GDNF homodimers bind to the GDNF receptor alpha (GFRA) isoform GFRA1 xref , and the GDNF-GFRA1 complex binds to the rearranged during transfection (RET) receptor tyrosine kinase, activating numerous signaling pathways and triggering cell survival, proliferation, differentiation, and migration xref – xref ."
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"Although the direct interaction of GDNF with the GFRalpha-1 and NCAM co-receptors may not be the only method to activate Fyn, this study does demonstrate that GDNF promotes SC differentiation via a Fyn dependent mechanism, either through GDNF binding with GFRalpha-1 and NCAM or homophilic binding of NCAM."
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"In contrast to this, the GFRα1 is the core receptor for the neurotrophic peptide GDNF. xref Originally, GDNF-GFRα1 was found to support survival of mid-brain dopaminergic neurons and was thus of interest in Parkinson's disease research, xref but has since been seen to be important also for neuronal maintenance and plasticity in homeostasis. xref , xref GDNF rather than GFRα1 has been investigated in experimental TBI xref , xref and showed some promise."
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"GDNF binds to the GDNF family receptor alpha-1 (GFRA1)/c-Ret; activates downstream RAS, AKT, and mitogen-activated protein kinase (MAPK) pathways; and regulates the transcription of ETS variant transcription factor 5, B-cell CLL/lymphoma 6 member B protein, and LIM homeobox 1 to promote the self-renewal of SSCs[8]."
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"Although GDNF responsiveness is abolished in Gfra1 (-/-) neurons, it can be restored upon addition of soluble GFRalpha1, a result that is only compatible with the existence of a previously unknown transmembrane signaling partner for the GDNF and GFRalpha1 complex in GABAergic neurons."
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"Together, these observations demonstrate the existence of a novel transmembrane receptor partner for the GDNF and GFRalpha1 complex and uncover an unexpected interplay between GDNF-GFRalpha1 and HGF-MET signaling in the early diversification of cortical GABAergic interneuron subtypes."
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"In mice engineered such that Shh is not expressed by dopaminergic neurons, Gonzalez-Reyes et al. (15) reported a progressive reduction in striatal GDNF mRNA and protein, and at 12 months, upregulation of the Ret GDNF receptor and its coreceptor GDNF Receptor Alpha 1, which binds all members of the GDNF ligand family."
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"A second consistent finding across human prepubertal IVS studies is the loss of SSCs and proliferative SSCs. [ xref ] In fetal tissues, the use of GDNF+EGF+FGF2 was credited with supporting SSC survival and proliferation in vitro, but this did not translate to infant tissues, and GDNF was likewise found to have no effect on SSC proliferation in older prepubertal tissues. [ xref , xref ] There is a need to study the efficacy of GDNF supplementation to support SSC self‐renewal in the testicular microenvironment in vitro as well as other conditions that may improve SSC survival and proliferation. [ xref ] Intriguingly, comparison of the core‐shell model to SSC cultures revealed a substantial increase in SSC expression of key regulatory factors, including UTF1 , TSPY4 , and DAZL . [ xref , xref , xref , xref ] This difference is likely attributed to Sertoli cell‐SSC paracrine interactions, perhaps including GDNF‐GFRA1 signaling."
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"A precedent for the potential therapeutic effects of neurotrophic factors in injured salivary glands has already been demonstrated in vivo with administration of GDNF or Neurturin, which bind Gfra1 and Gfra2 receptors and improve saliva secretion post-irradiation (Ferreira, et al., 2018; Xiao, et al., 2014; Knox, et al., 2013)."
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"Once activated by the complex GDNF and GFRalpha1, Ret isoforms undergo transphosphorylation on several tyrosine residues, activating the Ras and mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase and AKT, responsible for cell survival or differentiation, and the phospholipase C-gamma (PLCgamma) pathway."
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"Formation of the GDNF-GFRα1 signaling complex leads to the autophosphorylation of Ret and the subsequent activation of downstream signaling cascades, such as the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase and phospholipase Cγ/protein kinase C pathway ( xref ; xref )."
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"The GDNF–GFRα1 complex then binds the RET [ xref , xref ] present on neuronal cell bodies and terminals of several different pathways, such as nigro–striatal dopaminergic neurons [ xref , xref ], spinal motor neurons [ xref ], noradrenergic neurons of the locus coeruleus [ xref ], enteric neurons [ xref ], and sensory neurons [ xref ]."
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"In the classical signaling pathway GDNF homodimers bind to the GDNF receptor alpha (GFRA) isoform GFRA1 , and the GDNF-GFRA1 complex binds to the rearranged during transfection (RET) receptor tyrosine kinase, activating numerous signaling pathways and triggering cell survival, proliferation, differentiation, and migration ."
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"The 3D structure (hetero-2-2-mer) was built according to the homology of the 4ux8.1 template and showed a GMQE value of 0.63 with 74% of identity and a resolution of 24Å (method: Electron Microscopy) when compared to human GDNF-GFRA1 interaction (merged in the 3D structure) ( xref A, box 2, box 3)."
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"Based on this evidence, we aimed to explore whether Gdnf-GFRα1 expression contributes to cognitive decline in the F1 and F2 generations of mouse dams exposed to lipopolysaccharide (LPS) during late gestation, and to evaluate also the potential interference effect of pro-inflammatory cytokines."
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"Ret (rearranged during transformation) and the 140 kDa isoform of NCAM (neural cell adhesion molecule) have each been identified as receptors that can bind to the GDNF and GFRalpha1 complex and induce subsequent intracellular signaling, primarily via the PI3K and Akt and/or MEK and Erk MAPK pathways."
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"As expected, the positive controls (GDNF in GFRalpha1-RET and soluble GFRalpha1 and GDNF complex in GFP-RET expressing cells) increased RET pY by 3.8-fold (P = 0.0042, RM ANOVA with Dunnett 's post hoc test) and 4.9-fold (P = 0.0465, RM ANOVA with Dunnett 's post hoc test) in GFRalpha1-RET and GFP-RET expressing cells, respectively."
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"After GDNF and GFRalpha1 binding, Ret can either signal via the PI3K and Akt- or MEK and Erk-pathways depending upon its localization in lipid raft or non lipid raft compartments at the cell membrane, while NCAM is well recognized to signal via the MEK and Erk-pathway after activation of the Src family kinase Fyn."
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"Interestingly HS/SOS treatment had no effect on pre-formed GDNF-driven mGFRα1-mediated cell clusters (Supplementary Fig. xref ), indicating that upon formation of an adhesion complex HS proteoglycans are unable to dismantle pre-assembled trans -adhesive GDNF-GFRα1 complexes under these conditions."
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"Taken together, data from cell clustering and spine density assays argue that GFRα1 acts as a trans -synaptic organizing molecule in a manner that depends on the GFRα1 pentamer interface present in the GDNF 10 -GFRα1 10 complex and required for the proper development of hippocampal connectivity."
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"These studies revealed that exogenous GFRα1 supplied in soluble form to primary MGE cultures derived from mutant mice lacking GFRα1 could rescue the effects of the mutation, a result that is only compatible with the existence of a transmembrane signaling partner for the GDNF-GFRα1 complex in GABAergic neurons."
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"GDNF binds to its two receptors, GDNF family receptor alpha 1 (GFRA1) and rets proto-oncogene (RET) of SSCs, through a paracrine pathway,1112 and it promotes the self-renewal of SSCs through multiple signaling pathways, including extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway."
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"In human pancreatic adenocarcinoma (MiaPaCa-2) cells, GDNF binds to its receptor GFRalpha1, activates the RET co-receptor, and promotes mitogen-activated protein kinase (MAPK) signaling to induce cancer cell migration towards nerve in vitro and animal models of PNI [ xref , xref ]."
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"In vitro studies have shown that following GDNF binding to GFRalpha1 the resulting complex recruits RET, leading to its activation by dimerization and autophosphorylation at specific cytoplasmic tyrosine residues, thus initiating a number of downstream intracellular pathways [XREF_BIBR]."
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"According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF-GFRalpha1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFRalpha1 central region were found to be critical for GFRalpha1 binding to GDNF and eliciting downstream signal transduction."
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"GDNF binds to tyrosine kinase receptors, forming a GDNF-GDNF family receptor alpha-1 (GFRα1) binary complex, then assembly with co-receptor tyrosine kinase rearranged during transfection (RET), forming the GDNF-GFRα1-RET ternary complex domains that signal through the activation of RAS/MAPK, PI3K/Akt/mTOR pathway and Jun N-terminal kinases-mediated-transcription (Chen et al., 2009)."
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"In addition to Itgb4 (a subunit binding partner of ITGA6), Itga1, Itga2, Itga7, Itgb8, and Mcam, and the cadherins Cdh2, Cdh6, and Cdh19, ITGA6 cells also expressed genes coding for receptors that play a role in neural cell development and maintenance, including PLXNB3, GFRA1, and GFRA3, that preferentially bind SEMA5A, GDNF, and artemin (Figure 4C)."
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"In mice engineered such that Shh is not expressed by dopaminergic neurons, Gonzalez-Reyes et al. (15) reported a progressive reduction in striatal GDNF mRNA and protein, and at 12 mo, upregulation of the Ret GDNF receptor and its coreceptor GDNF Receptor Alpha 1, which binds all members of the GDNF ligand family."
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"In vitro studies have shown that following GDNF binding to GFRalpha1 the resulting complex recruits Ret, leading to its activation by dimerization and autophosphorylation at specific cytoplasmic tyrosine residues, thus initiating a number of downstream intracellular pathways XREF_BIBR."
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"The binding of GDNF to Ret and GFRalpha1 leads to Ret phosphorylation (Kjaer and Ibanez, 2003; Sariola and Saarma, 2003), and thereby leads to the activation of several intracellular signaling pathways, including RAS and mitogen activated protein kinase and extracellular signal regulated kinase pathway and phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, which in turn promotes neuronal survival and differentiation (Creedon et al., 1997; Uesaka et al., 2013)."
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"For instance, decreased expression of Gabra2 may lead to neuronal hyperexcitability and subsequent cognitive deficits [ xref ]; downregulation of Gfra1, which interacts with the neurotrophic factor GDNF to regulate integration of newborn neurons and synaptic plasticity, may affect cognitive function [ xref ]; overexpression of Vcam1 during neuroinflammation is associated with cognitive decline [ xref ]."
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"Branching morphogenesis begins with the interaction between the metanephric mesenchyme and the ureteric bud, whereby inductive signals from both embryonic derivatives (GDNF is released from the metanephric mesenchyme and binds to its receptors c-RET and GFRalpha1 at the tips of the ureteric bud) initiate the branching process [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"Botchkareva et al. had postulated that GDNF-GFRA1 signaling within proximal and distal outer root sheath (ORS) and inner root sheath (IRS) cells of HFs may play a direct role in blocking premature catagen entry based on their in situ mRNA expression pattern of Gfra1 and Gdnf xref ."
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"Briefly, GDNF binds its receptor GFRA1 on SSCs, followed by a subsequent signaling of a co-receptor RET, a transmembrane receptor tyrosine kinase, within all undifferentiated spermatogonia, which leads to upregulation in Src family kinase (SFK) signaling and activation of genes encoding key transcription factors (e.g., B cell CLL/lymphoma6, member B ( Bcl6b) , brachyury, Id4, ets variant gene 5 ( Etv5 ), and LIM homeobox protein 1 ( Lhx1 )), leading to self-renewal ( xref ) ( xref )."
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"GDNF binds to GFRA1 and plays a role in neuronal survival and differentiation, including that of GABAergic interneurons. xref Localized release of GDNF in the hippocampus of an animal model of epilepsy suppresses seizure activity. xref Thus, decreased GFRA1 may reflect a change in cell survival or result in reduced GDNF-mediated seizure suppression in patients at high risk for SUDEP."
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"XREF_BIBR, XREF_BIBR It has been shown that the GDNF and GFRalpha1 complex can activate not only the canonical GDNF receptor Ret, a receptor tyrosine kinase which signals through the sarcoma protein (Src)/rat sarcoma (Ras)/mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, NF-kappaB (nuclear factor ' kappa-light-chain-enhancer ' of activated B cells), JNK (c-Jun N-terminal kinases) and PLCgamma (phospholipase gamma) pathway, but also with other signaling inducing receptors."
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"Canonically, the GDNF and GFRA1 complex activates RET to potentiate downstream signaling through the mitogen activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) pathways, promoting the differentiation, proliferation, and survival of neurons."
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"Because the nervous system and the skin epidermis share an ectodermal origin, neurotrophic factors may play critical roles in controlling skin appendage formation and homeostasis. xref , xref , xref , xref Glial cell line‐derived neurotrophic factor (GDNF), a well‐studied neuroprotective factor, xref , xref has recently been identified as a neurotrophic factor that promotes the formation of hair follicles in mice. xref The GDNF family of ligands (which includes neurturin [NRTN], artemin [ARTN] and persephin [PSPN]) mediate RET tyrosine kinase activation via a ligand‐binding receptor subunit called GDNF factor receptor alpha (GFRA). xref There are four GFRA family members, with GDNF preferentially binding to GFRA1, NRTN, ARTN and PSPN binding to GFRA2, GFRA3 and GFRA4 respectively. xref Furthermore, in cells lacking RET, neural adhesion molecule (NCAM) can directly interact with GFRA1‐GDNF to regulate cell–cell communication, xref , xref , xref which has yet to be investigated in skin cells."
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"With a lower affinity, the GDNF and GFRalpha1 complex can signal via the RET independent mechanism with the neural cell adhesion molecule (NCAM); GDNF can also signal independently from GFRalpha1 by interacting with the heparin sulfate proteoglycan syndecan-3 [XREF_BIBR, XREF_BIBR]."
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"Disruption of the niche or related signaling leads to stem cell loss. xref , xref The niche aging in the ovary is associated with the decline in ovarian reproductive function. xref – xref CADHERIN-22, a member of the cadherin superfamily, promotes FGSC self-renewal through interaction with the JAK and β-CATENIN. xref Meanwhile, CADHERIN-22 enhances PI3K-AKT3 signaling, thus, upregulating the expression of N-MYC and CYCLIN, and GDNF-GFRA1 activates AKT3 via PI3K or SFK, subsequently promoting self-renewal of FGSCs. xref GSK3 inhibitor BIO promotes proliferation of FGSCs through activation of β-CATENIN and E-CADHERIN, xref indicating an important role of GSK3 signaling in FGSCs proliferation."
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"In the gastrointestinal tract, GDNF binds to the GDNF family receptor alpha-1 (GFRa1) and the transmembrane tyrosine kinase receptor (Ret) to form a co-receptor complex, which stimulates the intracellular P3K/Akt signaling pathway, thus exerting an important effect on enteric neuron survival and axon outgrowth [21,22]."
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"GDNF can bind to its ligand specific co-receptor, GDNF family receptor alpha-1 (GFRA1), which is a membrane protein that is expressed in most spermatogonial subtypes in mouse testes including As, Apr, and Aal spermatogonia, triggering signaling via the transmembrane receptor tyrosine kinase RET [XREF_BIBR - XREF_BIBR]."
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"Noncanonical signal transduction downstream of the GDNF-GFRA1 axis is achieved by affecting the concentration of intracellular second messengers (calcium ions), which in turn regulate lysosomal function, maintain the level of autophagic flux under metabolic stress, help tumor cells to survive and colonize in the metastatic microenvironment of the liver and, ultimately, promote the occurrence and development of GC liver metastases [ xref , xref ]."
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"As GFRalpha1 possesses no transmembrane domain, intracellular signalling by the GDNF and GFRalpha1 complex is induced via recruitment of one of two co-receptors : REarranged during Transfection (RET) or intracellular domain containing isoforms of neural cell adhesion molecule (NCAM)."
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"The GDNF/GFRa1 complex subsequently binds with the “rearranged during transfection” (RET) tyrosine kinase receptor or the neural cell adhesion molecule (NCAM), though with lower affinity to activate either the MAPK or P13K–Akt pathway (Treanor et al., 1996; Trupp et al., 1996; Paratcha and Ledda, 2008; Sergaki and Ibáñez, 2017)."
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"CNTF binds the CNTF receptor (CNTFR), ephrins bind to the Eph tyrosine kinase receptors, EGF binds to the EGF receptor (EGFR) or receptor homologs, GDNF binds predominantly GFRα1 in complex with the RET receptor, neuregulins bind the ErbB family of receptors, PGRN binds TNF receptors as well as the sortilin receptor, and lastly, TGF-β isoforms binds to the TGF-β type I, II, and III receptors (TβRI, TβRII, and TβRIII) ( xref ; xref ; xref ; xref ; xref ; xref ; xref ; xref )."
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"Some trace residues had been proved to be important in ligand-receptor binding, especially in rat GFRalpha1, where alanine scanning mutagenesis confirmed that sites N (152) N (153), R (259), S (316) N (317) S (318) and Q (247) D (248) S (249) were critical for GFRalpha1 binding to GDNF or Ret and thus affected the formation of GDNF, GFRalpha1, and Ret complex."
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"While the binding of GDNF to Gfra1 also requires the expression of Ret, Ret dimerizes with other receptors such as Gfra2, Gfra3, and Gfra4 to confer specificity of binding to other trophic factors (neurturin, artemin, and persephin, respectively) and is therefore not specific to GDNF (Airaksinen and Saarma, 2002)."
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"These observations are likely due to all immobilized GFRα1 forming a complex with GDNF and the effect of GDNF being saturated. [ xref , xref ] In contrast, the combination of GFRα1 with inhibition of GDNF‐GFRα1‐RET signaling was the most effective in promoting neurite outgrowth under all conditions tested (Figure xref )."
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"Then, membranes were blocked with 5% powdered milk (<1% fat) in PBS for 1 h at room temperature, followed by overnight incubation with primary antibodies: anti‐GFRα1 (1:1000, goat from R&D Systems), anti‐GDNF (1:1000, goat from R&D Systems), anti‐RET (1:1000, rabbit from Thermo Fisher Scientific), NCAM (1:1000, rabbit from GeneTex), integrin β1 (1:1000, goat from R&D Systems), integrin α7 (1:1000, rabbit from Thermo Fisher Scientific). anti‐FAK (1:1000 from sheep, R&D Systems), anti‐FAK (Phospho‐Tyr397)(1:1000 from rabbit, Signalway Antibody), anti‐Fyn (1:1000 from mouse, R&D Systems), anti‐Fyn (Phospho‐Tyr530)(1:1000 from rabbit, Signalway Antibody), anti‐PI3 kinase (1:500 from rabbit, BioVision), anti‐PI3K (Phospho‐Tyr607)(1:1000 from rabbit, Thermo Fisher), anti‐ERK1/ERK2 (1:1000 from mouse, R&D Systems), anti‐ERK1/ERK2 (Phospho‐Thr202/Tyr204)(1:1000 from rabbit, Cell Signaling), and GAPDH (1:1000, rabbit from Affinity Bioscience)."
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"Binding of AT-MSC-Exo-derived NGF and GDNF to the TrkA and GDNFR receptors induces recruitment of Shc/Grb2 and Gap1 adapter molecules in injured neural cells, resulting in the PI3K-dependent activation of AKT kinase which phosphorylates BAD protein and Caspase-9, inhibiting their pro-apoptotic functions [63]."
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"Activation of the GDNF pathway is initiated via the ligation of GDNF to its co-receptor, GDNF family receptor alpha1 (GFRalpha1), which is a glycosylphosphatidylinositol (GPI)-linked membrane associated protein, and the recruitment of Ret to the GFRalpha1 and GDNF complex (XREF_FIG)."
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"30 That Müller glia produces neurotrophins in response to selective neurotrophins is demonstrated by observations that binding of GDNF to the GFRα1 and GFRα2 increases their expression of BDNF, GDNF, and bFGF,30 and that binding of BDNF and GDNF to their corresponding receptors in Müller glia trigger a signalling cascade of activation that induces the production of neuronal survival factors, such as bFGF,44 demonstrating an additional mechanism by which Müller glia may promote neuroprotection."
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"According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF-GFRalpha1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFRalpha1 central region were found to be critical for GFRalpha1 binding to GDNF and eliciting downstream signal transduction."