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Differential Interaction Between GDNF Receptor-Α-Like (GFRAL)

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Differential Interaction Between GDNF Receptor-Α-Like (GFRAL) 117.02 RnDSy-lu-2945 Differential Interaction Between GDNF Receptor-α-like (GFRAL) Protein and GDNF Family Ligands on Binding and Neuroblastoma Cell Proliferation Assays Guangjian Wang, Liwen Xiong, Tatsiana Gerassenkov, Vassili Kalabokis, Anthony Person | R&D Systems, Inc., 614 McKinley Place NE, Minneapolis, MN, 55413 Abstract Putative Interactions Between GFLs GRLs Binding to GFRAL GFRAL Affects Neurturin-Induced Results Summary The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) is one of • GFRAL binds to Neurturin with an EC in the order of ng/mL. and GFRs Cell Proliferation 50 three neurotrophic factor families found in the nervous system. The GFLs, along with 3 • GFRAL binds to Artemin with an EC in the order of µg/mL. their receptors, play important roles in axon guidance, synapse formation, neuronal 1400 50 PSPN GDNF RET NRTN ARTN ? survival, neural regeneration, and are implicated in a number of neurological 2.5 Neurturin : GFRAL 1 diseases. There are four GFLs: GDNF, Neurturin, Artemin, and Persephin. These 1200 • GFRAL only weakly binds to GDNF. ligands are known to bind to the co-receptors GFRα-1, GFRα-2, GFRα-3, and 2 GFRα-4, respectively, through which they activate the common signal transducer, 1000 • GFRAL does not bind to Persephin. 2 the receptor tyrosine kinase RET (Rearranged during Transformation). A fi fth co- 1.5 800 • GFRAL acts as a co-receptor enabling Neurturin-induced proliferation of SH-SY5Y receptor, GDNF Receptor-α-Like (GFRAL) was identifi ed in 2005, but the function of GFRα-1 GFRα-2 GFRα-3 GFRAL this orphan receptor is currently unknown.3 We have synthesized recombinant GFRα-4 human neuroblastoma cells. 1 600 human GFRAL and tested the hypothesis that GFRAL interacts with known GFLs to Binding (Mean O.D.) ? • GFRAL-enabled-Neurturin-induced proliferation of SH-SY5Y human neuroblastoma change the dynamics of GFLs and their receptor networks. Both ELISA binding 400 0.5 (RFU) Cell Proliferation α studies and cell-based assays were carried out using standard methods.4,5 Our cells is increased in the presence of GFR -2. EC50=0.006–0.147 µg/mL results show that Neurturin binds to GFRAL with a high affi nity (EC50 = 8 ng/mL, 200 0 N=4). Artemin binds to GFRAL with a low affi nity (EC50 = 2 mg/mL, N=2). GDNF and 1e-4 0.001 0.01 0.1 Persephin have only minimal or no binding to GFRAL (N=3). Addition of GFRAL Neurturin (µg/mL) 0 Conclusion proteins at a concentration of 0.5 µg/mL in cell culture media stimulated Neurturin- 1e-4 0.001 0.01 0.1 1 10 100 Signaling Neurturin Binds GFRAL. Recombinant Human GFRAL was coated onto a microplate well at 1 µg/mL. Recombinant Human Neurturin (µg/mL) • GFRAL interacts with known GFLs, mainly, Neurturin and Artemin. Neurturin (Catalog # 1297-NE) binds GFRAL in a dose-dependent manner (N=4). induced cell proliferation in the SH-SY5Y human neuroblastoma cell line (EC50 of Key GFRAL Stimulates Neurturin-Induced Cell Proliferation. Proliferation of SH-SY5Y human neuroblastoma cells was assessed Neurturin = 0.5 µg/mL, N=4). This effect of GFRAL is similar to that of GFRα-2 (EC PSPN ARTN 50 Persephin Artemin following treatment with increasing concentrations of Recombinant Human Neurturin (Catalog # 1297-NE) while in the • Interaction between GFRAL and Neurturin enables Neurturin-induced proliferation of Neurturin = 1 µg/mL, N=4), although the maximal response by GFRAL is lower GDNF Glial Cell Line-Derived Neurotrophic Factor GFR GDNF Family Receptor presence of 0.5 µg/mL of Recombinant Human GFRAL. Cultures also contained 10 µM of retinoic acid (N=4). RET Rearranged during Transformation GFRAL GDNF Receptor-α-Like of SH-SY5Y cells through the RET signaling pathway. than that of GFRα-2. GFRα-2 dose-dependently increased the effect of GFRAL in NRTN Neurturin stimulating the Neurturin-induced cell proliferation in SH-SY5Y cells (N=2). On the 3 Artemin : GFRAL • Tissue expression of GFRAL may potentially affect local dynamics of GFLs and 3000 contrary, addition of GFRAL did not affect the stimulatory effect of GFRα-2 on receptor networks. Neurturin-induced stimulation of SH-SY5Y cell proliferation (N=2). This is the fi rst Neurturin Binding to GFRα-2 2500 study to demonstrate that GFRAL interacts with GFLs, primarily Neurturin and • Identifi cation of interactions between GFRAL and GFLs should be helpful in Artemin, and can play a major role in GFLs and receptor networks involved in 2 1.31 guiding biochemical and bioinformatics effort to uncover the missing ligand neuronal processes. These data also show that the biologically active recombinant 2000 of GFRAL. GFRAL protein can be used to identify new GFRAL ligands and as a tool to 2.5 investigate GDNF-related signaling mechanisms. The identifi cation of this novel Binding (Mean O.D.) 1 1500 interaction between GFRAL and GDNF family ligands will enhance our understanding 2 Update to GFLs and GFRs Interactions of the mechanisms and applications of GLFs and their receptors in 1000 Cell Proliferation (RFU) Cell Proliferation neurodegenerative and neuropsychiatric diseases. EC50=2.22–3.36 µg/mL PSPN GDNF RET NRTN ARTN ? 1.5 0 500 0.1 1 10 100 GFRAL (µg/mL) 1 Binding (Mean O.D.) 0 Introduction Artemin Binds GFRAL. Recombinant Human Artemin (Catalog # 2589-AR) was coated onto a microplate well at 1 µg/mL. Recombinant Human GFRAL binds Artemin in a dose-dependent manner (N=2). 1e-4 0.001 0.01 0.1 1 10 100 The GFLs, which include GDNF, Neurturin, Artemin, and Persephin, have been shown 0.5 Neurturin (µg/mL) GFRα-1 GFRα-2 to be critical for the proliferation, migration, and differentiation of several neuronal α GFRα-3 GFRAL EC =0.001–0.004 µg/mL 3 GFR -2 Enhances the Effects of GFRAL on Neurturin-Induced Cell Proliferation. Proliferation of SH-SY5Y human GFRα-4 populations, as well as axon guidance and neurite branching, synaptogenesis, and 50 neuroblastoma cells was assessed following treatment with increasing concentrations of Recombinant Human Neurturin 0 (Catalog # 1297-NE) while in the presence of 0.5 µg/mL of Recombinant Human GFRAL (blue line). Addition of 0.2 µg/mL (red adult synaptic plasticity. The GFLs signal through a multimolecular protein complex 1e-4 0.001 0.01 0.1 2.5 GDNF : GFRAL line) and 0.5 µg/mL (green line) of Recombinant Human GFRα-2 (Catalog # 613-FR) enhanced the effects of GFRAL on that includes receptors of the GFRα family and the RET receptor tyrosine kinase. Neurturin (µg/mL) Neurturin-induced cell proliferation. Cultures also contained 10 µM of retinoic acid (N=2). Although some cross-talk exists, GFLs preferentially signal as homodimers through Neurturin Binds GFRα-2. Recombinant Human GFRα-2 (Catalog # 613-FR) was coated onto a microplate well at 2 their cognate GFRα receptor. GFRα-1, GFRα-2, GFRα-3, and GFRα-4 are the co- 1 µg/mL. Recombinant Human Neurturin (Catalog # 1297-NE) binds GFRα-2 in a dose-dependent manner (N=4). receptors for GDNF, Neurturin, Artemin, and Persephin, respectively. Following ligand 2500 1.5 binding, the GFL-GFRα complexes associate with the extracellular domain of RET, which cause RET to dimerize, autophosphorylate, and stimulate the Ras/MAPK, PI α Signaling GFR -2 Stimulates Neurturin-Induced 2000 2+ 1 Key 3-Kinase/Akt, and PLC/Ca signaling pathways. Recently, a fi fth co-receptor for Binding (Mean O.D.) PSPN Persephin ARTN Artemin GFLs, termed GFRAL, has been identifi ed. However, the ligand and function of this Cell Proliferation GDNF Glial Cell Line-Derived Neurotrophic Factor GFR GDNF Family Receptor α receptor has yet to be determined. This study investigated a possible role of GFRAL 0.5 1500 RET Rearranged during Transformation GFRAL GDNF Receptor- -Like 1400 NRTN Neurturin in GFL-GFRα signaling. 0 1200 1000 0.01 0.1 1 10 Hypothesis: GFRAL interacts with known GFLs and may change the dynamics of (RFU) Cell Proliferation GDNF (µg/mL) References GFLs and their receptor networks. 1000 500 GDNF Exhibits Minimal Binding to GFRAL. Recombinant Human GFRAL was coated onto a microplate well at 1 µg/mL and incubated with increasing concentrations of Recombinant Human GDNF (Catalog # 212-GD). There was minimally binding of 1. Ibáñez, C.F. and J.O. Andressoo (2016) Neurobiol. Dis. [Epub ahead of print] doi: Signifi cance: Determination of such an interaction is important for better 800 GDNF to GFRAL (N=3). 10.1016/j.nbd.2016.01.021. 0 understanding the dynamics of GFLs and their receptors and for identifying the 1e-4 0.001 0.01 0.1 1 10 100 unknown ligand of GFRAL. 600 Neurturin (µg/mL) 2. Wang, X. (2013) Biochim. Biophys. Acta 1834:2205. 3 Persephin : GFRAL GFRAL Does Not Affect the Stimulatory Effects of GFRα-2 on Neurturin-Induced Cell Proliferation. Proliferation of SH-SY5Y Cell Proliferation (RFU) Cell Proliferation 400 human neuroblastoma cells was assessed following treatment with increasing concentrations of Recombinant Human 3. Li, Z. et al. (2005) J. Neurochem. 95:361. Neurturin (Catalog # 1297-NE) while in the presence of 0.5 µg/mL of Recombinant Human GFRα-2 (Catalog # 613-FR; blue 200 line). Addition of 0.2 µg/mL (red line) and 0.5 µg/mL (green line) of Recombinant Human GFRAL had no effect on the 2 stimulatory effects of GFRα-2 on Neurturin-induced cell proliferation. Cultures also contained 10 µM of retinoic acid (N=2). 4. Hishiki, T. et al. (1998) Cancer Res. 58:2158. 0 1e-4 0.001 0.01 0.1 1 10 100 5.
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