Kidins220/ARMS as a functional mediator of multiple receptor signalling pathways

An increasing body of evidence suggests that several membrane receptors – in addition to activating distinct signalling cascades – also engage in substantial crosstalk with each other, thereby adjusting their signalling outcome as a function of specific input information. However, little is known about the molecular mechanisms that control their coordination and integration of downstream signalling. A protein that is likely to have a role in this process is kinase-D-interacting substrate of 220 kDa [Kidins220, also known as ankyrin repeat-rich membrane spanning (ARMS), hereafter referred to as Kidins220/ARMS]. Kidins220/ARMS is a conserved membrane protein that is preferentially expressed in the nervous system and interacts with the microtubule and actin cytoskeleton. It interacts with neurotrophin, ephrin, vascular endothelial growth factor (VEGF) and glutamate receptors, and is a common downstream target of several trophic stimuli. Kidins220/ARMS is required for neuronal differentiation and survival, and its expression levels modulate synaptic plasticity. Kidins220/ARMS knockout mice show developmental defects mainly in the nervous and cardiovascular systems, suggesting a crucial role for this protein in modulating the cross talk between different signalling pathways. In this Commentary, we summarise existing knowledge regarding the physiological functions of Kidins220/ARMS, and highlight some interesting directions for future studies on the role of this protein in health and disease.This study was supported by research grants from: Cancer Research UK (to G.S.); the Italian Institute of Technology (to F.C. and F.B.); the Italian Ministry of University and Research [2008T4ZCNL grant number 2008T4ZCNL to F.B.]; the Compagnia di San Paolo, Torino (to F.B.); Telethon-Italy [grant number GGP09134 to F.B.] and the Spanish Ministry of Science and Innovation [grant number JCI-2008-01843 to V.N.].Peer reviewe

Efficient In Vitro and In Vivo Anti‐Inflammatory Activity of a Diamine‐PEGylated Oleanolic Acid Derivative

Recent evidence has shown that inflammation can contribute to all tumorigenic states. We have investigated the anti‐inflammatory effects of a diamine‐PEGylated derivative of oleanolic acid (OADP), in vitro and in vivo with inflammation models. In addition, we have determined the sub‐cytotoxic concentrations for anti‐inflammatory assays of OADP in RAW 264.7 cells. The in‐ flammatory process began with incubation with lipopolysaccharide (LPS). Nitric oxide production levels were also determined, exceeding 75% inhibition of NO for a concentration of 1 μg/mL of OADP. Cell‐cycle analysis showed a reversal of the arrest in the G0/G1 phase in LPS‐stimulated RAW 264.7 cells. Furthermore, through Western blot analysis, we have determined the probable molecular mechanism activated by OADP; the inhibition of the expression of cytokines such as TNF‐α, IL‐1β, iNOS, and COX‐2; and the blocking of p‐IκBα production in LPS‐stimulated RAW 264.7 cells. Finally, we have analyzed the anti‐inflammatory action of OADP in a mouse acute ear edema, in male BL/6J mice treated with OADP and tetradecanoyl phorbol acetate (TPA). Treatment with OADP induced greater suppression of edema and decreased the ear thickness 14% more than diclofenac. The development of new derivatives such as OADP with powerful anti‐inflammatory effects could represent an effective therapeutic strategy against inflammation and tumorigenic processes

Plekhg5 como diana farmacéutica para trastornos neurológicos

Plekhg5 como diana farmacéutica para trastornos neurológicos. La invención hace referencia al uso del gen Plekhg5 como diana farmacológica para el cribado, ensayo, y/o validación de moléculas, compuestos, agentes, y moduladores útiles en el tratamiento y/o prevención de enfermedades neurológicas, preferiblemente enfermedades neurodegenerativas. Más preferiblemente, la invención hace referencia también a moléculas, compuestos, agentes, y moduladores capaces de inhibir la expresión del gen Plekhg5, induciendo un fenotipo neuroprotector de células microgliales lo que posibilita reducir o detener los procesos de neurodegeneración que ocurren en mamíferos, preferiblemente en humanos.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Rhoq como diana farmacéutica para trastornos neurológicos

Rhoq como diana farmacéutica para trastornos neurológicos. La invención hace referencia al uso del gen Rhoq como diana farmacológica para el cribado, ensayo, y/o validación de moléculas, compuestos, agentes, y moduladores útiles en el tratamiento y/o prevención de enfermedades neurológicas, preferiblemente enfermedades neurodegenerativas. Más preferiblemente, la invención hace referencia también a moléculas, compuestos, agentes, y moduladores capaces de inhibir la expresión del gen Rhoq, induciendo un fenotipo neuroprotector de células microgliales lo que posibilita reducir o detener los procesos de neurodegeneración que ocurren mamíferos, preferiblemente humanos.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Arhgef6 como diana farmacéutica para trastornos neurológicos

Arhgef6 como diana farmacéutica para trastornos neurológicos. La invención hace referencia al uso del gen Arhgef6 como diana farmacológica para el cribado, ensayo, y/o validación de moléculas, compuestos, agentes, y moduladores útiles en el tratamiento y/o prevención de enfermedades neurológicas, preferiblemente enfermedades neurodegenerativas. Más preferiblemente, la invención hace referencia también a moléculas, compuestos, agentes, y moduladores capaces de inhibir la expresión del gen Arhgef6, induciendo un fenotipo neuroprotector de células microgliales lo que posibilita reducir o detener los procesos de neurodegeneración que ocurren en mamíferos, preferiblemente en humanos.Peer reviewedConsejo Superior de investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Correction to: The atypical RhoGTPase RhoE/Rnd3 is a key molecule to acquire a neuroprotective phenotype in microglia

In the version of this article that was originally published [1]; some information in the “Author’s contributions” section was omitted.Peer reviewe

The atypical RhoGTPase RhoE/Rnd3 is a key molecule to acquire a neuroprotective phenotype in microglia

Abstract Background Over-activated microglia play a central role during neuroinflammation, leading to neuronal cell death and neurodegeneration. Reversion of over-activated to neuroprotective microglia phenotype could regenerate a healthy CNS-supporting microglia environment. Our aim was to identify a dataset of intracellular molecules in primary microglia that play a role in the transition of microglia to a ramified, neuroprotective phenotype. Methods We exploited the anti-inflammatory and neuroprotective properties of conditioned medium of adipose-derived mesenchymal stem cells (CM) as a tool to generate the neuroprotective phenotype of microglia in vitro, and we set up a microscopy-based siRNA screen to identify its hits by cell morphology. Results We initially assayed an array of 157 siRNAs against genes that codify proteins and factors of cytoskeleton and activation/inflammatory pathways in microglia. From them, 45 siRNAs significantly inhibited the CM-induced transition from a neurotoxic to a neuroprotective phenotype of microglia, and 50 siRNAs had the opposite effect. As a proof-of-concept, ten of these targets were validated with individual siRNAs and by downregulation of protein expression. This validation step resulted essential, because three of the potential targets were false positives. The seven validated targets were assayed in a functional screen that revealed that the atypical RhoGTPase RhoE/Rnd3 is necessary for BDNF expression and plays an essential role in controlling microglial migration. Conclusions Besides the identification of RhoE/Rnd3 as a novel inducer of a potential neuroprotective phenotype in microglia, we propose a list of potential targets to be further confirmed with selective activators or inhibitors

Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio.

International audienceNeurite extension depends on extracellular signals that lead to changes in gene expression and rearrangement of the actin cytoskeleton. A factor that might orchestrate these signalling pathways with cytoskeletal elements is the integral membrane protein Kidins220/ARMS, a downstream target of neurotrophins. Here, we identified Trio, a RhoGEF for Rac1, RhoG and RhoA, which is involved in neurite outgrowth and axon guidance, as a binding partner of Kidins220. This interaction is direct and occurs between the N-terminus of Trio and the ankyrin repeats of Kidins220. Trio and Kidins220 colocalise at the tips of neurites in NGF-differentiated PC12 cells, where F-actin and Rac1 also accumulate. Expression of the ankyrin repeats of Kidins220 in PC12 cells inhibits NGF-dependent and Trio-induced neurite outgrowth. Similar results are seen in primary hippocampal neurons. Our data indicate that Kidins220 might localise Trio to specific membrane sites and regulate its activity, leading to Rac1 activation and neurite outgrowth