Anales RANF

CPL-04 COMINGS AND GOINGS OF SIGNALLING CASCADES ACTIVATED BY NUCLEOTIDES Raquel Perez-Sen. Complutense University of Madrid, Spain Nucleotide signalling network expands beyond signalling kinases to the inactivation mechanisms via protein phosphatases. In particular, the regulation of MAP kinase phosphatases (MKPs) with substrate selectivity towards ERK, p38 and JNK, allow nucleotides to participate in the homeostatic control of the biological processes activated by MAPKs. The MKPs are dual specificity phosphatases (DUSPs) with the ability to dephosphorylate in serine/threonine and tyrosine residues. MKPs/DUSPs are self-regulated by MAPKs forming part of negative feedback loops that efficiently terminate MAPK signalling. Based on studies performed by DUSP genetic overexpression or deletion, the DUSPs reveal as critical regulators of the final biological outcome of MAPK activation during the cancer progression and the immune response. However, little is known about how the DUSPs are regulated by extracellular mediators in the nervous system. The neurotrophins NGF and BDNF represent well- known regulators of DUSPs function that limit MAPK proliferative signalling during differentiation and development. Besides, endogenous cannabinoids also behave as potent inducers of DUSP expression in spinal cord cells, in relation to the pain relief and the resolution of inflammation. The third players involved in DUSP regulation in neurons and glial cells are extracellular nucleotides. P2Y 13 and P2X7 receptors trigger different regulatory mechanisms, such as DUSP gene induction, protein turnover, and protein stabilization, and exert tight control of MAPK activity during neuroprotection and differentiation. Of relevance, the activation or inhibition of DUSP activity can be of therapeutic value, since it efficiently ameliorates the detrimental effects of MAPK dysregulation occurring in brain injury and neurodegeneration. By restoring proper levels of DUSP activity and expression, nucleotides contribute to arbitrate the full neuroprotective response in brain diseases. Overall, nucleotides behave as fine tuners of MAPK signalling through its participation in the spatio-temporal regulation of the DUSPs/MKPs that allows their dynamic adaptations to different conditions and cellular contexts. References: Pérez-Sen R, Queipo MJ, Gil-Redondo JC et al., 2019. Dual-Specificity Phosphatase Regulation in Neurons and Glial Cells. Int J Mol Biol. Apr 23; 20(8). Queipo MJ, Gil-Redondo JC,et al. 2018. Nucleotide and EGF Receptors Exert Dual Modulation of the Dual-Specificity Phosphatase 6 (MKP-3) in Granule Neurons and Astrocytes, Contributing to Negative Feedback on ERK Signaling. Front Mol Neurosci . 2018, Jan 10;10:448.