Investigación

1)    Identification of molecular mechanisms underlying neurotrophin functions

We are interested in the understanding how neurotrophins (NGF, BDNF, NT-3 and NT-4) exert their functions. To this purpose, we focus in modifications such as ubiquitination that neurotrophin receptors (TrkA, TrkB and TrkC) to function properly. We identified an E3 ubiquitin ligase, Nedd4-2, which ubiquitinates specifically TrkA neurotrophin receptor (Arévalo, 2006). In addition, we have recently discovered that USP36 regulates indirectly TrkA receptor (Anta, 2016).

2)    Role of neurotrophins in pain

Chronic pain affects around 20% of population worldwide leading to huge social and economical costs. Neurotrophins play an essential role as mediators and modulators of pain. The understanding of the mechanisms that trigger chronic pain could help to develop better treatments to tackle this condition. To this purpose we are working on knee osteoarthritic pain (OA) using a mouse model with an enhanced NGF-mediated signaling and noxious pain sensation (Yu, 2014) identifying a novel neuro-immune pathway and suggest that NGF-induced production of PGD₂ in joint mast cells is critical for referred mechanical hypersensitivity in OA (Sousa-Valente, 2018).

3)    ARMS/Kidins220 function in the nervous system

ARMS/Kidins220 is a scaffold protein involved in neurotrophin-dependent and -independent functions. We have previously demonstrated that ARMS/Kidins220: 1) plays a seminal function on neurotrophin-mediated signaling (Arevalo, 2004, 2006); 2) is involved in AMPA receptor trafficking (Arévalo, 2010) and 3) is involved in NGF-mediated secretion (López-Benito, 2016) and BDNF secretion in physiological and pathological conditions (López-Benito, 2018).

References:

- Anta, B., Martín-Rodríguez, C., Gomis-Pérez, C., Calvo, L., López-Benito, S., Calderón-García, A.A., Vicente-García, C., Villarroel, A. and Arévalo, J.C. Ubiquitin Specific Protease 36 (USP36) controls Neuronal precursor cell-Expressed Developmentally Down-regulated 4-2 (Nedd4-2) actions over the neurotrophin receptor TrkA and potassium voltage-gated channels 7.2/3 (Kv7.2/3). J. Biol. Chem. 2016; 291: 19132-45.

- Arévalo, J.C.; Yano, H.; Teng, K.K., and Chao, M.V. A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane spanning protein. EMBO J. 2004; 23: 2358-68.

- Arévalo, J.C.; Waite, J.; Rajagopal, R.; Beyna, M.; Chen, Z.Y.; Lee, F.S., and *Chao, MV. Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination. Neuron 2006; 50: 549-559.

- Arévalo, J.C.; Pereira, D.; Yano, H.; Teng, K.K., and Chao, M.V. Identification of a switch in neurotrophin signaling by selective tyrosine-phosphorylation. J. Biol. Chem. 2006; 281:1001-7.

- López-Benito, S., Lillo, C., Hernández-Hernández, A., Chao, M.V. and Arévalo, J.C. ARMS/Kidins220 and Synembryn-B levels regulate NGF-mediated secretion. J. Cell Science. 2016; 129: 1866-77.

- López-Benito, S., Sánchez-Sánchez, J., Brito, V., Calvo, L., Lisa, S., Torres-Valle, M., Palko, M.E., Vicente-García, C., Fernández-Fernández, S., Bolaños, J.P., Ginés, S., Tessarollo,L. and Arévalo, J.C. Regulation of BDNF release by ARMS/Kidins220 through modulation of Synaptotagmin-IV levels. J. Neurosci. 2018; 38: 5415-5428.

- Sousa-Valente, J., Calvo, L., Vacca, V., Simeoli, R., Arévalo, J.C. and Malcangio, M. Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model. Osteoarthritis Cartilage 2018; 26:88-94.

- *Yu, T., *Calvo, L., Anta, B., López-Benito, S., López-Bellido, R., Vicente-Garcia, C., Tessarollo, L., Rodríguez, R.E. and Arévalo, J.C. In vivo regulation of NGF-mediated functions by Nedd4-2 ubiquitination of TrkA. J. Neurosci. 2014; 34: 6098-6106. *Equal contribution