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 discovered that USP36 regulates indirectly TrkA receptor (Anta, 2016) and that USP8 deubiquitinates and modulates TrkB-dependent functions such as neuronal differentation (Martín-Rodríguez, 2020).
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 using a mouse model with an enhanced NGF-mediated signaling and noxious pain sensation (Yu, 2014).
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); 4) modulates regulated BDNF secretion (López-Benito, 2018).
- 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 Jul 21. pii: jbc.M116.722637.
- 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.
- Martín-Rodríguez, C., Song, M., Anta, B., González-Calvo, F.J., Deogracias, R., Jing, D., Lee, F.S., Arevalo, J.C. TrkB deubiquitination by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation. J. Cell Science. 2020. Dec 7:jcs.247841. doi: 10.1242/jcs.247841.
- *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