2. Academic Validation
  3. 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)

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 Sep 2;291(36):19132-45. doi: 10.1074/jbc.M116.722637.
Begoña Anta 1,  Carlos Martín-Rodríguez 1,  Carolina Gomis-Perez 2,  Laura Calvo 1,  Saray López-Benito 1,  Andrés A Calderón-García 3,  Cristina Vicente-García 1,  Álvaro Villarroel 2,  Juan C Arévalo 4
Affiliations

Affiliations

  • 1 From the Departmento de Biología Celular y Patología, Instituto de Neurociencias de Castilla y León, University of Salamanca, Salamanca 37007, Spain, the Institute of Biomedical Research of Salamanca, 47195 Salamanca, Spain, and.
  • 2 the Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Universidad del País Vasco, barrio Sarriena s/n, 48940 Leoia, Spain.
  • 3 From the Departmento de Biología Celular y Patología, Instituto de Neurociencias de Castilla y León, University of Salamanca, Salamanca 37007, Spain.
  • 4 From the Departmento de Biología Celular y Patología, Instituto de Neurociencias de Castilla y León, University of Salamanca, Salamanca 37007, Spain, the Institute of Biomedical Research of Salamanca, 47195 Salamanca, Spain, and arevalojc@usal.es.
PMID: 27445338 DOI: 10.1074/jbc.M116.722637
Abstract

Ubiquitination of the TrkA neurotrophin receptor in response to NGF is critical in the regulation of TrkA activation and functions. TrkA is ubiquitinated, among other E3 ubiquitin ligases, by Nedd4-2. To understand mechanistically how TrkA ubiquitination is regulated, we performed a siRNA screening to identify deubiquitinating Enzymes and found that USP36 acts as an important regulator of TrkA activation kinetics and ubiquitination. However, USP36 action on TrkA was indirect because it does not deubiquitinate TrkA. Instead, USP36 binds to Nedd4-2 and regulates the association of TrkA and Nedd4-2. In addition, depletion of USP36 increases TrkA·Nedd4-2 complex formation, whereas USP36 expression disrupts the complex, resulting in an enhancement or impairment of Nedd4-2-dependent TrkA ubiquitination, respectively. Moreover, USP36 depletion leads to enhanced total and surface TrkA expression that results in increased NGF-mediated TrkA activation and signaling that augments PC12 cell differentiation. USP36 actions extend beyond TrkA because the presence of USP36 interferes with Nedd4-2-dependent Kv7.2/3 channel regulation. Our results demonstrate that USP36 binds to and regulates the actions of Nedd4-2 over different substrates affecting their expression and functions.

Keywords

Kv channels; Nedd4-2; TrkA; USP36; deubiquitylation (deubiquitination); neurite outgrowth; neurotrophic factor; neurotrophin; ubiquitylation (ubiquitination).

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