title: 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).
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.
authors.affiliation: 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.
authors.forename: Begoña
authors.initials: B
authors.lastname: Anta
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martín-Rodríguez
authors.affiliation: the Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Universidad del País Vasco, barrio Sarriena s/n, 48940 Leoia, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gomis-Perez
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Calvo
authors.affiliation: 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.
authors.forename: Saray
authors.initials: S
authors.lastname: López-Benito
authors.affiliation: From the Departmento de Biología Celular y Patología, Instituto de Neurociencias de Castilla y León, University of Salamanca, Salamanca 37007, Spain.
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Calderón-García
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vicente-García
authors.affiliation: the Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Universidad del País Vasco, barrio Sarriena s/n, 48940 Leoia, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Villarroel
authors.affiliation: 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.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Arévalo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000096:biosynthesis* / Q000235:genetics; D051659:KCNQ3 Potassium Channel / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C000611485:NTRK1 protein, human; C501066:USP36 protein, human; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D020917:Receptor, trkA; D043222:Ubiquitin Thiolesterase
keywords: Kv channels; Nedd4-2; TrkA; USP36; deubiquitylation (deubiquitination); neurite outgrowth; neurotrophic factor; neurotrophin; ubiquitylation (ubiquitination)