Regulations mechanisms of the Wnt signalling pathway by E3 ubiquitin ligase SCF(Fbxo7)

• Grant number: 16/21310-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2017
• End date: February 28, 2019
• Field of knowledge: Biological Sciences - Biochemistry
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Felipe Roberti Teixeira
• Grantee: Caio Almeida Batista de Oliveira
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil

Abstract

The activation of canonical Wnt pathway results in expression of genes related tocellular differentiation, proliferation and development. When it is inactivated, theeffector of this pathway - ²-catenin - is located in a destruction complex, constitutedby several proteins, including GSK3² (glycogen-synthase kinase-3 beta), CSNK1µ(casein kinase Iµ) and ²TRCP (²-transducin repeat containing). GSK3² modulates thispathway through ²-catenin phosphorylation, which is then recognised andubiquitinated by SCF(²TRCP) E3 ligase complex, addressing it to the proteasome fordegradation. GSK3² is also a target for an exquisite modulation, which occursthrough three described processes: phosphorylation of its serine 9, inhibition byLRP5/6 tail and recruitment to Multivesicular Bodies - last two cases are notcompletely elucidated yet about the stimulus that leads to inactivation. Recently,using protein microarrays as a substrate source to E3 ubiquitin ligases, wedemonstrated that GSK3² is a substrate for E3 ligase SCF(Fbxo7), whichubiquitinates it in vitro and in vivo, forming ubiquitin chains in lysine 63 (K63),which did not modify its stability. We verified that this modification lead to ²-cateninaccumulation and activation of genes regulated by this factor. Thus, we described anew mechanism to modulate GSK3² activity through its ubiquitination bySCF(Fbxo7), which lead to Wnt pathway activation. However, the mechanisms rulingthis regulation and the involvement of other factors are still unknown. Our in vitroresults showed that CSNK1µ and ²TRCP were also ubiquitinated by SCF(Fbxo7),adding two more factors that may contribute to Fbxo7 activating effect in Wntpathway. Given the important role that Fbxo7 plays in cancer and Parkinson'sDisease, this project aims to understand the activation mechanism of Wnt pathway byFbxo7, through the study of its functional relation with GSK3², CSNK1µ and ²TRCP,to further understand the Fbxo7 function in these two important pathologies. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SPAGNOL, VALENTINE; OLIVEIRA, CAIO A. B.; RANDLE, SUZANNE J.; PASSOS, PATRICIA M. S.; CORREIA, CAMILA R. S. T. B.; SIMAROLI, NATALIA B.; OLIVEIRA, JOICE S.; MEVISSEN, TYCHO E. T.; MEDEIROS, ANA CARLA; GOMES, MARCELO D.; et al. The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-kappa B signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1865, n. 1, JAN 2021. (16/25798-3, 16/21310-6, 16/00792-2, 17/22153-4, 17/07879-9, 18/09204-1, 19/03943-0, 18/01308-2)

DELBUE, DEBORAH; MENDONCA, BRUNA S.; ROBAINA, MARCELA C.; LEMOS, LAUANA G. T.; LUCENA, I, PEDRO; VIOLA, JOAO P. B.; MAGALHAES, LIDIA M.; CROCAMO, SUSANNE; OLIVEIRA, CAIO A. B.; TEIXEIRA, FELIPE R.; et al. Expression of nuclear XIAP associates with cell growth and drug resistance and confers poor prognosis in breast cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1867, n. 10, OCT 2020. (16/25798-3, 16/21310-6)