The funtion of the protein kinase Nek5 in normal and cancer cells: from the identification of physiological substrates to inhibitor design

• Grant number: 16/10530-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2016
• End date: April 30, 2021
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Jörg Kobarg
• Grantee: Camila de Castro Ferezin
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 19/11435-4 - NEK5 phosphoproteomic profiling: identification of phospho-substrates in cancer cells and validation of known targets, BE.EP.DD

Abstract

The genetic material is under constant exogenous and endogenous agressions, which cause DNA lesions. To protect and repair these lesions the cells have different responses that promote DNA repair or tolerance to lesions. The importance of the repair mechanisms is demonstrated by its high evolutionary conservation and by gentic diseases associated to defects in these repair systems and which can lead to carcinogenesis and neurodegeneration. Functional analyses of proteins from the Nek family -of kinases - Nima Related Kinases, specially their protein interaction profiles, pointed to important roles in the cell cycle and in the DNA damage response. Among the members of the family Nek5 family is the least studied. We demonstrated recently its involvement in apoptosis and defective cellular respiration and the formation of reactive oxygen species. Aditionally this protein has a role in DNA repair mechanisms (see manuscript in preparation attached), leading to the activation of important kinases such as ATM and Chk2. Therefore, an important part of this project is the characterization of the mechanisms of action of Nek5 in the repair of DNA. Another focus is the identification of it natural physiological protein substrates through the so called "Shokat" approach, involving the generation of artificial kinases that are sensitive to ATP analogs. Furthermore, the functional alterations of mutations found in the Nek5 gene in cancer will be studied. Finally, we will perform bioassays of inhibitor candidates to discover new inhibitors of Nek5 that may be come to use as anti-cancer reagents. (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)

FEREZIN, CAMILA DE CASTRO; SIAN, TERRY C. C. LIM KAM; WU, YUNJIAN; MA, XIUQUAN; CHUEEH, ANDERLY C.; HUANG, CHENG; SCHITTENHELM, RALF B.; KOBARG, JORG; DALY, ROGER J.. Identification of biological pathways and processes regulated by NEK5 in breast epithelial cells via an integrated proteomic approach. CELL COMMUNICATION AND SIGNALING, v. 20, n. 1, p. 15-pg., 2022-12-22. (16/10530-5, 19/11435-4, 17/03489-1)

FEREZIN, CAMILA DE CASTRO; BASEI, FERNANDA LUISA; MELO-HANCHUK, TALITA D.; DE OLIVEIRA, ANA LUISA; PERES DE OLIVEIRA, ANDRESSA; MORI, MATEUS P.; DE SOUZA-PINTO, NADJA C.; KOBARG, JORG. NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance. FEBS OPEN BIO, v. 11, n. 3, FEB 2021. (16/10530-5, 17/03489-1, 18/05350-3, 14/50938-8)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FEREZIN, Camila de Castro. The function of NEK5 kinase in normal and cancer cells: from the identification of physiological substrates to the development of new inhibitors. 2021. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.