Review Crosstalk between kinases, phosphatases and miRNAs in cancer Júlia L.F. Abrantes, Thaís F. Tornatore, Karin J. Pelizzaro-Rocha, Marcelo B. de Jesus, Rodrigo T. Cartaxo, Renato Milani, Carmen V. Ferreira-Halder * Department of Biochemistry, Institute of Biology, UNICAMP,13083-970 Campinas, Brazil article info Article history: Received 18 February 2014 Accepted 4 September 2014 Available online 16 September 2014 Keywords: Protein tyrosine kinases Protein tyrosine phosphatases miRNA Cell signaling Cancer aggressiveness Chemotherapy resistance abstract Reversible phosphorylation of proteins, performed by kinases and phosphatases, is the major post translational protein modification in eukaryotic cells. This intracellular event represents a critical regu- latory mechanism of several signaling pathways and can be related to a vast array of diseases, including cancer. Cancer research has produced increasing evidence that kinase and phosphatase activity can be compromised by mutations and also by miRNA silencing, performed by small non-coding and endoge- nously produced RNA molecules that lead to translational repression. miRNAs are believed to target about one-third of human mRNAs while a single miRNA may target about 200 transcripts simultaneously. Regulation of the phosphorylation balance by miRNAs has been a topic of intense research over the last years, spanning topics going as far as cancer aggressiveness and chemotherapy resistance. By addressing recent studies that have shown miRNA expression patterns as phenotypic signatures of cancers and how miRNA influence cellular processes such as apoptosis, cell cycle control, angiogenesis, inflammation and DNA repair, we discuss how kinases, phosphatases and miRNAs cooperatively act in cancer biology. © 2014 Elsevier B.V. and Soci et e française de biochimie et biologie Mol eculaire (SFBBM). All rights reserved. 1. Introduction Phosphorylation and dephosphorylation are the main type of post-translational modifications in eukaryotic cells, and are tightly regulated by protein kinases and protein phosphatases, respec- tively [1]. Indeed, phosphorylation and dephosphorylation are efficient strategies to modulate cellular response towards internal and external stimuli, since it is a reversible process that does not require synthesis and/or degradation of proteins. Therefore, these post-translational modifications allow cells to transiently regulate a set of proteins at the same time, in different cellular compartments and signaling pathways that in turn, define which metabolic response will be dominant under a specific stimulus. Under this context, a variety of cellular processes, such as proliferation, migration, apoptosis, autophagy, differentiation, metabolism, organelle trafficking, immunity, learning and memory depend on the action of kinases and phosphatases [2e4]. Thus, not surpris- ingly, abnormal kinase or phosphatase activities correlate with disease conditions such as cancer, diabetes and neurodegenerative or inflammatory disorders [5e7]. Specifically in relation to miRNAs metabolism and function, there are some evidences that kinases and phosphatases can be modulated and modulate miRNAs. Recent studies have proposed that oncogenic miRNAs can downregulate the expression of tumor suppressor kinases and phosphatases, which in turn contributes for tumor progression. The interplay between protein kinases, phos- phatases and miRNAs in cancer cells is very complex and depends of many features, such as cell type and tumor context, as well as the pattern of expression of tumor suppressor and oncogenic miRNAs. Therefore, it is clear that the complex crosstalk between protein kinases, phosphatases and miRNAs can contribute to increase cancer aggressiveness, giving tumor cells the ability to survive, increase proliferation, evade cell death routines and metastasize. This review will highlight what is already known about the inter- play between miRNAs, protein kinases and phosphatases and its importance in cancer. Besides, we also highlight the potential of those molecules as targets for more efficient cancer therapy. 1.1. Post translational modification: role of protein kinases and phosphatases About 2% of the human genome correspond to protein kinases, encoding 518 protein kinases, which constitute one of the largest gene families in eukaryotes [3,8,9]. Protein kinases (PKs) catalyze the phosphorylation on serine, threonine or tyrosine residues. * Corresponding author. Tel.: þ55 1935216659. E-mail addresses: verissimac@gmail.com, carmenv@unicamp.br (C.V. Ferreira- Halder). Contents lists available at ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi http://dx.doi.org/10.1016/j.biochi.2014.09.011 0300-9084/© 2014 Elsevier B.V. and Soci et e française de biochimie et biologie Mol eculaire (SFBBM). All rights reserved. Biochimie 107 (2014) 167e187