%0 Journal Article
%T Alternative Splicing in Oncogenic Kinases: From Physiological Functions to Cancer
%A Sabine Druillennec
%A Coralie Dorard
%A Alain Eych¨¨ne
%J Journal of Nucleic Acids
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/639062
%X Among the 518 protein kinases encoded by the human kinome, several of them act as oncoproteins in human cancers. Like other eukaryotic genes, oncogenes encoding protein kinases are frequently subjected to alternative splicing in coding as well as noncoding sequences. In the present paper, we will illustrate how alternative splicing can significantly impact on the physiological functions of oncogenic protein kinases, as demonstrated by mouse genetic model studies. This includes examples of membrane-bound tyrosine kinases receptors (FGFR2, Ret, TrkB, ErbB4, and VEGFR) as well as cytosolic protein kinases (B-Raf). We will further discuss how regular alternative splicing events of these kinases are in some instances implicated in oncogenic processes during tumor progression (FGFR, TrkB, ErbB2, Abl, and AuroraA). Finally, we will present typical examples of aberrant splicing responsible for the deregulation of oncogenic kinases activity in cancers (AuroraB, Jak2, Kit, Met, and Ron). 1. Introduction The process of alternative splicing increases the complexity of the proteome encoded by higher eukaryotic genomes through the synthesis of different products from a single gene. Genes encoding for protein kinases do not escape this rule. While the whole human genome sequencing revealed 518 protein kinases encoding genes [1], a recent bioinformatics survey identified a larger repertoire of about 918 putative protein kinases represented mainly by splice variants from these 518 human genes [2]. This retrospectively gives credit to Tony Hunter¡¯s previous witty estimate of ¡°A thousand and one protein kinases¡± [3]. Protein kinases are among the largest families of genes in eukaryotes, representing approximately 1.7% of all human genes [1]. They are implicated in most of the essential cellular functions, and their deregulation often leads to pathological disorders, including cancer. Alteration of the expression and/or the activity of a number of protein kinases by point mutations, chromosomal translocations, or epigenetic mechanisms can directly initiate or contribute to the development of tumors. The first example came from the seminal discovery of the existence of cellular oncogenes, when the tyrosine kinase c-Src was identified thanks to its retroviral counterpart in the Rous Sarcoma Virus [4]. Since then, numerous oncogenic protein kinases have been discovered, among which EGFR, Abl, Kit, and B-Raf represent typical examples of success in the development of targeted drug therapy [5¨C7]. While in most cases constitutive activation of the protein catalytic activity is
%U http://www.hindawi.com/journals/jna/2012/639062/