Regulation of the Ras-MAPK and PI3K-mTOR Signalling Pathways by Alternative Splicing in Cancer

Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events. 1. Introduction In the past several decades cancer research has focused on genetic alterations such as mutations, copy number variations, and translocations that are detected in malignant tissues and contribute to the initiation and progression of cancer. In recent years it is becoming clear that epigenetic changes, including transcriptional and posttranscriptional alterations, also play a major role in cancer development and thus should be the direction of future research [1–4]. Mutations and copy number variations in splicing regulators have been identified in several types of cancer, supporting the notion that changes in splicing fidelity contribute to cancer development [5–9]. Alternative splicing plays a major role in cancer development and progression as many tumor suppressors and oncogenes are modulated by alternative splicing [10, 11]. However, the role of alternative splicing regulators in cancer development is mostly unknown, and only recently the first direct evidence for an oncogenic role of a splicing factor has been shown [9, 12–15]. The Ras-MAPK and PI3K-mTOR signalling pathways are deregulated in many cancers by genetic and epigenetic aberrations [16–18]. Several key components in these pathways, such as Ras, B-RAF, C-RAF, MEK1, PI3K, and Akt, are activated by mutations or gene amplifications, while other components that inhibit these pathways, such as PTEN, LKB1, and TSC1/2, are inactivated by genomic deletions and mutations [16–20]. Pharmacological inhibitors of enzymes in these pathways, such as BRAF inhibitors and mTOR inhibitors, are already being used in clinical settings to treat cancer, while