Signaling Pathways Driving Aberrant Splicing in Cancer Cells

Abstract

Aberrant profiles of pre-mRNA splicing are frequently observed in cancer. At the molecular level, an altered profile results from a complex interplay between chromatin modifications, the transcriptional elongation rate of RNA polymerase, and effective binding of the spliceosome to the generated transcripts. Key players in this interplay are regulatory splicing factors (SFs) that bind to gene-specific splice-regulatory sequence elements. Although mutations in genes of some SFs were described, a major driver of aberrant splicing profiles is oncogenic signal transduction pathways. Signaling can affect either the transcriptional expression levels of SFs or the post-translational modification of SF proteins, and both modulate the ratio of nuclear versus cytoplasmic SFs in a given cell. Here, we will review currently known mechanisms by which cancer cell signaling, including the mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 (PI3)-kinase pathway (PI3K) and wingless (Wnt) pathways but also signals from the tumor microenvironment, modulate the activity or subcellular localization of the Ser/Arg rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) families of SFs.

Keywords: alternative splicing; cancer cell; genetic program; signaling pathway; tumor microenvironment; tumorigenesis.

Figure 1

Schematic representation of the important connections between cancer cell signaling and the regulation of alternative splicing that the manuscript summarizes. Shown are the key components of the receptor tyrosine kinase (RTK), activated rat sarcoma viral oncogene homolog (RAS), rapidly accelerated fibrosarcoma (RAF)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)/ v-akt murine thymoma viral oncogene homolog (AKT) pathways as well as the wingless (Wnt) pathway. Their activation can occur by the several oncogenic mechanisms described in the manuscript and lead to the modulation of splicing factor (SF) activity, localization or expression levels, as exemplified. These modifications have consequences for the choice of alternative exons during pre-mRNA splicing in the nucleus and cause the expression of variant proteins with distinct functional properties. These variants provide selective advantage for tumor cell progression and some of the examples described in the manuscript are mentioned.