SAM68: Signal Transduction and RNA Metabolism in Human Cancer

Figure 3

Model of SAM68 interaction with pre-mRNAs and splicing regulation. (a) SAM68 recognition of A/U-rich bipartite sequence in the pre-mRNA homodimerization allows simultaneous binding to the pre-mRNA and to U2AF65 [69–73]. Tyrosine phosphorylation of SAM68 reduces the RNA binding affinity and thus releases SAM68 from the pre-mRNA. (b) Model of alternative splicing events regulated by SAM68 in cancer cells. (A) SAM68 promotes inclusion of CD44 variable exon v5. Inclusion of variable exons in the CD44 pre-mRNA is specific to cancer cells and correlates with cancer progression and invasiveness [71]. (B) SAM68 promotes splicing events that regulate cell proliferation. Binding of SAM68 to CCND1 intron 4 interferes with the correct recruitment of U1 snRNP at the exon 4 5′ splice sites, thus enhancing retention of intron 4 and generating the Cyclin D1b isoform. In prostate cancer, the expression of Cyclin D1b interrupts a negative feedback in the regulation of androgen receptor (AR) transcriptional activity, thereby promoting cell proliferation [74]. (C) As for CCND1, SAM68 promotes retention of SRSF1 intron 4, thus stabilizing SRSF1 pre-mRNA and inhibiting its degradation by nonsense-mediated decay (NMD) [75]. Accumulation of SRSF1 in turn favors the splicing of ΔRON, an oncogenic variant of RON that triggers epithelial-mesenchymal transition (EMT). (D) SAM68 regulates the alternative splicing of BCL2L1 leading to the short (BCL-X(s)) proapoptotic isoform [19]. This activity can be reverted by tyrosine phosphorylation of SAM68 from SRC family kinases, thereby switching the role of SAM68 from being proapoptotic to being antiapoptotic and allowing cells to differentially react to external cues. (E) SAM68 regulates mTOR alternative splicing thus leading to the correct mRNA isoform and avoiding retention of intron 5 that generates a premature termination codon and the consequent reduction of mTOR protein levels [35]. Notably, mTOR is a critical effector in cell-signalling pathways commonly deregulated in human cancers and overexpression of the components involved in the PI3K/AKT/mTOR pathway has been shown to induce malignant transformation.

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