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

Figure 2

Alternative splicing regulation of the PI3K-mTOR pathway. Growth factors and cytokines activate receptor tyrosine kinases (RTKs) which in turn lead to activation of PI3K. PI3K phosphorylates phospholipids inducing the recruitment of Akt to the plasma membrane and its activation by PDK1. A splicing variant of the catalytic subunit of PI3K (p37 delta) is an active form that enhances PI3K activity. Akt phosphorylates and inactivates the tumor suppressor TSC2, which inhibits the small GTPase Rheb. GTP-bound Rheb can activate mTOR. mTORβ is an active splicing isoform of mTOR. mTOR phosphorylates S6K1 and 4E-PB1. 4E-BP1 phosphorylation induces its release from eIF4E, enhancing cap-dependent translation and malignant transformation. Oncogenic splicing factor SRSF1 can affect the alternative splicing of S6K1 inducing oncogenic short isoforms of this kinase (h6A, h6C) which bind mTOR and enhance 4E-BP1 phosphorylation and cap-dependent translation. Blue: tumor suppressors, red: oncogenes.