S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1

SummaryRibosomal S6 kinase 1 (S6K1) is a major mTOR downstream signaling molecule that regulates cell size and translation efficiency. Here, we report that short isoforms of S6K1 are overproduced in breast cancer cell lines and tumors. Overexpression of S6K1 short isoforms induces transformation of human breast epithelial cells. The long S6K1 variant (Iso-1) induced opposite effects. It inhibits Ras-induced transformation and tumor formation, while its knockdown or knockout induces transformation, suggesting that Iso-1 has a tumor-suppressor activity. Furthermore, we found that S6K1 short isoforms bind and activate mTORC1, elevating 4E-BP1 phosphorylation, cap-dependent translation, and Mcl-1 protein levels. Both a phosphorylation-defective 4E-BP1 mutant and the mTORC1 inhibitor rapamycin partially blocked the oncogenic effects of S6K1 short isoforms, suggesting that these are mediated by mTORC1 and 4E-BP1. Thus, alternative splicing of S6K1 acts as a molecular switch in breast cancer cells, elevating oncogenic isoforms that activate mTORC1.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► The long S6K1 isoform functions as a tumor suppressor
► S6K1 short isoforms are upregulated in breast cancer and possess oncogenic properties
► S6K1 short isoforms bind mTORC1 and enhance cap-dependent translation
► Inhibition of mTORC1 can reverse the oncogenic properties of the S6K1 short isoforms