Abstract 162: Identification of novel targets of Serine/arginine-rich protein-specific kinase 2

Abstract Altered metabolism is one of the hallmarks of cancer cells, supporting aberrant proliferation and survival in nutrient scarce and stressful environments. The reprogrammed metabolism supports the acquisition of malignant traits, increasing cellular fitness and providing a selective advantage in tumorigenesis. Multiple signaling cascades converge to regulate cancer cell metabolism to maintain a delicate balance between anabolic and catabolic processes, with the overall goal to fuel ATP production, biosynthesis of macromolecules and maintaining redox balance. Specifically, 70% of human cancers have hyperactivated mechanistic target of rapamycin (mTOR) signaling, the master regulator of cellular metabolism. As an important signaling node, mTOR complex 1(mTORC1) integrates upstream stimuli such as growth factors, amino acids and oxygen levels to regulate a myriad of anabolic processes including protein and nucleotide synthesis, RNA biogenesis and lipid metabolism, thereby promoting cell growth. The highly proliferative state of cancer cells, coupled with a change in energy demands, forces these cells to rewire their cellular metabolism to increase production of cellular building blocks like proteins, lipids and nucleotides. De novo lipogenesis provides lipids which act as an integral component of the plasma membrane as well as functioning as signaling molecules. In addition to promoting various anabolic processes, our lab has demonstrated that mTORC1-activated serine/arginine-rich protein-specific kinase 2 (SRPK2) phosphorylates splicing factors that stabilize lipogenic transcripts, protecting them from nonsense-mediated decay and thereby increasing de novo lipogenesis. This is in contrast to another serine/arginine-rich protein-specific kinase 1 (SRPK1), which is not regulated by mTORC1. Inhibition of the mTORC1-SRPK2 signaling axis blunts de novo lipogenesis and impedes tumor growth in several tumor xenograft models. SRPK2 overexpression is also observed in lung and colon cancers, suggesting SRPK2 may promote the growth of some human tumors. Despite the emerging role for SRPK2 in tumor growth, very few substrates of this kinase are known. We conducted a phospho-proteomics screen to identify novel substrates of SRPK1 and SRPK2. While some of the targets we identified are regulated in an mTORC1-dependent manner, many appear to be regulated independent of mTORC1, such as PTP1B, EGLN1 and EI24. We hypothesize that these mTORC1-independent targets could be SRPK1-dependent revealing potential distinct branches of SRPK signaling. Future studies will focus on not only validating a subset of these novel targets and their role in tumor growth, but also on exploring mTORC1-dependent and independent SRPK signaling. Citation Format: Kripa Shobana Ganesh, Bethany Schaffer, Gina Lee, Jared Johnson, Tomer M. Yaron, Noah Dephoure, Lewis C. Cantley, John Blenis. Identification of novel targets of Serine/arginine-rich protein-specific kinase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 162.