RACK1 (Receptor for Activated C Kinases) is a scaffolding protein with 7 WD repeats that interacts with the Insulin-like Growth Factor I receptor (IGF-IR), integrins, and other signalling proteins. RACK1 functions as a scaffolding protein and regulator of many key biological processes and it is highly expressed in most tissue. We recently reported that RACK1 is essential for IGF-I-mediated regulation of PP2A activity and AGAP2 activity at focal adhesions. Downstream of IGF-1R signaling in cancer cells, the scaffolding properties of RACK1 are altered providing distinct migratory advantages to the cell and suggesting that RACK1 is an important regulator of IGF-I signalling in cancer progression. It is important to further characterise the role of RACK1 in cancer and to delineate the molecular mechanisms by which it regulates key signalling pathways. We have identified Protein Kinase A (PKA) as RACK1 interacting protein. PKA is a complex, multicomponent enzyme which is a fundamental protein that functions in cell survival, proliferation, and cytoskeletal remodelling among others. Our hypothesis is that RACK1 regulates the PKA axis in cancer cells leading to Akt and MAP Kinase activation downstream of IGF-1R signalling. We have demonstrated that RACK1 is required to mediate PKA activity in colon cancer cells. Although we show that PKA expression is not altered in colon cancer tissue, we believe that PKA activity is altered significantly in the disease state. Using PKA inhibitors, we have shown that PKA regulates IGF-I-mediated MAP Kinase activation in colon cancer cell lines. In conclusion, this research project will help elucidate the role of PKA in colon cancer. Inhibiting or promoting specific protein interactions with RACK1 will provide very novel therapeutic opportunities and anti-cancer drug targets.

Citation Format: Sheri L. Hayes, Catríona M. Dowling, John C. Coffey, Patrick A. Kiely. RACK1 regulates PKA activity to drive tumorigenesis in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2382. doi:10.1158/1538-7445.AM2017-2382