Grant: Travel Awards - Institute Community Support

Alternative splicing is a process by which the human cell uses distinct gene blocks to generate several proteins from a single primary sequence. Consequently, the cell can produce a vast array of proteins from a more efficient genome size. As similar protein isoforms often have different or even opposite functions, the flexibility granted by this process is also crucial in fast adaptation to stress and external cues. It is thought that more than 95% of all expressed genes are subjected to splicing. Misregulation of alternative splicing therefore often leads to diseases, namely up to 50% of all known genetic diseases but also cancer. Indeed, malignant cells often take advantage of the flexibility yielded by alternative splicing to proliferate, invade surrouding tissues and escape death. Although the field of splicing research is expanding quickly, how this process is regulated by the cell is still poorly understood. ERK1/2 is central protein kinase involved in the control of cell growth and division. It is activated downstream of one of the most often mutated oncogene in cancer, leading to anarchic cel growth and tumor invasion. Many functions of ERK1/2 have been thoroughly studied, but several novel partners continue to arise indicating an even larger role. Interestingly, our lab has identified several potential regulators of alternative splicing as direct targets of ERK1/2. In the present study, we describe the mechanism by which ERK1/2 phosphorylates one of these, the CDK12 protein kinase. This research subscribes in a cancer-related perspective, as we also evaluate how overactivation of ERK1/2 driven by upstream oncogene mutation affect alternative splicing in favor of tumor progression. Elucidating the molecular mechanisms of this process can also shed light on new pharmacological targets and deliver a unique take from a signaling standpoint.