GRK5 regulates mitotic progression and promotes resistance against anti-mitotic agents in a CDK1 and AKT1 dependent manner

G protein receptor kinase 5 (GRK5) is a serine/threonine protein kinase that belongs to the family of G protein receptor kinases (GRKs), which are important regulators of G protein-coupled receptor (GPCR) functions. GRK5 regulates signaling by binding to various receptors on the plasma membrane or by regulating transcription within the nucleus. It also has been found to critically regulate several physiological processes including vascular remodelling, invasion, metastasis and migration of the cells. Although its role in cancer progression and metastasis is known, its role in cell division, and particularly in mitosis has not been investigated much. Here, we report that GRK5 is an important mitotic protein and is regulated by well-known cellular proteins that have a critical role in cell cycle regulation, especially mitosis. In particular, we show that GRK5 is regulated by two key players of mitosis, AKT1 and CDK1, which regulate GRK5 by interacting with it. We also provide evidence that GRK5 protein levels fluctuate throughout the cell cycle and reach their maximum during mitosis. Further, we report that overexpression of GRK5 promotes resistance against cell death that is induced by polyomavirus small T (PolST) antigen and different chemotherapeutic drugs including paclitaxel. Additionally, we found that GRK5 levels are upregulated in colorectal cancers supporting a potential role in tumor progression. Our findings thus add GRK5 to the growing list of mitotic kinases, which play a role in the regulation of cell cycle and promotion of drug resistance in cancer.