A hallmark of tumor cells is an inability to control their proliferation, which implies that these cells are capable of bypassing cell cycle checkpoints and regulation by tumor suppressor signaling pathways.听 Aberrant chromosome segregation generates aneuploid cells and genome instability, which has been postulated to be a major mechanism for tumorigenesis.听 Aneuploidy is primarily caused by errors during mitosis.听 In normal cells, correct segregation of chromosomes is ensured by an evolutionarily conserved surveillance signal transduction pathway called the mitotic spindle checkpoint听听 TTK/Mps1, a dual specificity protein kinase, has emerged as a master regulator of mitosis and an upstream component of spindle checkpoint signaling pathway (Liu and Winey 2012).听 Our previous work led to identification of Smad proteins as substrates for Mps1 in mitosis (Zhu et al. 2007).听 Recently we solved the crystal structure of the Mps1 kinase domain in collaboration with Ming Lei's group (Wang et al. 2008).听 We demonstrated that autophosphorylation of Mps1 is a priming mechanism for Mps1 activation and critical for kinetochore targeting (Wang et al. 2008, Xu et al. 2009; Sun et al. 2010; Zhang et al. 2011).听 Currently we are interested in understanding how Mps1 kinase is turned on and off in a cell cycle dependent manner and how its activity is perturbed in tumor cells to weaken the spindle checkpoint.听听听