MPS1

Monopolar spindle 1 (Mps1) is a conserved serine/threonine protein kinase that plays a central role in the spindle assembly checkpoint (SAC) during mitosis. In humans, the Mps1 protein is encoded by the TTK gene and functions as a key regulator of chromosome segregation fidelity by delaying anaphase until all chromosomes are properly attached to the mitotic spindle.

Mps1 localizes to kinetochores and centrosomes as cells enter mitosis, where its activity increases. It phosphorylates multiple SAC components, including Bub1, Mad1, and Mad2, and promotes their recruitment to unattached kinetochores. Through these activities, Mps1 helps generate and sustain the mitotic checkpoint signal, ensuring that sister chromatids do not separate until proper attachments and tension are established. Beyond the SAC, Mps1 also participates in centrosome function and, in some contexts, may influence centriole duplication and microtubule-kinetochore attachment quality control.

Regulation of Mps1 is achieved in part by autophosphorylation and by interactions with other checkpoint proteins and kinases. Inhibition or loss of Mps1 disrupts SAC signaling, often leading to premature mitotic progression and an increased risk of chromosome mis-segregation and aneuploidy. Pharmacological inhibition of Mps1 has been explored as a therapeutic approach in cancer, aiming to exploit mitotic vulnerabilities in tumor cells.

Several Mps1 inhibitors have been described, including NMS-P715, Mps1-IN-1, Mps1-IN-2, and AZ3146. These compounds are used in research to study SAC function and to model potential anticancer strategies that induce mitotic errors in cancer cells.