Abstract
Discovered in 1991 in a screen for genes involved in spindle pole body duplication, the monopolar spindle 1 (Mps1) kinase has since claimed a central role in processes that ensure error-free chromosome segregation. As a result, Mps1 kinase activity has become an attractive candidate for pharmaceutical companies in the search for compounds that target essential cellular processes to eliminate, for example, tumour cells or pathogens. Research in recent decades has offered many insights into the molecular function of Mps1 and its regulation. In this review, we integrate the latest knowledge regarding the regulation of Mps1 activity and its spatio-temporal distribution, highlight gaps in our understanding of these processes and propose future research avenues to address them.
Highlights
When a cell divides, the two resulting daughter cells each inherit an exact copy of its genetic content in order to maintain healthy cell function
Central in the connection of the processes is monopolar spindle 1 (Mps1)/TTK, an evolutionary conserved kinase that is indispensable for error correction, and that is the chief conductor of the spindle assembly checkpoint (SAC) [28]
Though the SAC is essential in many but not all model organisms, Mps1’s involvement in a number of additional processes makes it essential for cell viability in many of them, including human cells [40,41,42]. It is expressed in the majority of proliferating tissues examined in humans, and its protein and kinase activity levels are cell cycle-dependent: they peak in early mitosis and decline rapidly as cells re-enter the G1 phase of the subsequent cell cycle [45,46]
Summary
A few years after the initial discovery of budding yeast Mps1 [29] and its identification as a kinase [30], two human cDNA library screens for proteins recognized by anti-phospho-tyrosine antibodies identified a kinase (named PYT ( phospho-tyrosine picked threonine kinase) and TTK, respectively) that had homology to yeast Mps1 [31,32]. In contrast to most fungi, vertebrate Mps proteins harbour an N-terminal tetratricopeptide repeat (TPR) domain (figure 1, box 2), involved in regulating its subcellular localization to kinetochores and centrosomes. This domain is ancient but was lost in many eukaryotic lineages, for unknown reasons [39]. Mps phosphorylates the Dam complex in yeast and the Ska complex in human cell lines These complexes are analogous [59], and they promote attachment of kinetochores to dynamic microtubule plusends [60,61,62,63]. For the remainder of this review, we will focus on the events leading to Mps localization and activation, and we refer to several papers for more detailed insights into the SAC events downstream of Mps activity [67,68,71,72,73]
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