Structural Biochemistry/Kinase/MPS1

MPS1

MPS1 kinases play many roles in mitosis. This kinases' most highly conserved and important role is to make sure the orientation of sister chromatids of spindles at kinetochores are correct. The kinetichores are structures that hold spindle microtubules and acts as a platform for signaling for the spindle checkpoint. In humans it is also involved in activating and maintaining spindle checkpoints.

Role in Spindle Pole Body

MPS1 kinase phosphorylates multiple spindle pole body (SPB) components. In fungi, Spc29 and Spc42 are phosphorylated, giving then stability. Centrin (Cdc31), Spc98 a γ-tubulin complex component, and Spc110 are some of the more conserved parts of SPB. Phosphorylation of Spc98 has possible effects on its contact with Spc110. Phosphorylation of some of these parts is necessary for them to interact with each other. If Mps1 is over expressed in mammals, centrosomes can be over duplicated, and overexpressed kinase-inactive allele will block centrosome duplication. However, some research with RNA interference has shown results that contradict the statement that Mps1 is needed for centrosome duplication. For example, Mps1 was removed from human cells with cre-lox, but these cells were still able to duplicate their centrosomes. Other species lack MPS1 orthologs but they can still perform centrosome duplication. Even with those contradictions, MPS1 still plays a role in centrosome duplication in humans. This is proven by the fact that substrates like centrin 2 are phosphorylated by MPS1 and is required for centriole, the core of a centrosome) stimulation.

Kinetochores and Spindle Assembly Checkpoint

MPS1 is localized in kinetochores. The spindle check point is used to ensure bipolar attachment and tension of all the chromosomes are correct in the mitotic spindle. The cell pauses at its metaphase until every chromosome is attached correctly. When they are all checked to be good, the anaphase can start.

Localization of kinetochores in checkpoint proteins is needed for their function. Research not really shown kinetochore localization of checkpoint proteins being dependent on MPS1. However, some of these studies have shown that these checkpoint proteins can be loss from the kinetochore if MPS1 is inactivated. Also if MPS1 is over expressed, cell arrest can occur. It is concluded from these results that MPS1 has a large influence in the checkpoint signaling pathway. Another view if MPS1 is absent, several checkpoint activities are interrupted and devastating effects can occur, such as failure of spindle function. But it is difficult to tell if this is true, because MPS1 has many substrates.

MPS1 can carry out its role in the checkpoint without being in the kinetochore. Similarly, truncated alleles of hMPS1 in human cells that are not localized at kinetochores can still activate the mitotic checkpoint complex. MPS1 also helps in the forming of an interphase APC inhibitor that has some of the same components as the mitotic checkpoint complex. The importance of MPS1 in normal mitosis progression can be seen from the fact that cells lacking MPS1 have a faster mitosis.

MPS1 and Cytokinesis

RNA interference studies have shown that if there is no MPS1 multinucleated cells can occur. This also showed that MPS1 plays a role in helping the cell exit mitosis. MPS1 binds to Mob1, activating Dbf2 protein kinase. This complex plays a role in the mitotic exit pathway. MPS1 is then deactivated once the cell exits mitosis. MPS1 and cytokinesis can also be linked by the hMPS1-binding partner/substrate, which is part of the actin cytoskeleton. However it is not clear how hMPS1 affects MPS1's function.

MPS1 and Meiosis

If MPS1 function is disrupted in meiotic cells, then chromosomes can be divided unevenly. This could come from the mutated MPS1 inability to maintain the spindle checkpoint and failure to attach chromosomes to the meiotic spindle correctly. This suggests similar MPS1 function in meiosis and mitosis.

References

The MPS1 Family of Protein Kinases - Xuedong Liu and Mark Winey