Structural Biochemistry/The MPS1 Family of Protein Kinases

Introduction
MPS1 protein kinases are found in eukaryotes and contribute to the regulation of several steps of mitosis in addition to cyclin dependent kinases (CDKs). One of the widely conserved functions of MPS1 involves interactions at the kinetochore in both the chromosome attachment and spindle checkpoint. Spindle checkpoint is the mechanism that ensures proper chromosome attachment to microtubules prior to chromosome separation. MPS1 also influence centrosome assembly, which is the cellular structure that contains centrioles, nucleates, and organizes mitotic spindles. Other critical functions include development, cytokinesis, and signaling pathways. The C-terminal kinase domain identifies members of MPS1 protein kinase family even though the N-terminal domain is different. Crystallized structures of the kinase domain reveal that activity, level, and subcellular localization of MPS1 family are tightly regulated during cell-cycle progression. Mitotic functions of MPS1 kinases have become the interest for the development of inhabitors for anticancer drugs.

Discovery
The first monopolar spindle of MPS1 gene was first discovered in yeast called Saccharomyces cerevisiase. Msp1-1 was the original mutant allele that was identified as consequence of a defect in yeast spindle pole body (SPB) duplication, a cell cycle critical to form a bipolar spindle. At a restrictive temperature, all MPS1 alleles caused defects in SPB duplication and in spindle assembly checkpoint, but interestingly, electron microscope examination reveals the importance of MPS1 for SPB assembly.

MPS1 Kinase Structures
MPS1 kinase members are ~85-95 kDa and have conserved C-terminal kinase domains while the N-terminal domain is often quite divergent.

MPS1 Functions
The most widely conserved and critical function of MPS1 is to properly position the sister chromatids on the mitotic spindle at kinetochores prior to segregation. MPS1 is also involved in spindle pole duplication and also cytokinesis. MSP1 is also considered a dual-specificity protein kinase because of its ability to autophosphorylate serine, threonine and tyrosine residues. Other functions may include a role in chromosome segregation in mitotic cells.
 * MPS1 in Spindle Pole Duplication
 * The original mutation, MPS1-1, causes cells to fail in SPB duplication at the restrictive temperature which resulted in a monopolar spindle in mitotic cells. When these cells replicate it grows a bud that suggests that MSP1 regulates SPB duplication. MPS1-1 cells do show cell cycle arrest, but continue to carry out mitosis. This occurrence reveals the additional role of kinase in spindle assembly checkpoint.

MPS1 Regulation
The diverse roles of members of MPS1 kinase family suggest extensive regulation of the kinase. It is regulated at a number of levels:
 * Transcription: MPS1 is extensively regulated at the transcription level by E2F family of transcription factors. E2F1 binds to the MPS1 promoter region of Mps1 mRNA.HPS1 mRNA levels are low at G1/S phase and increase throughout the S phase. Then the mRNA levels peak at G2/M phase and drop upon cells entering G1 phase
 * Localization: MPS1 kinases are localized at kinetochores and centrosomes.
 * Inactivation: Kinase genes are inactivated by APC-dependent degradation, which is required for cells to exit mitosis properly.

Misregulation in Tumor Cells
MPS1 transcription is deregulated in many human tumors. Increases mRNA levels are found in cancers such as breast cancer, gastric cancer tissue, lung cancer, bronchogenic carcinoma, and thyroid papillary carcinoma.
 * MPS1 missense mutations are found in noncatalytic N-terminus of bladder, lung cancers, and in kinase domain of pancreatic and lung cancers
 * Frameshift mutations are present in gastric and colorectal cancers