View source for Kinase Subfamily MASTL

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[[kinase classification|Kinase Classification]]: [[Kinase_Group_AGC|Group AGC]]: [[Kinase_Family_MAST|Family MAST]]: [[Kinase_Subfamily_MASTL|Subfamily MASTL]]

MASTL is an animal/fungal kinase that activates mitosis by inhibition of an inhibitory phosphatase.

====Evolution====
MASTL is found in fungi and animals, but is lost in nematodes. Members include MASTL in humans and gwl in Drosophila. The fungal form, RIM15 has a different domain structure and is not a definitive ortholog by sequence analysis, but has analogous functions.

====Domain Structure====
Animal MASTL consists just of a kinase domain that has a long atypical insert. Other [[Kinase_Group_AGC|AGC]] and  [[Kinase_Family_MAST|MAST]] kinases have the AGC C-terminal tail domain. In MASTL this is truncated and degraded, and lacks the hydrophobic motif that is used by PDK1 to activate other [[Kinase_Group_AGC|AGC]] kinases, though it retains other motifs and is seen to wrap around the kinase domain <cite>Ocasio</cite>.

Fungal RIM15 homologs have divergent kinase domains and are longer, including an N-terminal PAS domain and a C-terminal histidine kinase receiver domain.

====Functions====
MASTL controls entry into mitosis by phosphorylation of enosulfine (ensa in Drosophila, ENSA and ARPP-19 in human, igo1/2 in yeast). Endosulfine in turn binds and inhibits the PPA2/B55 phosphatase complex, which is an antagonist of the CDK1 mitotic kinase. Hence, MASTL function is required to drive mitosis, by inhibiting an inhibitor of CDK1. This has been shown in human, mouse, Xenopus, Drosophila and yeast (for review, see <cite>Castro</cite>).

MASTL kinase activity fluctuates through the cell cycle. CDK1 phosphorylates MASTL in a conserved region within the kinase insert (T194 and T207 in human), which allows autophosphorylation on the tail (S875 in human, equivalent to the turn motif in other AGC kinases) <cite>Blake-Hodek</cite>. These sites are widely conserved in animals but not in fungi. Turn motif mutants were functional in mouse MEFs suggesting that this phosphorylation is not essential (Erguvin et al, 2021 [https://www.biorxiv.org/content/10.1101/2020.06.30.179580v3.abstract bioarchiv]).

In turn, both MASTL and endosulfine are substrates of PP2A/B55 as well as FCP1 phosphatase <cite>Monica, Hegarat</cite>

PP2A and endosulfine are found in most eukaryotes <cite>Labandera, Chen</cite>, but MASTL is restricted to animals and fungi. The MASTL phosphorylation site is conserved in all endosulfine, suggesting that other kinases may activate it in these other species. However, MASTL has been lost from C. elegans and mutation of the phosphorylation site in the endosulfine, ensa-1, does not appreciably alter cell division, suggesting that no other kinase controls this site in nematodes <cite>Kim</cite>.

In yeast, RIM15 phosphorylation of endosuflines igo1/2 appears to activate rather than repress PP2A, which in yeast is a promoter rather than inhibitor of mitosis <cite>Juanes</cite>. RIM15 is best known for transducing multiple nutrient sensors to drive either quiescence (G0) or meiosis, during nutrient limitation. In growth conditions, TORC1 is activated, which activates PKA, which phosphorylates RIM15. This causes it to bind 14-3-3 proteins and be sequestered in the cytoplasm. Nutrient stress inactivates TORC1 and PKA, leading to nuclear entry for RIM15, where is modulates G1 arrest or meiosis <cite>Sarkar</cite>. Some RIM15 is seen in the nucleus, where it may be inhibited by phosphorylation on the PAS domain by CDK8 kinase <cite>Willis</cite>.

MASTL is associated with human cancers due to its role in regulating mitosis. MASTL protein is overexpression in a variety of colorectal tumors and cell lines <cite>Vera</cite>. Overexpression in immortalized MCF10A mammary gland cells, NIH 3T3 cells, or TERT-immortalized human primary fibroblasts drove transformation, while a kinase-dead form caused cell death <cite></cite>.

AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation. Our results suggest that AKT increases CDK1-mediated phosphorylation and hence the activity of MASTL, which, in turn, promotes mitotic progression through PP2A inhibition. We also show that the oncogenic potential of AKT is augmented by MASTL activation, since AKT-mediated proliferation in colorectal cell lines can be attenuated by inhibiting and/or silencing MASTL. = Reshi, 32123010

Overexpression of human MASTL also drove phosphorylation and activation of Akt <cite>Vera</cite>, via an indirect mechanism - MASTL promoted dephosphorylation and activation of GSK3, causing degradation of the PHLPP phosphatase, which reduced dephosphorylation of Akt on S473. This effect appeared to be independent of endosulfines, the only known MASTL substrates.

====References====
<biblio>
#Ocasio pmid=27563826
#Castro pmid=30355803
#Blake-Hodek pmid=22354989
#Monica pmid=26653855
#Hegarat pmid=24391510
#Kim pmid=22649080
#Vera pmid=26613407
#Sarkar pmid=24968058
#Juanes pmid=23861665
#Willis pmid=35433688
#Labandera pmid=25666948
#Chen pmid=28400531
</biblio>