MASTL (Greatwall kinase, Q96GX5) - curation notes

Identity

HGNC symbol MASTL; aliases GW, GWL, hGWL, THC2, FLJ14813. Atypical AGC-family Ser/Thr kinase
(879 aa) with a >500-residue insertion splitting the catalytic domain; AGC C-terminal domain
836-879; ATP-binding 41-49/Lys62; catalytic Asp156 [file:human/MASTL/MASTL-uniprot.txt].
Established as the functional human Greatwall orthologue by two 2010 RNAi studies
PMID:20538976
PMID:20818157.
Not to be confused with MAST1-4 (PDZ-domain MAST kinases), Drosophila MAST/Orbit, or yeast Rim15
(a divergent family member with nutrient-stress roles) - see deep research identity section.

Activated at mitotic entry by cyclin B-CDK1 (Thr741; UniProt "Phosphorylation at Thr-741 by CDK1 during M phase activates its kinase activity") and autophosphorylation (Ser875, Reactome R-HSA-2465910).
Substrates: ENSA Ser67 and ARPP19 Ser62. Phospho-endosulfines bind and inhibit PP2A-B55
PMID:21164014
PMID:21164013
PMID:38123684.
Cryo-EM of PP2A:B55-pARPP19 (2024) shows pSer62 occupying the catalytic site ("unfair competition"
substrate-inhibitor); ARPP19 "strictly requires phosphorylation by MASTL kinase to inhibit PP2A:B55" PMID:38123684.
Consequence in human cells: full depletion -> G2 arrest; partial depletion -> prometaphase delay,
premature CDK substrate dephosphorylation, SAC failure, cytokinesis defects; rescued by PP2A
co-depletion or okadaic acid
PMID:20538976
PMID:20538976
PMID:20818157
PMID:20818157.
Reactome models the two human reactions (R-HSA-2168079 ARPP19 S62; R-HSA-2430535 ENSA S67) and the
pathway R-HSA-2465910. The repository module modules/g2_m_transition.yaml carries the
Greatwall-endosulfine axis as an optional part; this review is consistent with it.

Interphase: nuclear PMID:20818157
PMID:19460416; HPA IF: nucleoplasm.
After NEBD: cytoplasm and centrosomes; mitotic exit: cleavage furrow
[file:human/MASTL/MASTL-uniprot.txt "During interphase is mainly nuclear, upon nuclear envelope breakdown localizes at the cytoplasm and during mitosis at the centrosomes. Upon mitotic exit moves to the cleavage furrow."].
Added a NEW cytoplasm (GO:0005737) annotation because the endosulfine phosphorylation that matters
for mitosis happens in the mitotic cytoplasm, and no existing CC term covers it.

DNA damage checkpoint recovery: Xenopus Gwl is inhibited by the DDR and promotes recovery
(source of the human ISS to GO:0006974); UniProt: "Following DNA damage, it is also involved in checkpoint recovery by being inhibited." Kept as non-core: it is the same G2/M-promoting activity applied after checkpoint release.
Thrombocytopenia (THC2): E167D segregates with autosomal dominant thrombocytopenia in one pedigree;
zebrafish morpholino knockdown reduces thrombocytes
PMID:19460416.
Mouse E166D knock-in (Hurtado et al. 2018, JCI; summarised in deep research) behaves as a
gain-of-PP2A-suppression allele affecting platelet actin dynamics. Not annotated in GOA; no NEW proposed.
Kinase-independent MRTF-A/SRF contractility signalling (Taskinen et al. 2020, JCB; deep research)
single-lab, cell-based; not proposed as an annotation.

ACCEPT: G2/M transition (IMP x2), Ser/Thr kinase activity (IBA/IDA/IEA/TAS x2), protein kinase
activity and protein serine kinase activity (IEA), ATP binding, nucleus (EXP/IBA/IDA x2/IEA),
nucleoplasm (IDA/TAS x2), centrosome (IDA/IEA), regulation of mitotic cell cycle (IBA/TAS),
microtubule cytoskeleton (IBA), cleavage furrow (IDA x2/IEA).
MODIFY: GO:0016301 kinase activity (IDA) -> GO:0004674; GO:0051726 regulation of cell cycle (IMP)
-> GO:0007346 regulation of mitotic cell cycle (all phenotypes are mitotic).
KEEP_AS_NON_CORE: GO:0006974 DNA damage response (ISS from Xenopus); GO:0035556 intracellular
signal transduction (deep AGC-node IBA; true but generic).
MARK_AS_OVER_ANNOTATED: GO:0051721 protein phosphatase 2A binding (ISS from Xenopus co-IP data that
predate the endosulfine mechanism; UniProt: MASTL "does not directly inhibit PP2A but acts by
mediating phosphorylation and subsequent activation of ARPP19 and ENSA").
REMOVE: GO:0044325 transmembrane transporter binding (IEA, Ensembl Compara from mouse Mastl IPI with
Slc12a6/KCC3; the mouse source paper PMID:27782176 is listed as retracted on PubMed; no human
evidence, no connection to known biology).
NEW: GO:0005737 cytoplasm (IDA, PMID:20818157 via UniProt subcellular location note).