STK3 (MST2) review notes
Automated deep research was unavailable for this review (no deep-research provider
keys), so no *-deep-research-*.md file exists. These notes are compiled by hand from
the cached publications in publications/, the UniProt record (Q13188) and the
cached GO-CAM index. Quotes are verbatim from the cached files.
Identity
- Human STK3 / MST2, UniProt Q13188, 491 aa. STE20 group, GCKII subfamily
(MST1/STK4 and MST2/STK3), ortholog of Drosophila Hippo.
- Domains (UniProt): protein kinase 27-278, SARAH 437-484, coiled coils 287-328
and 442-475, caspase-3 site Asp-322.
- InterPro includes IPR036674 "p53_tetramer_sf" (fold-level structural
superfamily that the SARAH helix matches), plus SARAH-specific IPR011524,
IPR024205, IPR049568.
- Paralog STK4 (MST1): 78% identity PMID:8566796.
Many papers (and many GOA rows) treat "MST1/2" jointly; attribution to MST2 must be
checked per paper.
Catalytic activity (core)
Regulation / complexes
- SARAH heterodimers with SAV1: PMID:29063833
Note: this is a genuine 2:2 tetramer containing MST2, but the dimer-of-dimers
contact is made by SAV1 WW domains, not by the MST2 SARAH helix.
- SARAH homo/heterodimer crystal structures: PMID:25004971; MST1 SARAH homodimer and conversion of tetrameric RASSF5 SARAH to dimers PMID:17517604.
- STRIPAK/SLMAP-PP2A inactivates MST2: PMID:29063833; PMID:30622739.
- RASSF1A protects MST2 phosphorylation and stabilizes it PMID:21199877
- RASSF2 stabilizes MST2 and relocalizes PMID:19525978.
- Raf-1/AKT crosstalk PMID:20086174.
- DLG5 links MARK3 to MST1/2 and inhibits them PMID:28087714.
- WWC proteins organize SAV1-MST1/2 activation of LATS1/2 PMID:35429439.
Localization
- Full-length MST is cytoplasmic; caspase-cleaved kinase enters the nucleus in apoptosis
PMID:11278283.
- Centrosome: Mst1/2 and hSav1 are centrosomal and recruit Nek2A PMID:21076410.
Processes
- Hippo signaling: core initiating kinase, MST1/2-SAV1 -> LATS1/2-MOB1 -> YAP/TAZ.
GO:0035329 definition names STK4/MST1 and STK3/MST2 explicitly.
- Contact inhibition via YAP: PMID:17974916
- Apoptosis: caspase substrate, proapoptotic upon overexpression PMID:11278283.
- PPARgamma/adipogenesis with SAV1 PMID:22292086; mechanism of PPARγ activation unresolved PMID:22292086.
- Wnt crosstalk is via TAZ-DVL PMID:20412773 (abstract only; indirect for STK3).
- FOXO / oxidative stress pathway described for MST1 PMID:16751106 (abstract only; MST2 not mentioned in abstract).
- Autophagy: STK3 binds ATG8 family proteins via an LIR PMID:31857374.
GO-CAM
gocams/index.tsv contains STK3 (UniProtKB:Q13188) in 8 human models:
- 7 Hippo models (e.g. 65a1f4f800003391 "Hippo signaling core components (Human).",
65c57c3400001478 "Negative regulation of Hippo signaling by SLMAP-STRIPAK complex")
all as GO:0004674 protein serine/threonine kinase activity, part of GO:0035329
hippo signaling, occurs in GO:0005737 cytoplasm.
- 65039e8700001110 "TRIM69 activation of STK3 by ubiquitination leading to centrosome
separation" as GO:0004674, part of GO:0071539 protein localization to centrosome,
in GO:0005813 centrosome (NEK2 carries centrosome separation in that model).
This matches the core functions chosen here.
Premetazoan context (ancestral vs animal-specific)
- Hippo kinase is the most ancient core Hippo component PMID:38729842.
The SARAH domain is lost in most fungal Hippo-like kinases PMID:38729842.
- Capsaspora coHpo (repo review genes/CAPO3/coHpo): kinase domain + SARAH. Knockout makes
coYki nuclear PMID:38517944,
does not change proliferation PMID:38517944,
and increases a contractile/elongated cell state. In Drosophila cells coHpo
phosphorylates Wts and Yki PMID:22832104.
- S. rosetta hippo (repo review genes/SALRS/hippo): knockout slows proliferation but
rosette size is unchanged [DOI:10.1101/2024.07.13.603360 "The size of hippopac1 and yorkiepac1 rosettes did not significantly differ from wild type"].
- Synthesis (Phillips, Zheng & Pan review): ancestral function is cytoskeletal; proliferation/
tissue-size control is a later co-option PMID:38729842
- Conclusion for STK3:
- Ancestral (pre-Holozoa for the kinase+SARAH architecture; Holozoa for the
Hpo-Wts-Yki cascade): Ser/Thr kinase activity, SARAH-mediated dimerization,
activation of the Warts/LATS kinase and cytoplasmic restraint of
Yorkie/YAP (hippo signaling sensu GO:0035329).
- Animal-specific recruitments: contact inhibition of proliferation, organ/tissue growth
control, apoptosis (caspase-cleavage-dependent), crosstalk with Wnt/TGF-beta/PPARγ,
adipogenesis, ER-alpha regulation; centrosome disjunction role unknown outside animals.
Tetramerization row (InterPro2GO IPR036674)
Human STK3 carries the same IEA GO:0051262 protein tetramerization from IPR036674
(p53 tetramerisation superfamily) as coHpo. The structural evidence is that the MST2
SARAH domain forms homodimers and 1:1 heterodimers (PMID:23972470, PMID:25004971,
PMID:17517604). Unlike coHpo, human MST2 has one documented tetrameric assembly, the
2:2 SAV1-MST2 complex (PMID:29063833), but the dimer-of-dimers interface there is made by
SAV1 WW domains, not by STK3. So the InterPro2GO basis (a p53-like tetramerisation fold)
is still wrong; I marked it MARK_AS_OVER_ANNOTATED rather than REMOVE because a
STK3-containing tetramer does exist in human cells.
Protein binding rows
93 IPI protein binding rows. Policy: MODIFY where the cited paper supports a more
informative MF (SARAH heterodimerization with SAV1 / RASSF5 shown in focused studies;
self-interaction -> protein homodimerization activity), otherwise REMOVE as uninformative
(the interactions themselves are not disputed). No GO term for "Atg8-family protein
binding" was found in QuickGO, so the ATG8-family rows are removed rather than modified.