{"gene":"LATS1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"LATS1 directly binds to and phosphorylates YAP (Yes-associated protein) in vitro and in vivo, and inactivates YAP oncogenic function by sequestering YAP in the cytoplasm after phosphorylation. The consensus phosphorylation sequence for LATS/Ndr kinase substrates was identified as HX(R/H/K)XX(S/T).","method":"In vitro kinase assay, co-immunoprecipitation, subcellular fractionation, microarray analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus in vivo phosphorylation, consensus motif defined, cytoplasmic sequestration demonstrated with multiple orthogonal methods","pmids":["18158288"],"is_preprint":false},{"year":2005,"finding":"Human Mst2 (Ste20-like kinase, MST2) phosphorylates and activates LATS1 at two conserved regulatory sites: S909 in the activation loop and T1079 within the hydrophobic motif, identified by mass spectrometry. Regulation occurs through the C-terminal catalytic domain of LATS1.","method":"In vitro kinase assay, deletion analysis, mass spectrometry, co-immunoprecipitation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mass spectrometry identification of phosphosites, deletion analysis, multiple orthogonal methods in single study","pmids":["15688006"],"is_preprint":false},{"year":2003,"finding":"In Drosophila, Hippo (Hpo) acts together with Salvador (Sav) and Warts (Wts/LATS) in a signaling module. Sav binds to a regulatory domain of Hpo essential for its function, placing Wts/LATS downstream in this pathway that coordinately regulates cell proliferation (via Cyclin E) and apoptosis (via DIAP1 and hid).","method":"Genetic epistasis, co-immunoprecipitation, Drosophila mutant analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in Drosophila with reciprocal binding assay, multiple tissue phenotypes, replicated across labs","pmids":["14502294"],"is_preprint":false},{"year":2005,"finding":"LATS1 interacts with MOB1A (a protein whose yeast homologue associates with mitotic exit network kinases). Moderate overexpression of LATS1 in cells exposed to microtubule poisons facilitated mitotic exit in a MOB1A-dependent manner; siRNA-mediated suppression of LATS1 or MOB1A prolonged telophase.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression in cells with microtubule poisons, live cell analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional rescue/loss-of-function with defined cellular phenotype in two orthogonal approaches","pmids":["16061636"],"is_preprint":false},{"year":2002,"finding":"LATS1 associates with CDC2 in early mitosis and its ectopic expression in cancer cells down-regulates Cyclin A and Cyclin B protein levels, reduces CDC2 kinase activity, causes G2/M blockade, up-regulates BAX, and induces apoptosis. LATS1 kinase activity is required for these effects.","method":"Adenoviral overexpression, cell cycle analysis, kinase activity assay, western blot, soft agar/xenograft assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant used to establish catalytic requirement, multiple orthogonal readouts (cell cycle, apoptosis, tumorigenesis) in single study","pmids":["11850843"],"is_preprint":false},{"year":2012,"finding":"LATS1 phosphorylates MYPT1 (myosin phosphatase-targeting subunit 1) at serine 445. This phosphorylation enables MYPT1 to dephosphorylate PLK1 Thr210, thereby antagonizing PLK1 activity. LATS1 depletion increased PLK1 activity and reduced G2 DNA-damage checkpoint arrest.","method":"Phosphoproteomic screening, in vitro kinase assay, phospho-specific antibodies, siRNA knockdown, LATS1 knockout mouse fibroblasts","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus phosphoproteomic identification plus knockout cells and phospho-specific readouts, multiple orthogonal methods","pmids":["22641346"],"is_preprint":false},{"year":2022,"finding":"WWC proteins (WWC1/2/3) directly interact with both LATS1/2 and SAV1; SAV1 in turn recruits MST1/2 to phosphorylate and activate LATS1/2. WWC proteins thus act as organizers in a signaling module mediating LATS1/2 activation by MST1/2, and a minimum interaction interface on WWC sufficient to activate LATS1/2 was defined.","method":"Co-immunoprecipitation, in vitro kinase assay, structure-function analysis (minigene), tumor xenograft model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct interaction mapped with co-IP, in vitro kinase assay, functional domain defined and validated in multiple tumor models","pmids":["35429439"],"is_preprint":false},{"year":2014,"finding":"PTPN14 interacts with Kibra protein (via PTPN14 PPXY domain and Kibra WW domain) and both independently and cooperatively activate LATS1, leading to cytoplasmic sequestration of YAP. PTPN14 also increases LATS1 protein stability. LATS1 activation by PTPN14 is independent of MST kinases.","method":"Co-immunoprecipitation, domain mapping, LATS1 kinase assay, siRNA knockdown, 3D morphogenesis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping and functional rescue, single lab with multiple orthogonal assays","pmids":["25023289"],"is_preprint":false},{"year":2015,"finding":"PARD3 promotes interaction between PP1A phosphatase and LATS1, leading to LATS1 dephosphorylation and inactivation, thereby causing dephosphorylation and activation of TAZ. The cytoplasmic (but not tight-junction-associated) form of PARD3 mediates this regulation.","method":"Co-immunoprecipitation, phosphorylation assay, domain analysis, siRNA knockdown, reporter assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of the three-protein complex, domain-specific function shown, single lab with multiple assays","pmids":["26116754"],"is_preprint":false},{"year":2010,"finding":"LATS1 phosphorylates FOXL2 (Forkhead L2) at a serine residue, enhances FOXL2's activity as a transcriptional repressor of the StAR promoter (a marker of granulosa cell differentiation). This effect requires LATS1 kinase activity. LATS1 and FOXL2 are co-expressed in developing mouse gonads and granulosa cells.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, promoter reporter assay, immunohistochemistry in mouse ovary","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus co-IP plus promoter reporter with kinase-dead controls, single lab","pmids":["20407010"],"is_preprint":false},{"year":2016,"finding":"Loss of LATS1/2 in tumor cells causes secretion of nucleic-acid-rich extracellular vesicles that induce a type I interferon response via the Toll-like receptors–MYD88/TRIF pathway, enhancing anti-tumor immune responses and causing tumor regression dependent on adaptive immunity.","method":"Syngeneic mouse tumor models (B16, SCC7, 4T1), LATS1/2 genetic deletion, extracellular vesicle characterization, immune cell depletion experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent syngeneic tumor models, genetic deletion, mechanistic pathway (TLR-MYD88/TRIF) identified, immune depletion confirms requirement for adaptive immunity","pmids":["27912060"],"is_preprint":false},{"year":2017,"finding":"In the presence of LATS1/2, estrogen receptor-α (ERα) is targeted for ubiquitination and DCAF1-dependent proteasomal degradation. Absence of LATS1/2 stabilizes ERα together with YAP and TAZ, which together control breast cell fate. This represents a non-canonical (YAP/TAZ-independent) role of LATS.","method":"shRNA screen in primary human breast epithelial cells, co-immunoprecipitation, ubiquitination assay, proteasome inhibition experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Moderate — high-content screen plus mechanistic co-IP, ubiquitination assay, proteasome rescue, identification of E3 ligase adaptor (DCAF1)","pmids":["28068668"],"is_preprint":false},{"year":2019,"finding":"LATS1, but not LATS2, represses autophagy in hepatocellular carcinoma cells through a kinase-independent scaffolding mechanism: LATS1 stabilizes Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263, and this ubiquitination promotes inactive Beclin-1 dimer formation, negatively regulating autophagy.","method":"LATS1 knockout/knockdown, in vitro ubiquitination assay, site-directed mutagenesis of Beclin-1 ubiquitination sites, co-immunoprecipitation, kinase-dead mutant","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination assay with mutagenesis defining specific Lys residues, kinase-dead controls confirm scaffold mechanism, single lab with multiple orthogonal methods","pmids":["31848340"],"is_preprint":false},{"year":2022,"finding":"LATS1/2 phosphorylate and inhibit MTF1, an essential transcription factor for heavy metal response gene transcription, thereby attenuating cellular responses to heavy metals. Accumulated zinc directly binds and inhibits LATS kinase activity, creating a feedback loop. This function is independent of canonical YAP/TAZ effectors.","method":"In vitro kinase assay, Hippo pathway knockout cells, transcriptome analysis, zinc-binding assay, reporter assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay showing direct phosphorylation of MTF1, direct zinc-LATS binding demonstrated, YAP/TAZ-independent mechanism confirmed with orthogonal assays","pmids":["35027733"],"is_preprint":false},{"year":2022,"finding":"LATS1 constitutively binds the type I interferon receptor IFNAR2 and is rapidly tyrosine-phosphorylated by Tyk2 upon IFN-I engagement. Tyrosine-phosphorylated/activated LATS1 translocates to the nucleus and induces CDK8-Ser62 phosphorylation, which in turn phosphorylates STAT1 at Ser727 to achieve full IFN-I antiviral activity.","method":"Co-immunoprecipitation (LATS1-IFNAR2), phosphorylation assays (Tyk2→LATS1, LATS1→CDK8, CDK8→STAT1), LATS1 knockout cells, in vivo antiviral experiments","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and sequential phosphorylation cascade defined with multiple substrates, single lab, in vivo confirmation","pmids":["35394840"],"is_preprint":false},{"year":2022,"finding":"LATS1/2 directly interact with and phosphorylate STAT1 at Ser727, promoting STAT1 nuclear accumulation and transcriptional activation of IRF1/NLRC5, which in turn upregulates MHC-I expression. Loss of LATS1/2 reduces MHC-I expression and promotes immune evasion independently of the Hippo-YAP pathway.","method":"Co-immunoprecipitation, GST pull-down, in vitro kinase assay (mass spectrometry), ChIP-qPCR, CRISPR-Cas9 knockout, flow cytometry","journal":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mass spectrometry plus GST pull-down and ChIP confirming transcriptional outcome, CRISPR-KO validation, multiple orthogonal methods","pmids":["38383447"],"is_preprint":false},{"year":2020,"finding":"SPOP (an E3 ubiquitin ligase adaptor) specifically interacts with LATS1 and promotes its poly-ubiquitination and proteasomal degradation in a degron-dependent manner via Cullin3. Depletion of Cullin3 upregulates LATS1 protein abundance by prolonging its half-life.","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, Cullin3 knockdown, overexpression/knockdown in kidney cancer cells","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus protein stability assay, single lab with multiple orthogonal methods","pmids":["32460168"],"is_preprint":false},{"year":2019,"finding":"PMEPA1 isoform a (PMEPA1a) associates with LATS1 and promotes proteasomal degradation of LATS1 by recruiting the E3 ubiquitin ligase NEDD4. Alanine substitution in PMEPA1a at PY motifs abolishes LATS1 degradation. This leads to silencing of Hippo signaling and promotes glioma growth.","method":"Co-immunoprecipitation, site-directed mutagenesis (PY motifs), ubiquitination assay, xenograft model, shRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis defining PY motif requirement, ubiquitination assay, in vivo rescue with YAP shRNA, single lab","pmids":["31605013"],"is_preprint":false},{"year":2019,"finding":"E3 ligase HERC4 ubiquitinates LATS1 and promotes its proteasomal degradation. miRNA-136-5p and miRNA-1285-5p suppress HERC4 expression, thus indirectly stabilizing LATS1.","method":"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments, in vivo tumor assay","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay demonstrate direct E3-substrate relationship, in vivo confirmation, single lab","pmids":["30710319"],"is_preprint":false},{"year":2023,"finding":"WWP2 (WW domain-containing E3 ubiquitin ligase 2) interacts with LATS1 and promotes its ubiquitination and subsequent proteasomal degradation, leading to increased YAP1 transcriptional activity.","method":"Co-immunoprecipitation, immunofluorescence, cycloheximide chase, in vivo ubiquitination assay, xenograft model","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vivo ubiquitination plus protein stability assay, single lab with multiple orthogonal methods","pmids":["36803368"],"is_preprint":false},{"year":2021,"finding":"LATS1 is acetylated by acetyltransferase CBP at K751 and deacetylated by SIRT3 and SIRT4. Acetylation at K751 stabilizes LATS1 (by reducing ubiquitination) but inhibits its kinase activation (by reducing phosphorylation), resulting in reduced YAP phosphorylation and increased YAP nuclear translocation. K751Q (acetylation mimic) promotes lung cancer cell migration/invasion; K751R (acetylation-deficient) inhibits these functions.","method":"Site-directed mutagenesis, in vitro acetyltransferase assay, co-immunoprecipitation, ubiquitination assay, phosphorylation assay, functional cancer cell assays","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of acetylation site with functional validation, writer/eraser identified, single lab","pmids":["33945069"],"is_preprint":false},{"year":2015,"finding":"In Drosophila wing imaginal discs, Warts (LATS) is organized into distinct junctional complexes separate from Hippo, Salvador, and Expanded. Upon Hippo pathway activation, Warts shifts from associating with its inhibitor Jub to its activator Expanded, and Hippo concentrates at Salvador sites. Warts activation occurs specifically at apical junctions where Expanded, Salvador, Hippo, and Warts overlap, as shown by phospho-specific antisera.","method":"Live imaging, phospho-specific antisera, genetic manipulation (Drosophila), fractionation/localization analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-specific antisera directly demonstrates activation site in vivo, genetic manipulations define localization requirements, multiple orthogonal approaches","pmids":["26420589"],"is_preprint":false},{"year":2014,"finding":"MAP4K4 (mammalian homolog of Drosophila Misshapen) interacts with LATS1 (Warts homolog) and promotes inhibition of YAP (Yorkie homolog) in mammalian cells, acting as an MST1/2-independent activator of LATS.","method":"Co-immunoprecipitation, epistasis analysis in Drosophila and mammalian cells, YAP phosphorylation assay","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP showing direct interaction, functional epistasis in both fly and mammalian systems, single lab","pmids":["25453828"],"is_preprint":false},{"year":2015,"finding":"LATS1 physically interacts with and regulates the stability of Cdc25B phosphatase. Loss of LATS1 causes abnormal accumulation of Cdc25B protein and hyperactivation of Cdk2 toward nucleophosmin (NPM/B23), suppressing centrosome overduplication. LATS1 does not directly phosphorylate Cdc25B.","method":"Co-immunoprecipitation, Lats1 knockout MEFs, centrosome duplication assay, Cdk2 kinase assay, western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus knockout MEFs plus direct Cdk2 kinase assay, negative result (no direct phosphorylation) specified, single lab","pmids":["26530630"],"is_preprint":false},{"year":2015,"finding":"LATS1/2 phosphorylate CHO1 at Ser716 in its F-actin-interacting region (absent in MKLP1 splice variant). Phosphorylated CHO1 localizes to centrosomes and midbody, and recruits LIMK1 as binding partner. Overexpression of constitutively phosphorylated or non-phosphorylated CHO1 alters LIMK1 mitotic localization/activation at centrosomes, inhibiting cytokinesis through excessive Cofilin phosphorylation and mislocalization of Ect2.","method":"In vitro kinase assay, phospho-specific localization, co-immunoprecipitation (LIMK1-CHO1), overexpression of phospho-mutants in HeLa cells","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay identifies substrate site, phospho-mutant overexpression reveals functional consequence, binding partner identified by co-IP, single lab","pmids":["25786116"],"is_preprint":false},{"year":2021,"finding":"lncRNA SNHG9 and its associated phosphatidic acids interact with the C-terminal domain of LATS1, promoting LATS1 liquid-liquid phase separation (LLPS). LATS1 phase separation inhibits LATS1-mediated YAP phosphorylation.","method":"RNA pull-down, co-immunoprecipitation, in vitro phase separation assay, YAP phosphorylation assay, domain mapping","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phase separation assay plus RNA pull-down with functional readout (YAP phosphorylation), single lab with multiple methods; note this is a lncRNA paper but the mechanistic claim is about LATS1 protein behavior","pmids":["34267352"],"is_preprint":false},{"year":2019,"finding":"Gα13 activation induces phosphorylation of LATS1 at serine 909 (activation loop), which recruits ITCH E3 ubiquitin ligase to trigger LATS1 proteasomal degradation, thereby promoting EMT in ovarian cancer.","method":"Chimeric G-protein/mutant GPCR synthetic biology, co-immunoprecipitation, ubiquitination assay, phospho-LATS1 S909 western blot","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism-of-action defined using chimeric G-protein approach plus co-IP and ubiquitination assay, single lab","pmids":["31569999"],"is_preprint":false},{"year":2023,"finding":"METTL3 methylates LATS1 mRNA at m6A sites; YTHDF2 recognizes these m6A modifications and reduces LATS1 mRNA stability, thereby decreasing LATS1 protein levels and activating YAP/TAZ in the Hippo pathway.","method":"MeRIP-seq, RNA pull-down assay, RIP-qPCR, RNA stability analysis, METTL3/YTHDF2 knockout","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq identifies methylation sites, pull-down confirms reader-mRNA interaction, RNA stability measured, single lab","pmids":["36609396"],"is_preprint":false},{"year":2024,"finding":"HPV18 E7 degrades PTPN14, which results in decreased phosphorylation of LATS1 at T1079 and of YAP at S127, thereby inhibiting LATS1 kinase activity and activating YAP. PTPN14-dependent keratinocyte differentiation requires LATS kinases and certain PPxY motifs in PTPN14, but not MST1/2 or PTPN14 phosphatase active site.","method":"PTPN14 knockout, phospho-specific antibodies (LATS1 T1079, YAP S127), site-directed mutagenesis (PPxY motifs), keratinocyte differentiation assay","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-specific readouts confirm LATS1 activity change, genetic knockout and mutagenesis of PPxY motifs, single lab","pmids":["39248565"],"is_preprint":false},{"year":2022,"finding":"TRIM65 promotes ubiquitination and proteasomal degradation of LATS1 in triple-negative breast cancer cells, promoting cell invasion and migration.","method":"Co-immunoprecipitation, cycloheximide chase, endogenous ubiquitination assay, rescue experiments","journal":"Oxidative medicine and cellular longevity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP plus ubiquitination assay, single lab, single method quality for each mechanistic claim","pmids":["36035221"],"is_preprint":false},{"year":2020,"finding":"In Lats1/2-null intestinal epithelium, nuclear YAP/TAZ interact with Groucho/TLE to block Wnt/TCF-mediated transcription, inhibiting Wnt pathway activity. This YAP/TAZ-mediated Wnt inhibition is TEAD-independent.","method":"Conditional Lats1/2 knockout mice, chemical TEAD inhibitor, proteomics, nuclear co-immunoprecipitation of YAP/TAZ with TLE","journal":"Cell stem cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO combined with chemical tool and proteomic approach, co-IP of YAP/TAZ-TLE interaction, single lab","pmids":["32259481"],"is_preprint":false}],"current_model":"LATS1 is a Ser/Thr kinase (NDR/LATS subfamily of AGC kinases) that functions as the central effector kinase of the Hippo tumor suppressor pathway: it is activated by MST1/2 (via direct phosphorylation of S909 and T1079) through scaffolding by WWC proteins and SAV1, and it phosphorylates YAP/TAZ to sequester them in the cytoplasm; beyond this canonical role, LATS1 phosphorylates additional substrates including MYPT1 (antagonizing PLK1 at the G2 DNA-damage checkpoint), MTF1 (attenuating heavy-metal responses), STAT1-Ser727 (promoting MHC-I expression and IFN-γ signaling), FOXL2 (regulating granulosa cell differentiation), and CHO1 (controlling cytokinesis via LIMK1); LATS1 protein stability is controlled by multiple E3 ubiquitin ligases (SPOP/Cullin3, NEDD4 recruited by PMEPA1a, HERC4, WWP2, TRIM65, ITCH recruited upon Gα13 activation) and is also regulated by CBP-mediated acetylation at K751 (writer) and SIRT3/4 (erasers), as well as by METTL3/YTHDF2-dependent m6A destabilization of its mRNA; additionally, LATS1 exerts a kinase-independent scaffolding function to stabilize Beclin-1 via K27-linked ubiquitination and suppress autophagy, and acts as a signal transducer downstream of the IFN-I receptor IFNAR2 via Tyk2-mediated tyrosine phosphorylation."},"narrative":{"mechanistic_narrative":"LATS1 is a Ser/Thr kinase that serves as the central effector of the Hippo tumor-suppressor pathway, a module first defined genetically in Drosophila where Warts (LATS) acts downstream of Hippo and Salvador to restrain proliferation and promote apoptosis [PMID:14502294]. In its canonical role, LATS1 directly binds and phosphorylates YAP, sequestering this oncoprotein in the cytoplasm and inactivating its transcriptional output [PMID:18158288]. LATS1 is itself switched on by upstream kinases: MST2 phosphorylates the activation-loop site S909 and the hydrophobic-motif site T1079 [PMID:15688006], a step organized by WWC proteins and SAV1 that recruit MST1/2 to LATS [PMID:35429439], with additional MST-independent activators including the Kibra–PTPN14 axis [PMID:25023289] and MAP4K4 [PMID:25453828]; PARD3-directed PP1A dephosphorylation provides an off-switch [PMID:26116754]. Beyond YAP, LATS1 phosphorylates a diverse substrate set linking it to genome integrity and immunity: MYPT1-Ser445 to antagonize PLK1 at the G2 DNA-damage checkpoint [PMID:22641346], MTF1 to attenuate heavy-metal responses in a zinc-gated feedback loop [PMID:35027733], STAT1-Ser727 to drive IRF1/NLRC5-dependent MHC-I expression [PMID:38383447], FOXL2 to control granulosa-cell differentiation [PMID:20407010], and CHO1 to govern cytokinesis through LIMK1 [PMID:25786116]. LATS1 also exerts YAP/TAZ-independent functions, including kinase-independent scaffolding that stabilizes Beclin-1 via K27-linked ubiquitination to suppress autophagy [PMID:31848340] and signal transduction downstream of the type I interferon receptor IFNAR2 via Tyk2-mediated tyrosine phosphorylation [PMID:35394840]. LATS1 abundance is tightly set by numerous E3 ubiquitin ligases that drive its proteasomal degradation—SPOP/Cullin3 [PMID:32460168], NEDD4 recruited by PMEPA1a [PMID:31605013], HERC4 [PMID:30710319], WWP2 [PMID:36803368], and ITCH recruited upon Gα13 activation [PMID:31569999]—as well as by CBP-mediated acetylation at K751 [PMID:33945069] and METTL3/YTHDF2-dependent m6A destabilization of its mRNA [PMID:36609396].","teleology":[{"year":2003,"claim":"Established the genetic architecture placing LATS/Warts within a defined kinase module, answering how an upstream growth-control signal is relayed to proliferation and apoptosis decisions.","evidence":"Genetic epistasis and co-immunoprecipitation in Drosophila mutants","pmids":["14502294"],"confidence":"High","gaps":["Did not identify the LATS substrate executing growth control","Mammalian relevance not yet demonstrated"]},{"year":2002,"claim":"Showed that LATS1 catalytic activity drives cell-cycle arrest and apoptosis, defining it functionally as a tumor suppressor rather than a passive scaffold.","evidence":"Adenoviral overexpression with kinase-dead mutant, cell-cycle and xenograft assays in cancer cells","pmids":["11850843"],"confidence":"High","gaps":["Direct kinase substrate for these effects not identified","CDC2 association mechanism not resolved"]},{"year":2005,"claim":"Defined the upstream activation mechanism by identifying the two regulatory phosphosites through which MST2 turns LATS1 on.","evidence":"In vitro kinase assay with mass-spectrometry mapping of S909 and T1079, deletion analysis","pmids":["15688006"],"confidence":"High","gaps":["Scaffolding requirements for the MST2-LATS1 reaction not addressed","Did not link activation to a downstream output"]},{"year":2005,"claim":"Linked LATS1 to mitotic exit via MOB1A, connecting the kinase to control of cell division timing.","evidence":"Reciprocal co-IP plus siRNA and overexpression with microtubule poisons and live-cell analysis","pmids":["16061636"],"confidence":"High","gaps":["Molecular mechanism of MOB1A-dependent mitotic exit unresolved","No substrate identified for this function"]},{"year":2007,"claim":"Identified the central canonical substrate, showing LATS1 directly phosphorylates YAP to drive its cytoplasmic sequestration and a substrate consensus motif.","evidence":"In vitro kinase assay, co-IP, subcellular fractionation and microarray","pmids":["18158288"],"confidence":"High","gaps":["Did not enumerate non-YAP substrates","Physiological contexts of YAP control not delineated"]},{"year":2010,"claim":"Extended the LATS1 substrate repertoire to transcription-factor control, phosphorylating FOXL2 in granulosa-cell differentiation.","evidence":"Yeast two-hybrid, co-IP, in vitro kinase assay and promoter reporter with kinase-dead controls in mouse ovary context","pmids":["20407010"],"confidence":"Medium","gaps":["Phosphosite on FOXL2 not precisely mapped","In vivo gonadal requirement not genetically tested"]},{"year":2012,"claim":"Connected LATS1 to the DNA-damage checkpoint by identifying MYPT1-Ser445 phosphorylation as the means to antagonize PLK1.","evidence":"Phosphoproteomics, in vitro kinase assay, phospho-specific antibodies and LATS1-knockout fibroblasts","pmids":["22641346"],"confidence":"High","gaps":["Integration with canonical Hippo signaling not addressed","Upstream activation of LATS1 in this context unclear"]},{"year":2014,"claim":"Revealed MST-independent LATS1 activation, with Kibra-PTPN14 and MAP4K4 each able to engage and activate the kinase.","evidence":"Co-IP, domain mapping, LATS1 kinase assays and Drosophila/mammalian epistasis","pmids":["25023289","25453828"],"confidence":"Medium","gaps":["Relative contribution versus MST pathway in vivo unquantified","How these inputs converge on the activation loop not resolved"]},{"year":2015,"claim":"Defined inhibitory and localization controls of LATS1 activity, including PARD3-PP1A dephosphorylation and junctional activation sites, plus new mitotic substrates and stability targets.","evidence":"Co-IP, phosphatase and kinase assays, phospho-specific antisera and live imaging across mammalian and Drosophila systems","pmids":["26116754","26420589","26530630","25786116"],"confidence":"Medium","gaps":["Spatial coordination of activation versus inactivation not unified","Cdc25B regulation occurs without direct phosphorylation, mechanism incomplete"]},{"year":2016,"claim":"Demonstrated that LATS1/2 loss reshapes anti-tumor immunity through nucleic-acid-rich extracellular vesicles, expanding LATS function beyond cell-autonomous growth control.","evidence":"Syngeneic mouse tumor models with genetic deletion, EV characterization and immune-depletion experiments","pmids":["27912060"],"confidence":"High","gaps":["Kinase-substrate basis of EV phenotype not defined","Whether effect depends on LATS catalytic activity unaddressed"]},{"year":2017,"claim":"Uncovered a YAP/TAZ-independent role: LATS-dependent ERα degradation, broadening the non-canonical reach of the pathway.","evidence":"shRNA screen in primary breast epithelial cells, co-IP, ubiquitination and proteasome-inhibition assays identifying DCAF1","pmids":["28068668"],"confidence":"High","gaps":["Direct enzymatic role of LATS in this degradation not defined","Generalizability beyond breast cells untested"]},{"year":2019,"claim":"Defined a kinase-independent scaffolding function of LATS1, stabilizing Beclin-1 by K27-linked ubiquitination to suppress autophagy.","evidence":"Knockout/knockdown, in vitro ubiquitination with site mutagenesis and kinase-dead controls in hepatocellular carcinoma cells","pmids":["31848340"],"confidence":"High","gaps":["The ubiquitin ligase recruited by LATS1 not identified","Distinction from LATS2 mechanistically unexplained"]},{"year":2019,"claim":"Established LATS1 protein abundance as a heavily regulated node, with multiple E3 ligases and degron-dependent inputs controlling its half-life.","evidence":"Co-IP, ubiquitination and cycloheximide-chase assays defining HERC4, PMEPA1a-NEDD4, and Gα13-recruited ITCH","pmids":["30710319","31605013","31569999"],"confidence":"Medium","gaps":["Hierarchy and context-specificity among ligases unresolved","Endogenous physiological triggers not fully defined"]},{"year":2020,"claim":"Showed downstream consequences of LATS1/2 loss in tissue, including TEAD-independent YAP/TAZ-TLE inhibition of Wnt signaling and SPOP/Cullin3-mediated LATS1 turnover.","evidence":"Conditional knockout mice, TEAD-inhibitor and proteomics; co-IP and stability assays in kidney cancer cells","pmids":["32259481","32460168"],"confidence":"Medium","gaps":["Tissue specificity of these effects not generalized","Crosstalk with canonical TEAD output not quantified"]},{"year":2021,"claim":"Identified post-translational and biophysical tuning of LATS1, with K751 acetylation balancing stability against activity and lncRNA-driven phase separation suppressing YAP phosphorylation.","evidence":"Acetyltransferase and phase-separation assays, site mutagenesis, ubiquitination and YAP-phosphorylation readouts","pmids":["33945069","34267352"],"confidence":"Medium","gaps":["Physiological stimuli driving acetylation/phase separation unclear","Single-lab findings for each mechanism"]},{"year":2022,"claim":"Expanded LATS1 into innate immunity and stress sensing, signaling downstream of IFNAR2 via Tyk2 and gating MHC-I and heavy-metal responses through STAT1-Ser727 and MTF1.","evidence":"Co-IP, sequential phosphorylation cascades, in vitro kinase assays, zinc-binding assays and knockout cells with in vivo confirmation","pmids":["35394840","38383447","35027733","35429439"],"confidence":"Medium","gaps":["Tyrosine-phosphorylation step is non-canonical and mechanistically distinct from Ser/Thr activation","Integration of these branches with Hippo signaling not unified"]},{"year":2023,"claim":"Added mRNA-level and ligase-level control of LATS1, via METTL3/YTHDF2 m6A destabilization and WWP2-mediated degradation, each activating YAP.","evidence":"MeRIP-seq, RIP-qPCR, RNA-stability analysis; co-IP and in vivo ubiquitination assays","pmids":["36609396","36803368"],"confidence":"Medium","gaps":["Conditions selecting mRNA versus protein control not defined","Single-lab studies"]},{"year":2024,"claim":"Showed viral subversion of LATS1 activation, with HPV18 E7 degrading PTPN14 to lower LATS1 T1079 phosphorylation and de-repress YAP.","evidence":"PTPN14 knockout, phospho-specific antibodies, PPxY-motif mutagenesis and keratinocyte differentiation assays","pmids":["39248565"],"confidence":"Medium","gaps":["MST-independence versus dependence in keratinocytes only partially resolved","Single-lab finding"]},{"year":null,"claim":"How LATS1's many non-canonical branches—autophagy scaffolding, interferon and metal-stress signaling, immune-vesicle output—are coordinated with its canonical YAP-suppressing kinase activity within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking kinase-dependent and kinase-independent functions","Context determinants selecting among substrates unknown","Structural basis of differential substrate recognition uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,5,9,13,15,24]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,5,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator 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The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288, PubMed:26437443, PubMed:28068668). Phosphorylation of YAP1 by LATS1 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288, PubMed:26437443, PubMed:28068668). Acts as a tumor suppressor which plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G1 tetraploidy checkpoint (PubMed:15122335, PubMed:19927127). Negatively regulates G2/M transition by down-regulating CDK1 kinase activity (PubMed:9988268). Involved in the control of p53 expression (PubMed:15122335). Affects cytokinesis by regulating actin polymerization through negative modulation of LIMK1 (PubMed:15220930). May also play a role in endocrine function. Plays a role in mammary gland epithelial cell differentiation, both through the Hippo signaling pathway and the intracellular estrogen receptor signaling pathway by promoting the degradation of ESR1 (PubMed:28068668). Acts as an activator of the NLRP3 inflammasome by mediating phosphorylation of 'Ser-265' of NLRP3 following NLRP3 palmitoylation, promoting NLRP3 activation by NEK7 (PubMed:39173637)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Midbody; Cytoplasm, cytoskeleton, microtubule organizing center, spindle pole body","url":"https://www.uniprot.org/uniprotkb/O95835/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LATS1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LATS1","total_profiled":1310},"omim":[{"mim_id":"620119","title":"LONG NONCODING RNA CRYBG3","url":"https://www.omim.org/entry/620119"},{"mim_id":"620110","title":"WW AND C2 DOMAINS-CONTAINING PROTEIN 2; WWC2","url":"https://www.omim.org/entry/620110"},{"mim_id":"618452","title":"PLECKSTRIN HOMOLOGY DOMAIN-CONTAINING PROTEIN, FAMILY B, MEMBER 2; PLEKHB2","url":"https://www.omim.org/entry/618452"},{"mim_id":"617652","title":"MOB KINASE ACTIVATOR 3B; MOB3B","url":"https://www.omim.org/entry/617652"},{"mim_id":"613733","title":"MENIN 1; MEN1","url":"https://www.omim.org/entry/613733"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LATS1"},"hgnc":{"alias_symbol":["WARTS"],"prev_symbol":[]},"alphafold":{"accession":"O95835","domains":[{"cath_id":"3.30.200.20","chopping":"700-787_1048-1098","consensus_level":"medium","plddt":74.0036,"start":700,"end":1098},{"cath_id":"1.10.510.10","chopping":"789-861_895-1030","consensus_level":"medium","plddt":86.1976,"start":789,"end":1030}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95835","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95835-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95835-F1-predicted_aligned_error_v6.png","plddt_mean":55.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LATS1","jax_strain_url":"https://www.jax.org/strain/search?query=LATS1"},"sequence":{"accession":"O95835","fasta_url":"https://rest.uniprot.org/uniprotkb/O95835.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95835/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95835"}},"corpus_meta":[{"pmid":"18158288","id":"PMC_18158288","title":"Tumor suppressor LATS1 is a negative regulator of oncogene YAP.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18158288","citation_count":675,"is_preprint":false},{"pmid":"14502294","id":"PMC_14502294","title":"Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway.","date":"2003","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14502294","citation_count":658,"is_preprint":false},{"pmid":"17318211","id":"PMC_17318211","title":"The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network.","date":"2007","source":"Nature reviews. 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sexual abuse or not?","date":"1993","source":"International journal of STD & AIDS","url":"https://pubmed.ncbi.nlm.nih.gov/8218514","citation_count":27,"is_preprint":false},{"pmid":"31930595","id":"PMC_31930595","title":"Intralesional immunotherapy for pediatric warts: A review.","date":"2020","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31930595","citation_count":26,"is_preprint":false},{"pmid":"27736001","id":"PMC_27736001","title":"Human papillomaviruses genotyping in plantar warts.","date":"2016","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/27736001","citation_count":26,"is_preprint":false},{"pmid":"36803368","id":"PMC_36803368","title":"WWP2 drives the progression of gastric cancer by facilitating the ubiquitination and degradation of LATS1 protein.","date":"2023","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/36803368","citation_count":26,"is_preprint":false},{"pmid":"25814698","id":"PMC_25814698","title":"Immunomodulators in warts: Unexplored or ineffective?","date":"2015","source":"Indian journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25814698","citation_count":25,"is_preprint":false},{"pmid":"28434174","id":"PMC_28434174","title":"Molecular Alterations and Expression Dynamics of LATS1 and LATS2 Genes in Non-Small-Cell Lung Carcinoma.","date":"2017","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/28434174","citation_count":25,"is_preprint":false},{"pmid":"31323030","id":"PMC_31323030","title":"LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation.","date":"2019","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/31323030","citation_count":25,"is_preprint":false},{"pmid":"26530630","id":"PMC_26530630","title":"Lats1 suppresses centrosome overduplication by modulating the stability of Cdc25B.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26530630","citation_count":24,"is_preprint":false},{"pmid":"24766274","id":"PMC_24766274","title":"Sinecatechins (Polyphenon E) ointment for treatment of external genital warts and possible future indications.","date":"2014","source":"Expert opinion on biological therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24766274","citation_count":24,"is_preprint":false},{"pmid":"28152516","id":"PMC_28152516","title":"TNFAIP8 interacts with LATS1 and promotes aggressiveness through regulation of Hippo pathway in hepatocellular carcinoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28152516","citation_count":24,"is_preprint":false},{"pmid":"32151264","id":"PMC_32151264","title":"Transcriptome analysis of HPV-induced warts and healthy skin in humans.","date":"2020","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32151264","citation_count":23,"is_preprint":false},{"pmid":"36443313","id":"PMC_36443313","title":"Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36443313","citation_count":23,"is_preprint":false},{"pmid":"30710319","id":"PMC_30710319","title":"A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1.","date":"2019","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/30710319","citation_count":23,"is_preprint":false},{"pmid":"28259899","id":"PMC_28259899","title":"LATS1 suppresses proliferation and invasion of cervical cancer.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28259899","citation_count":22,"is_preprint":false},{"pmid":"30308519","id":"PMC_30308519","title":"A FUS-LATS1/2 Axis Inhibits Hepatocellular Carcinoma Progression via Activating Hippo Pathway.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30308519","citation_count":22,"is_preprint":false},{"pmid":"31010295","id":"PMC_31010295","title":"Photodynamic Therapy for Genital Warts Causes Activation of Local Immunity.","date":"2019","source":"Journal of cutaneous medicine and surgery","url":"https://pubmed.ncbi.nlm.nih.gov/31010295","citation_count":22,"is_preprint":false},{"pmid":"25712415","id":"PMC_25712415","title":"17-AAG suppresses growth and invasion of lung adenocarcinoma cells via regulation of the LATS1/YAP pathway.","date":"2015","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25712415","citation_count":22,"is_preprint":false},{"pmid":"33945069","id":"PMC_33945069","title":"LATS1 K751 acetylation blocks activation of Hippo signalling and switches LATS1 from a tumor suppressor to an oncoprotein.","date":"2021","source":"Science China. 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Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete","url":"https://pubmed.ncbi.nlm.nih.gov/11220242","citation_count":20,"is_preprint":false},{"pmid":"28926138","id":"PMC_28926138","title":"TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer.","date":"2017","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28926138","citation_count":20,"is_preprint":false},{"pmid":"25041856","id":"PMC_25041856","title":"TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors.","date":"2014","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25041856","citation_count":19,"is_preprint":false},{"pmid":"38383447","id":"PMC_38383447","title":"LATS1/2 loss promote tumor immune evasion in endometrial cancer through downregulating MHC-I expression.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38383447","citation_count":18,"is_preprint":false},{"pmid":"2835929","id":"PMC_2835929","title":"Genital warts, papillomaviruses, and genital malignancies.","date":"1988","source":"Annual review of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2835929","citation_count":17,"is_preprint":false},{"pmid":"27761802","id":"PMC_27761802","title":"Contribution of LATS1 and LATS2 promoter methylation in OSCC development.","date":"2016","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/27761802","citation_count":14,"is_preprint":false},{"pmid":"31575647","id":"PMC_31575647","title":"Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme.","date":"2019","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31575647","citation_count":14,"is_preprint":false},{"pmid":"8394232","id":"PMC_8394232","title":"Anogenital warts in children.","date":"1993","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/8394232","citation_count":14,"is_preprint":false},{"pmid":"31569999","id":"PMC_31569999","title":"Gα13-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31569999","citation_count":14,"is_preprint":false},{"pmid":"25786116","id":"PMC_25786116","title":"Phosphorylation of CHO1 by Lats1/2 regulates the centrosomal activation of LIMK1 during cytokinesis.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25786116","citation_count":14,"is_preprint":false},{"pmid":"38022045","id":"PMC_38022045","title":"A Comprehensive Review of Treatment Approaches for Cutaneous and Genital Warts.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38022045","citation_count":13,"is_preprint":false},{"pmid":"22359650","id":"PMC_22359650","title":"Control of tissue growth and cell transformation by the Salvador/Warts/Hippo pathway.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22359650","citation_count":13,"is_preprint":false},{"pmid":"39088322","id":"PMC_39088322","title":"METTL3 regulates cartilage development and homeostasis by affecting Lats1 mRNA stability in an m6A-YTHDF2-dependent manner.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39088322","citation_count":12,"is_preprint":false},{"pmid":"31511495","id":"PMC_31511495","title":"Salvador-Warts-Hippo pathway regulates sensory organ development via caspase-dependent nonapoptotic signaling.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31511495","citation_count":12,"is_preprint":false},{"pmid":"9891689","id":"PMC_9891689","title":"Treatment of anogenital warts.","date":"1998","source":"Dermatologic clinics","url":"https://pubmed.ncbi.nlm.nih.gov/9891689","citation_count":12,"is_preprint":false},{"pmid":"36808829","id":"PMC_36808829","title":"Inhibition of EZH2 exerts antitumorigenic effects in renal cell carcinoma via LATS1.","date":"2023","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/36808829","citation_count":12,"is_preprint":false},{"pmid":"36035221","id":"PMC_36035221","title":"TRIM65 Promotes Malignant Cell Behaviors in Triple-Negative Breast Cancer by Impairing the Stability of LATS1 Protein.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36035221","citation_count":12,"is_preprint":false},{"pmid":"11205298","id":"PMC_11205298","title":"Angiogenesis and vasodilation in skin warts. 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The consensus phosphorylation sequence for LATS/Ndr kinase substrates was identified as HX(R/H/K)XX(S/T).\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, subcellular fractionation, microarray analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus in vivo phosphorylation, consensus motif defined, cytoplasmic sequestration demonstrated with multiple orthogonal methods\",\n      \"pmids\": [\"18158288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human Mst2 (Ste20-like kinase, MST2) phosphorylates and activates LATS1 at two conserved regulatory sites: S909 in the activation loop and T1079 within the hydrophobic motif, identified by mass spectrometry. Regulation occurs through the C-terminal catalytic domain of LATS1.\",\n      \"method\": \"In vitro kinase assay, deletion analysis, mass spectrometry, co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mass spectrometry identification of phosphosites, deletion analysis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15688006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In Drosophila, Hippo (Hpo) acts together with Salvador (Sav) and Warts (Wts/LATS) in a signaling module. Sav binds to a regulatory domain of Hpo essential for its function, placing Wts/LATS downstream in this pathway that coordinately regulates cell proliferation (via Cyclin E) and apoptosis (via DIAP1 and hid).\",\n      \"method\": \"Genetic epistasis, co-immunoprecipitation, Drosophila mutant analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in Drosophila with reciprocal binding assay, multiple tissue phenotypes, replicated across labs\",\n      \"pmids\": [\"14502294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LATS1 interacts with MOB1A (a protein whose yeast homologue associates with mitotic exit network kinases). Moderate overexpression of LATS1 in cells exposed to microtubule poisons facilitated mitotic exit in a MOB1A-dependent manner; siRNA-mediated suppression of LATS1 or MOB1A prolonged telophase.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression in cells with microtubule poisons, live cell analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional rescue/loss-of-function with defined cellular phenotype in two orthogonal approaches\",\n      \"pmids\": [\"16061636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"LATS1 associates with CDC2 in early mitosis and its ectopic expression in cancer cells down-regulates Cyclin A and Cyclin B protein levels, reduces CDC2 kinase activity, causes G2/M blockade, up-regulates BAX, and induces apoptosis. LATS1 kinase activity is required for these effects.\",\n      \"method\": \"Adenoviral overexpression, cell cycle analysis, kinase activity assay, western blot, soft agar/xenograft assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant used to establish catalytic requirement, multiple orthogonal readouts (cell cycle, apoptosis, tumorigenesis) in single study\",\n      \"pmids\": [\"11850843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LATS1 phosphorylates MYPT1 (myosin phosphatase-targeting subunit 1) at serine 445. This phosphorylation enables MYPT1 to dephosphorylate PLK1 Thr210, thereby antagonizing PLK1 activity. LATS1 depletion increased PLK1 activity and reduced G2 DNA-damage checkpoint arrest.\",\n      \"method\": \"Phosphoproteomic screening, in vitro kinase assay, phospho-specific antibodies, siRNA knockdown, LATS1 knockout mouse fibroblasts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus phosphoproteomic identification plus knockout cells and phospho-specific readouts, multiple orthogonal methods\",\n      \"pmids\": [\"22641346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WWC proteins (WWC1/2/3) directly interact with both LATS1/2 and SAV1; SAV1 in turn recruits MST1/2 to phosphorylate and activate LATS1/2. WWC proteins thus act as organizers in a signaling module mediating LATS1/2 activation by MST1/2, and a minimum interaction interface on WWC sufficient to activate LATS1/2 was defined.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, structure-function analysis (minigene), tumor xenograft model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct interaction mapped with co-IP, in vitro kinase assay, functional domain defined and validated in multiple tumor models\",\n      \"pmids\": [\"35429439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPN14 interacts with Kibra protein (via PTPN14 PPXY domain and Kibra WW domain) and both independently and cooperatively activate LATS1, leading to cytoplasmic sequestration of YAP. PTPN14 also increases LATS1 protein stability. LATS1 activation by PTPN14 is independent of MST kinases.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, LATS1 kinase assay, siRNA knockdown, 3D morphogenesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping and functional rescue, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"25023289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PARD3 promotes interaction between PP1A phosphatase and LATS1, leading to LATS1 dephosphorylation and inactivation, thereby causing dephosphorylation and activation of TAZ. The cytoplasmic (but not tight-junction-associated) form of PARD3 mediates this regulation.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, domain analysis, siRNA knockdown, reporter assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of the three-protein complex, domain-specific function shown, single lab with multiple assays\",\n      \"pmids\": [\"26116754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LATS1 phosphorylates FOXL2 (Forkhead L2) at a serine residue, enhances FOXL2's activity as a transcriptional repressor of the StAR promoter (a marker of granulosa cell differentiation). This effect requires LATS1 kinase activity. LATS1 and FOXL2 are co-expressed in developing mouse gonads and granulosa cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, promoter reporter assay, immunohistochemistry in mouse ovary\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus co-IP plus promoter reporter with kinase-dead controls, single lab\",\n      \"pmids\": [\"20407010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of LATS1/2 in tumor cells causes secretion of nucleic-acid-rich extracellular vesicles that induce a type I interferon response via the Toll-like receptors–MYD88/TRIF pathway, enhancing anti-tumor immune responses and causing tumor regression dependent on adaptive immunity.\",\n      \"method\": \"Syngeneic mouse tumor models (B16, SCC7, 4T1), LATS1/2 genetic deletion, extracellular vesicle characterization, immune cell depletion experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent syngeneic tumor models, genetic deletion, mechanistic pathway (TLR-MYD88/TRIF) identified, immune depletion confirms requirement for adaptive immunity\",\n      \"pmids\": [\"27912060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In the presence of LATS1/2, estrogen receptor-α (ERα) is targeted for ubiquitination and DCAF1-dependent proteasomal degradation. Absence of LATS1/2 stabilizes ERα together with YAP and TAZ, which together control breast cell fate. This represents a non-canonical (YAP/TAZ-independent) role of LATS.\",\n      \"method\": \"shRNA screen in primary human breast epithelial cells, co-immunoprecipitation, ubiquitination assay, proteasome inhibition experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-content screen plus mechanistic co-IP, ubiquitination assay, proteasome rescue, identification of E3 ligase adaptor (DCAF1)\",\n      \"pmids\": [\"28068668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LATS1, but not LATS2, represses autophagy in hepatocellular carcinoma cells through a kinase-independent scaffolding mechanism: LATS1 stabilizes Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263, and this ubiquitination promotes inactive Beclin-1 dimer formation, negatively regulating autophagy.\",\n      \"method\": \"LATS1 knockout/knockdown, in vitro ubiquitination assay, site-directed mutagenesis of Beclin-1 ubiquitination sites, co-immunoprecipitation, kinase-dead mutant\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination assay with mutagenesis defining specific Lys residues, kinase-dead controls confirm scaffold mechanism, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31848340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LATS1/2 phosphorylate and inhibit MTF1, an essential transcription factor for heavy metal response gene transcription, thereby attenuating cellular responses to heavy metals. Accumulated zinc directly binds and inhibits LATS kinase activity, creating a feedback loop. This function is independent of canonical YAP/TAZ effectors.\",\n      \"method\": \"In vitro kinase assay, Hippo pathway knockout cells, transcriptome analysis, zinc-binding assay, reporter assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay showing direct phosphorylation of MTF1, direct zinc-LATS binding demonstrated, YAP/TAZ-independent mechanism confirmed with orthogonal assays\",\n      \"pmids\": [\"35027733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LATS1 constitutively binds the type I interferon receptor IFNAR2 and is rapidly tyrosine-phosphorylated by Tyk2 upon IFN-I engagement. Tyrosine-phosphorylated/activated LATS1 translocates to the nucleus and induces CDK8-Ser62 phosphorylation, which in turn phosphorylates STAT1 at Ser727 to achieve full IFN-I antiviral activity.\",\n      \"method\": \"Co-immunoprecipitation (LATS1-IFNAR2), phosphorylation assays (Tyk2→LATS1, LATS1→CDK8, CDK8→STAT1), LATS1 knockout cells, in vivo antiviral experiments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and sequential phosphorylation cascade defined with multiple substrates, single lab, in vivo confirmation\",\n      \"pmids\": [\"35394840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LATS1/2 directly interact with and phosphorylate STAT1 at Ser727, promoting STAT1 nuclear accumulation and transcriptional activation of IRF1/NLRC5, which in turn upregulates MHC-I expression. Loss of LATS1/2 reduces MHC-I expression and promotes immune evasion independently of the Hippo-YAP pathway.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, in vitro kinase assay (mass spectrometry), ChIP-qPCR, CRISPR-Cas9 knockout, flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mass spectrometry plus GST pull-down and ChIP confirming transcriptional outcome, CRISPR-KO validation, multiple orthogonal methods\",\n      \"pmids\": [\"38383447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPOP (an E3 ubiquitin ligase adaptor) specifically interacts with LATS1 and promotes its poly-ubiquitination and proteasomal degradation in a degron-dependent manner via Cullin3. Depletion of Cullin3 upregulates LATS1 protein abundance by prolonging its half-life.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, Cullin3 knockdown, overexpression/knockdown in kidney cancer cells\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus protein stability assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32460168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PMEPA1 isoform a (PMEPA1a) associates with LATS1 and promotes proteasomal degradation of LATS1 by recruiting the E3 ubiquitin ligase NEDD4. Alanine substitution in PMEPA1a at PY motifs abolishes LATS1 degradation. This leads to silencing of Hippo signaling and promotes glioma growth.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (PY motifs), ubiquitination assay, xenograft model, shRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis defining PY motif requirement, ubiquitination assay, in vivo rescue with YAP shRNA, single lab\",\n      \"pmids\": [\"31605013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"E3 ligase HERC4 ubiquitinates LATS1 and promotes its proteasomal degradation. miRNA-136-5p and miRNA-1285-5p suppress HERC4 expression, thus indirectly stabilizing LATS1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments, in vivo tumor assay\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay demonstrate direct E3-substrate relationship, in vivo confirmation, single lab\",\n      \"pmids\": [\"30710319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WWP2 (WW domain-containing E3 ubiquitin ligase 2) interacts with LATS1 and promotes its ubiquitination and subsequent proteasomal degradation, leading to increased YAP1 transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, cycloheximide chase, in vivo ubiquitination assay, xenograft model\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vivo ubiquitination plus protein stability assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36803368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LATS1 is acetylated by acetyltransferase CBP at K751 and deacetylated by SIRT3 and SIRT4. Acetylation at K751 stabilizes LATS1 (by reducing ubiquitination) but inhibits its kinase activation (by reducing phosphorylation), resulting in reduced YAP phosphorylation and increased YAP nuclear translocation. K751Q (acetylation mimic) promotes lung cancer cell migration/invasion; K751R (acetylation-deficient) inhibits these functions.\",\n      \"method\": \"Site-directed mutagenesis, in vitro acetyltransferase assay, co-immunoprecipitation, ubiquitination assay, phosphorylation assay, functional cancer cell assays\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of acetylation site with functional validation, writer/eraser identified, single lab\",\n      \"pmids\": [\"33945069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Drosophila wing imaginal discs, Warts (LATS) is organized into distinct junctional complexes separate from Hippo, Salvador, and Expanded. Upon Hippo pathway activation, Warts shifts from associating with its inhibitor Jub to its activator Expanded, and Hippo concentrates at Salvador sites. Warts activation occurs specifically at apical junctions where Expanded, Salvador, Hippo, and Warts overlap, as shown by phospho-specific antisera.\",\n      \"method\": \"Live imaging, phospho-specific antisera, genetic manipulation (Drosophila), fractionation/localization analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-specific antisera directly demonstrates activation site in vivo, genetic manipulations define localization requirements, multiple orthogonal approaches\",\n      \"pmids\": [\"26420589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAP4K4 (mammalian homolog of Drosophila Misshapen) interacts with LATS1 (Warts homolog) and promotes inhibition of YAP (Yorkie homolog) in mammalian cells, acting as an MST1/2-independent activator of LATS.\",\n      \"method\": \"Co-immunoprecipitation, epistasis analysis in Drosophila and mammalian cells, YAP phosphorylation assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing direct interaction, functional epistasis in both fly and mammalian systems, single lab\",\n      \"pmids\": [\"25453828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LATS1 physically interacts with and regulates the stability of Cdc25B phosphatase. Loss of LATS1 causes abnormal accumulation of Cdc25B protein and hyperactivation of Cdk2 toward nucleophosmin (NPM/B23), suppressing centrosome overduplication. LATS1 does not directly phosphorylate Cdc25B.\",\n      \"method\": \"Co-immunoprecipitation, Lats1 knockout MEFs, centrosome duplication assay, Cdk2 kinase assay, western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus knockout MEFs plus direct Cdk2 kinase assay, negative result (no direct phosphorylation) specified, single lab\",\n      \"pmids\": [\"26530630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LATS1/2 phosphorylate CHO1 at Ser716 in its F-actin-interacting region (absent in MKLP1 splice variant). Phosphorylated CHO1 localizes to centrosomes and midbody, and recruits LIMK1 as binding partner. Overexpression of constitutively phosphorylated or non-phosphorylated CHO1 alters LIMK1 mitotic localization/activation at centrosomes, inhibiting cytokinesis through excessive Cofilin phosphorylation and mislocalization of Ect2.\",\n      \"method\": \"In vitro kinase assay, phospho-specific localization, co-immunoprecipitation (LIMK1-CHO1), overexpression of phospho-mutants in HeLa cells\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay identifies substrate site, phospho-mutant overexpression reveals functional consequence, binding partner identified by co-IP, single lab\",\n      \"pmids\": [\"25786116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"lncRNA SNHG9 and its associated phosphatidic acids interact with the C-terminal domain of LATS1, promoting LATS1 liquid-liquid phase separation (LLPS). LATS1 phase separation inhibits LATS1-mediated YAP phosphorylation.\",\n      \"method\": \"RNA pull-down, co-immunoprecipitation, in vitro phase separation assay, YAP phosphorylation assay, domain mapping\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phase separation assay plus RNA pull-down with functional readout (YAP phosphorylation), single lab with multiple methods; note this is a lncRNA paper but the mechanistic claim is about LATS1 protein behavior\",\n      \"pmids\": [\"34267352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Gα13 activation induces phosphorylation of LATS1 at serine 909 (activation loop), which recruits ITCH E3 ubiquitin ligase to trigger LATS1 proteasomal degradation, thereby promoting EMT in ovarian cancer.\",\n      \"method\": \"Chimeric G-protein/mutant GPCR synthetic biology, co-immunoprecipitation, ubiquitination assay, phospho-LATS1 S909 western blot\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism-of-action defined using chimeric G-protein approach plus co-IP and ubiquitination assay, single lab\",\n      \"pmids\": [\"31569999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3 methylates LATS1 mRNA at m6A sites; YTHDF2 recognizes these m6A modifications and reduces LATS1 mRNA stability, thereby decreasing LATS1 protein levels and activating YAP/TAZ in the Hippo pathway.\",\n      \"method\": \"MeRIP-seq, RNA pull-down assay, RIP-qPCR, RNA stability analysis, METTL3/YTHDF2 knockout\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq identifies methylation sites, pull-down confirms reader-mRNA interaction, RNA stability measured, single lab\",\n      \"pmids\": [\"36609396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HPV18 E7 degrades PTPN14, which results in decreased phosphorylation of LATS1 at T1079 and of YAP at S127, thereby inhibiting LATS1 kinase activity and activating YAP. PTPN14-dependent keratinocyte differentiation requires LATS kinases and certain PPxY motifs in PTPN14, but not MST1/2 or PTPN14 phosphatase active site.\",\n      \"method\": \"PTPN14 knockout, phospho-specific antibodies (LATS1 T1079, YAP S127), site-directed mutagenesis (PPxY motifs), keratinocyte differentiation assay\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-specific readouts confirm LATS1 activity change, genetic knockout and mutagenesis of PPxY motifs, single lab\",\n      \"pmids\": [\"39248565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM65 promotes ubiquitination and proteasomal degradation of LATS1 in triple-negative breast cancer cells, promoting cell invasion and migration.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase, endogenous ubiquitination assay, rescue experiments\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP plus ubiquitination assay, single lab, single method quality for each mechanistic claim\",\n      \"pmids\": [\"36035221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Lats1/2-null intestinal epithelium, nuclear YAP/TAZ interact with Groucho/TLE to block Wnt/TCF-mediated transcription, inhibiting Wnt pathway activity. This YAP/TAZ-mediated Wnt inhibition is TEAD-independent.\",\n      \"method\": \"Conditional Lats1/2 knockout mice, chemical TEAD inhibitor, proteomics, nuclear co-immunoprecipitation of YAP/TAZ with TLE\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO combined with chemical tool and proteomic approach, co-IP of YAP/TAZ-TLE interaction, single lab\",\n      \"pmids\": [\"32259481\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LATS1 is a Ser/Thr kinase (NDR/LATS subfamily of AGC kinases) that functions as the central effector kinase of the Hippo tumor suppressor pathway: it is activated by MST1/2 (via direct phosphorylation of S909 and T1079) through scaffolding by WWC proteins and SAV1, and it phosphorylates YAP/TAZ to sequester them in the cytoplasm; beyond this canonical role, LATS1 phosphorylates additional substrates including MYPT1 (antagonizing PLK1 at the G2 DNA-damage checkpoint), MTF1 (attenuating heavy-metal responses), STAT1-Ser727 (promoting MHC-I expression and IFN-γ signaling), FOXL2 (regulating granulosa cell differentiation), and CHO1 (controlling cytokinesis via LIMK1); LATS1 protein stability is controlled by multiple E3 ubiquitin ligases (SPOP/Cullin3, NEDD4 recruited by PMEPA1a, HERC4, WWP2, TRIM65, ITCH recruited upon Gα13 activation) and is also regulated by CBP-mediated acetylation at K751 (writer) and SIRT3/4 (erasers), as well as by METTL3/YTHDF2-dependent m6A destabilization of its mRNA; additionally, LATS1 exerts a kinase-independent scaffolding function to stabilize Beclin-1 via K27-linked ubiquitination and suppress autophagy, and acts as a signal transducer downstream of the IFN-I receptor IFNAR2 via Tyk2-mediated tyrosine phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LATS1 is a Ser/Thr kinase that serves as the central effector of the Hippo tumor-suppressor pathway, a module first defined genetically in Drosophila where Warts (LATS) acts downstream of Hippo and Salvador to restrain proliferation and promote apoptosis [#2]. In its canonical role, LATS1 directly binds and phosphorylates YAP, sequestering this oncoprotein in the cytoplasm and inactivating its transcriptional output [#0]. LATS1 is itself switched on by upstream kinases: MST2 phosphorylates the activation-loop site S909 and the hydrophobic-motif site T1079 [#1], a step organized by WWC proteins and SAV1 that recruit MST1/2 to LATS [#6], with additional MST-independent activators including the Kibra–PTPN14 axis [#7] and MAP4K4 [#22]; PARD3-directed PP1A dephosphorylation provides an off-switch [#8]. Beyond YAP, LATS1 phosphorylates a diverse substrate set linking it to genome integrity and immunity: MYPT1-Ser445 to antagonize PLK1 at the G2 DNA-damage checkpoint [#5], MTF1 to attenuate heavy-metal responses in a zinc-gated feedback loop [#13], STAT1-Ser727 to drive IRF1/NLRC5-dependent MHC-I expression [#15], FOXL2 to control granulosa-cell differentiation [#9], and CHO1 to govern cytokinesis through LIMK1 [#24]. LATS1 also exerts YAP/TAZ-independent functions, including kinase-independent scaffolding that stabilizes Beclin-1 via K27-linked ubiquitination to suppress autophagy [#12] and signal transduction downstream of the type I interferon receptor IFNAR2 via Tyk2-mediated tyrosine phosphorylation [#14]. LATS1 abundance is tightly set by numerous E3 ubiquitin ligases that drive its proteasomal degradation—SPOP/Cullin3 [#16], NEDD4 recruited by PMEPA1a [#17], HERC4 [#18], WWP2 [#19], and ITCH recruited upon Gα13 activation [#26]—as well as by CBP-mediated acetylation at K751 [#20] and METTL3/YTHDF2-dependent m6A destabilization of its mRNA [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the genetic architecture placing LATS/Warts within a defined kinase module, answering how an upstream growth-control signal is relayed to proliferation and apoptosis decisions.\",\n      \"evidence\": \"Genetic epistasis and co-immunoprecipitation in Drosophila mutants\",\n      \"pmids\": [\"14502294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the LATS substrate executing growth control\", \"Mammalian relevance not yet demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that LATS1 catalytic activity drives cell-cycle arrest and apoptosis, defining it functionally as a tumor suppressor rather than a passive scaffold.\",\n      \"evidence\": \"Adenoviral overexpression with kinase-dead mutant, cell-cycle and xenograft assays in cancer cells\",\n      \"pmids\": [\"11850843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrate for these effects not identified\", \"CDC2 association mechanism not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the upstream activation mechanism by identifying the two regulatory phosphosites through which MST2 turns LATS1 on.\",\n      \"evidence\": \"In vitro kinase assay with mass-spectrometry mapping of S909 and T1079, deletion analysis\",\n      \"pmids\": [\"15688006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Scaffolding requirements for the MST2-LATS1 reaction not addressed\", \"Did not link activation to a downstream output\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked LATS1 to mitotic exit via MOB1A, connecting the kinase to control of cell division timing.\",\n      \"evidence\": \"Reciprocal co-IP plus siRNA and overexpression with microtubule poisons and live-cell analysis\",\n      \"pmids\": [\"16061636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of MOB1A-dependent mitotic exit unresolved\", \"No substrate identified for this function\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the central canonical substrate, showing LATS1 directly phosphorylates YAP to drive its cytoplasmic sequestration and a substrate consensus motif.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, subcellular fractionation and microarray\",\n      \"pmids\": [\"18158288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not enumerate non-YAP substrates\", \"Physiological contexts of YAP control not delineated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the LATS1 substrate repertoire to transcription-factor control, phosphorylating FOXL2 in granulosa-cell differentiation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, in vitro kinase assay and promoter reporter with kinase-dead controls in mouse ovary context\",\n      \"pmids\": [\"20407010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite on FOXL2 not precisely mapped\", \"In vivo gonadal requirement not genetically tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected LATS1 to the DNA-damage checkpoint by identifying MYPT1-Ser445 phosphorylation as the means to antagonize PLK1.\",\n      \"evidence\": \"Phosphoproteomics, in vitro kinase assay, phospho-specific antibodies and LATS1-knockout fibroblasts\",\n      \"pmids\": [\"22641346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration with canonical Hippo signaling not addressed\", \"Upstream activation of LATS1 in this context unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed MST-independent LATS1 activation, with Kibra-PTPN14 and MAP4K4 each able to engage and activate the kinase.\",\n      \"evidence\": \"Co-IP, domain mapping, LATS1 kinase assays and Drosophila/mammalian epistasis\",\n      \"pmids\": [\"25023289\", \"25453828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution versus MST pathway in vivo unquantified\", \"How these inputs converge on the activation loop not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined inhibitory and localization controls of LATS1 activity, including PARD3-PP1A dephosphorylation and junctional activation sites, plus new mitotic substrates and stability targets.\",\n      \"evidence\": \"Co-IP, phosphatase and kinase assays, phospho-specific antisera and live imaging across mammalian and Drosophila systems\",\n      \"pmids\": [\"26116754\", \"26420589\", \"26530630\", \"25786116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Spatial coordination of activation versus inactivation not unified\", \"Cdc25B regulation occurs without direct phosphorylation, mechanism incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that LATS1/2 loss reshapes anti-tumor immunity through nucleic-acid-rich extracellular vesicles, expanding LATS function beyond cell-autonomous growth control.\",\n      \"evidence\": \"Syngeneic mouse tumor models with genetic deletion, EV characterization and immune-depletion experiments\",\n      \"pmids\": [\"27912060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase-substrate basis of EV phenotype not defined\", \"Whether effect depends on LATS catalytic activity unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered a YAP/TAZ-independent role: LATS-dependent ERα degradation, broadening the non-canonical reach of the pathway.\",\n      \"evidence\": \"shRNA screen in primary breast epithelial cells, co-IP, ubiquitination and proteasome-inhibition assays identifying DCAF1\",\n      \"pmids\": [\"28068668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic role of LATS in this degradation not defined\", \"Generalizability beyond breast cells untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a kinase-independent scaffolding function of LATS1, stabilizing Beclin-1 by K27-linked ubiquitination to suppress autophagy.\",\n      \"evidence\": \"Knockout/knockdown, in vitro ubiquitination with site mutagenesis and kinase-dead controls in hepatocellular carcinoma cells\",\n      \"pmids\": [\"31848340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ubiquitin ligase recruited by LATS1 not identified\", \"Distinction from LATS2 mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established LATS1 protein abundance as a heavily regulated node, with multiple E3 ligases and degron-dependent inputs controlling its half-life.\",\n      \"evidence\": \"Co-IP, ubiquitination and cycloheximide-chase assays defining HERC4, PMEPA1a-NEDD4, and Gα13-recruited ITCH\",\n      \"pmids\": [\"30710319\", \"31605013\", \"31569999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy and context-specificity among ligases unresolved\", \"Endogenous physiological triggers not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed downstream consequences of LATS1/2 loss in tissue, including TEAD-independent YAP/TAZ-TLE inhibition of Wnt signaling and SPOP/Cullin3-mediated LATS1 turnover.\",\n      \"evidence\": \"Conditional knockout mice, TEAD-inhibitor and proteomics; co-IP and stability assays in kidney cancer cells\",\n      \"pmids\": [\"32259481\", \"32460168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue specificity of these effects not generalized\", \"Crosstalk with canonical TEAD output not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified post-translational and biophysical tuning of LATS1, with K751 acetylation balancing stability against activity and lncRNA-driven phase separation suppressing YAP phosphorylation.\",\n      \"evidence\": \"Acetyltransferase and phase-separation assays, site mutagenesis, ubiquitination and YAP-phosphorylation readouts\",\n      \"pmids\": [\"33945069\", \"34267352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological stimuli driving acetylation/phase separation unclear\", \"Single-lab findings for each mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded LATS1 into innate immunity and stress sensing, signaling downstream of IFNAR2 via Tyk2 and gating MHC-I and heavy-metal responses through STAT1-Ser727 and MTF1.\",\n      \"evidence\": \"Co-IP, sequential phosphorylation cascades, in vitro kinase assays, zinc-binding assays and knockout cells with in vivo confirmation\",\n      \"pmids\": [\"35394840\", \"38383447\", \"35027733\", \"35429439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tyrosine-phosphorylation step is non-canonical and mechanistically distinct from Ser/Thr activation\", \"Integration of these branches with Hippo signaling not unified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added mRNA-level and ligase-level control of LATS1, via METTL3/YTHDF2 m6A destabilization and WWP2-mediated degradation, each activating YAP.\",\n      \"evidence\": \"MeRIP-seq, RIP-qPCR, RNA-stability analysis; co-IP and in vivo ubiquitination assays\",\n      \"pmids\": [\"36609396\", \"36803368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conditions selecting mRNA versus protein control not defined\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed viral subversion of LATS1 activation, with HPV18 E7 degrading PTPN14 to lower LATS1 T1079 phosphorylation and de-repress YAP.\",\n      \"evidence\": \"PTPN14 knockout, phospho-specific antibodies, PPxY-motif mutagenesis and keratinocyte differentiation assays\",\n      \"pmids\": [\"39248565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MST-independence versus dependence in keratinocytes only partially resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LATS1's many non-canonical branches—autophagy scaffolding, interferon and metal-stress signaling, immune-vesicle output—are coordinated with its canonical YAP-suppressing kinase activity within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking kinase-dependent and kinase-independent functions\", \"Context determinants selecting among substrates unknown\", \"Structural basis of differential substrate recognition uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 5, 9, 13, 15, 24]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 5, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [24, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 1, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 23, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 14, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 17, 18, 19, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YAP1\", \"MST2\", \"MOB1A\", \"SAV1\", \"WWC1\", \"PTPN14\", \"MAP4K4\", \"IFNAR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}