{"gene":"SAV1","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2002,"finding":"Salvador (SAV1/WW45) contains two WW domains and directly binds to the Warts (LATS) protein kinase, promoting both cell cycle exit and apoptosis in Drosophila; loss of sav results in elevated Cyclin E and DIAP1 levels.","method":"Genetic loss-of-function screen, co-immunoprecipitation/binding assay, in vivo phenotypic analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — founding paper with genetic LOF, binding assay, and phenotypic readouts; independently replicated by multiple labs in subsequent years","pmids":["12202036"],"is_preprint":false},{"year":2003,"finding":"Hippo (Drosophila MST1/2 ortholog) binds to a regulatory domain of Salvador (Sav) through its SARAH domain; this interaction is essential for Hippo kinase function and for the Hpo-Sav-Wts signaling module that coordinately regulates cell proliferation and apoptosis.","method":"Co-immunoprecipitation, genetic epistasis, dominant-negative and gain-of-function experiments in Drosophila","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interaction confirmed, genetic epistasis established, replicated across two independent labs in same year (PMID 14502294 and 14502295)","pmids":["14502294","14502295"],"is_preprint":false},{"year":2003,"finding":"Hippo (Drosophila MST1/2) phosphorylates DIAP1 in a Hpo-dependent manner in S2 cells and can phosphorylate DIAP1 in vitro; Sav is an unstable protein that is stabilized by Hpo binding.","method":"In vitro kinase assay, S2 cell phosphorylation assay, co-expression stabilization experiments","journal":"Nature Cell Biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus cell-based phosphorylation, single lab","pmids":["14502295"],"is_preprint":false},{"year":2003,"finding":"Hippo (Hpo) kinase phosphorylates Salvador (Sav) directly; hpo, sav, and wts define a genetic pathway that regulates diap1 at the transcriptional level; human MST2 (hpo homolog) completely rescues Drosophila hpo mutant overgrowth.","method":"In vitro kinase assay, genetic epistasis, cross-species rescue experiment","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct phosphorylation assay, genetic epistasis, and cross-species functional conservation shown","pmids":["12941273"],"is_preprint":false},{"year":2007,"finding":"RASSF1A, MST2, WW45 (SAV1), and LATS1 form a complex in human cells; MST2 enhances the RASSF1A-WW45 interaction, which requires the C-terminal SARAH domain of both proteins; the complex localizes to centrosomes and spindle poles through mitosis and to the midbody during cytokinesis; RASSF1A and WW45 activate MST2 by promoting MST2 autophosphorylation and LATS1 phosphorylation.","method":"Co-immunoprecipitation, immunofluorescence/subcellular localization, in vitro kinase assay, domain-deletion mapping","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP, functional kinase assays, localization studies, and domain mutagenesis in one study","pmids":["17379520"],"is_preprint":false},{"year":2008,"finding":"WW45 (SAV1) is required for MST1 activation and its translocation to the nucleus upon differentiation signal in mouse epithelial cells; WW45 mediates LATS1/2 activation downstream of MST1, leading to YAP phosphorylation and cytoplasmic translocation, resulting in cell-cycle exit and terminal differentiation of epithelial progenitors.","method":"Conditional knockout mice, immunofluorescence, immunoprecipitation, western blot for pathway activation","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular phenotype, pathway dissection with multiple orthogonal readouts","pmids":["18369314"],"is_preprint":false},{"year":2009,"finding":"Human WW45 (hSAV1) physically associates with MST1 (confirmed by co-immunoprecipitation and co-localization); hWW45 is present in both cytoplasm and nucleus; hWW45 enhances MST1-induced apoptosis when co-expressed, and siRNA depletion of hWW45 suppresses MST1-induced apoptosis.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown with apoptosis readout","journal":"International Journal of Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple methods (Y2H, Co-IP, localization, RNAi phenotype) in single lab","pmids":["19212654"],"is_preprint":false},{"year":2010,"finding":"Liver-specific ablation of WW45 (SAV1) in mice leads to increased liver size, expansion of hepatic oval cells, and eventual hepatoma; WW45 loss increases YAP abundance and promotes its nuclear localization specifically in oval cells, driving their proliferation.","method":"Liver-specific conditional knockout mice, immunofluorescence, immunohistochemistry, western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic KO with mechanistic pathway dissection (YAP nuclear localization) and tumor phenotype","pmids":["20404163"],"is_preprint":false},{"year":2011,"finding":"SAV1 (Salvador) promotes apoptosis in human cells and interacts with RASSF1A; RASSF1A requires Salvador for full apoptotic activity and to activate p73; this effect does not require direct MST kinase activation or canonical Hippo pathway signaling, indicating SAV1 has Hippo pathway-independent functions.","method":"Co-immunoprecipitation, siRNA knockdown, apoptosis assays, cell cycle analysis, transformation assays","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional assays in human cells; single lab","pmids":["21489991"],"is_preprint":false},{"year":2011,"finding":"MST2-mediated phosphorylation of SAV1 at Thr-26, Ser-27, Ser-36, and Ser-269 promotes cell death; mutation of all four residues (SAV1-4A) weakens SAV1 interaction with MST2, reduces SAV1 self-dimerization, and inhibits MST2- and K-RasG12V-induced cell death.","method":"Mass spectrometric phosphorylation mapping, site-directed mutagenesis, co-immunoprecipitation, cell death assays","journal":"BMB Reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS-based phospho-mapping plus mutagenesis with functional readout; single lab","pmids":["21944251"],"is_preprint":false},{"year":2012,"finding":"MST2 stimulates binding of SAV1 to PPARγ via the WW domains of SAV1 and PPYY motif of PPARγ; SAV1 stabilizes PPARγ protein and increases PPARγ transactivation; SAV1 knockdown decreases PPARγ levels in 3T3-L1 adipocytes and impairs adipocyte differentiation.","method":"Co-immunoprecipitation, domain deletion/mutation analysis, siRNA knockdown, luciferase reporter assay, western blot","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — binding domain mapped, functional readout (adipogenesis), multiple methods; single lab","pmids":["22292086"],"is_preprint":false},{"year":2013,"finding":"Par-1 kinase physically interacts with both Hippo (Hpo) and Salvador (Sav) in Drosophila; Par-1 phosphorylates Hpo at Ser30, restricting its activity; Par-1 inhibits Hpo-Sav association, resulting in Sav dephosphorylation and destabilization; this regulation is conserved in mammalian cells.","method":"Co-immunoprecipitation, in vitro kinase assay, genetic epistasis, gain/loss-of-function in Drosophila, mammalian cell validation","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct kinase assay, co-IP of interaction, genetic epistasis, cross-species validation","pmids":["23940457"],"is_preprint":false},{"year":2014,"finding":"The MST1/2-SAV1 complex promotes ciliogenesis: MST1 activates during ciliogenesis and localizes to the basal body; MST1/2 binds and phosphorylates Aurora kinase A (AURKA), leading to dissociation of the AURKA/HDAC6 cilia-disassembly complex; MST1/2-SAV1 also associates with the NPHP transition-zone complex promoting ciliary cargo localization; depletion of MST1/2 or SAV1 impairs ciliogenesis in cultured cells and zebrafish.","method":"Co-immunoprecipitation, in vitro kinase assay, immunofluorescence/subcellular localization, siRNA knockdown, zebrafish morpholino knockdown","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, Co-IP, localization, LOF in two systems (cells + zebrafish), multiple orthogonal methods","pmids":["25367221"],"is_preprint":false},{"year":2015,"finding":"In Drosophila, Hippo kinase stabilizes its adaptor Salvador by antagonizing the HECT ubiquitin ligase Herc4; Herc4 promotes Salvador ubiquitylation and degradation; Hippo reduces Salvador/Herc4 interaction in a kinase-dependent manner, creating a positive feedback loop.","method":"RNAi screen, co-immunoprecipitation, ubiquitylation assay, genetic interaction","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitylation assay, Co-IP, RNAi phenotypes; single lab, Drosophila system","pmids":["26125558"],"is_preprint":false},{"year":2016,"finding":"WW45 (SAV1) interacts with Gli1; WW45 promotes Gli1 ubiquitination and inhibits expression of Gli1 target genes, thereby negatively regulating Hedgehog signaling in lung cancer cells independently of canonical Hippo pathway activity.","method":"Mass spectrometry (binding partner identification), co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, siRNA and overexpression functional studies","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MS-identified interaction, Co-IP, functional ubiquitination data; single lab","pmids":["27661123"],"is_preprint":false},{"year":2017,"finding":"SAV1 promotes MST1/2 activation by directly binding to and inhibiting the PP2A complex STRIPAK(SLMAP), protecting MST2 activation-loop phosphorylation; SAV1 and MST2 heterodimerize through their SARAH domains; two SAV1-MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer enabling MST2 trans-autophosphorylation; SLMAP binds autophosphorylated MST2 linker, recruits STRIPAK, and promotes PP2A-mediated dephosphorylation of MST2 activation loop; genetic ablation of SLMAP in human cells leads to spontaneous Hippo pathway activation and alleviates the need for SAV1.","method":"Crystal structure, biochemical reconstitution, in vitro phosphatase assay, co-immunoprecipitation, CRISPR/Cas9 knockout, mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, in vitro reconstitution with mutagenesis, genetic KO validation; multiple orthogonal methods in one rigorous study","pmids":["29063833"],"is_preprint":false},{"year":2017,"finding":"Tubular epithelial cell-specific deletion of Sav1 in mice leads to tubulointerstitial fibrosis; Sav1 depletion increases TGF-β and activates β-catenin; TAZ (downstream Hippo effector) is significantly activated in Sav1-knockout mice; in vitro, TAZ directly regulates TGF-β and TGF-β receptor II expression.","method":"Conditional knockout mice, western blot, luciferase reporter assay, siRNA knockdown, in vivo fibrosis model (UUO)","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with pathway dissection, in vitro mechanistic follow-up; single lab","pmids":["27550469"],"is_preprint":false},{"year":2017,"finding":"Sav1 loss in mouse renal epithelium induces Stat3 activation and a senescence-associated secretory phenotype (SASP) coinciding with tubulointerstitial fibrosis; YAP inhibition with verteporfin inhibits senescence, SASP, and Stat3 activation downstream of Sav1 loss.","method":"Conditional knockout mice, western blot, pharmacological inhibition (verteporfin), gene expression analysis","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with pharmacological rescue, pathway placement; single lab","pmids":["28320873"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of Drosophila Salvador (Sav) and Hippo (Hpo) SARAH domains in complex reveals that Salvador SARAH domain has a folded N-terminal extension that expands the binding interface with Hpo and is unique to Salvador; this extension enhances binding affinity and is required for proper Hippo kinase modulation; Salvador/Sav SARAH domain interaction with Hippo/Hpo is mutually exclusive with dRassF/Hippo SARAH domain interaction; human Salvador increases MST2 autophosphorylation in cells, but isolated Salvador SARAH domain inhibits MST2 autophosphorylation in vitro.","method":"X-ray crystallography, cross-linked mass spectrometry, co-transfection with western blot, in vitro kinase assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determined and validated by cross-linked MS; in vitro kinase assay; single lab","pmids":["29519817"],"is_preprint":false},{"year":2019,"finding":"SAV1 inhibits Akt activation independently of its Hippo pathway role by binding to a proline-tyrosine motif in the Akt-PH domain, blocking Akt movement to the plasma membrane; MERTK phosphorylates Akt1 at Y26, releasing SAV1 binding and enabling Akt plasma membrane recruitment and activation; cancer-associated SAV1 mutations impair SAV1-Akt binding leading to Akt hyperactivation.","method":"Co-immunoprecipitation, domain mapping, phospho-specific western blot, subcellular fractionation/localization, site-directed mutagenesis, cancer mutation analysis","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding domain mapped, localization experiment, mutation analysis; single lab","pmids":["30944303"],"is_preprint":false},{"year":2020,"finding":"The GCKIII kinase STK25 (a STRIPAK component) directly phosphorylates SAV1 and diminishes SAV1's ability to inhibit STRIPAK, thereby promoting STRIPAK-mediated inhibition of MST2; depletion of STK25 enhances MST2 activation without affecting STRIPAK(SLMAP) integrity, establishing a mutual antagonism between STRIPAK and SAV1 that controls Hippo pathway initiation.","method":"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, western blot for MST2 phosphorylation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay demonstrates direct phosphorylation, siRNA with biochemical readout, mechanistically extends prior structural study (PMID 29063833); single lab","pmids":["32292165"],"is_preprint":false},{"year":2020,"finding":"SAV1 WW tandem with its short Pro-rich extension (WW12ex) forms a domain-swapped homodimer; the crystal structure reveals that the Pro-rich extension of one subunit binds to both WW domains of the other subunit; SAV1 WW12ex-mediated dimerization is required for MST/SAV1 complex assembly and MST kinase activation; several cancer-related SAV1 variants disrupt dimer formation.","method":"X-ray crystallography, biochemical binding assays, mutagenesis, co-immunoprecipitation, kinase activation assay","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis validation and functional kinase assay; single rigorous study","pmids":["32905778"],"is_preprint":false},{"year":2022,"finding":"The cell adhesion molecule KIRREL1 physically interacts with SAV1 and recruits SAV1 to cell-cell contact sites; KIRREL1 knockout increases YAP activity in neighboring cells; in mouse liver regeneration, KIRREL1 upregulation enhances Hippo signaling and its ablation increases hepatic YAP activity.","method":"Co-immunoprecipitation, live-cell imaging/localization, CRISPR/KO, YAP reporter assay, mouse liver regeneration model","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, localization to cell-cell contacts, genetic KO with pathway readout; single lab","pmids":["35177623"],"is_preprint":false},{"year":2023,"finding":"GRK2 phosphorylates, ubiquitinates, and promotes degradation of SAV1 in fibroblast-like synoviocytes (FLSs); GRK2 is upregulated by GPCR agonists such as prostaglandin E2 (PGE2) in rheumatoid arthritis; SAV1 degradation by GRK2 leads to decreased YAP phosphorylation, nuclear YAP accumulation, and aberrant FLS proliferation; GRK2 depletion or inhibition with paroxetine rescues SAV1 expression and YAP phosphorylation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pharmacological inhibition (paroxetine), western blot, in vivo rat arthritis model","journal":"Acta Pharmaceutica Sinica B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic and pharmacological LOF with defined molecular and cellular readouts; single lab","pmids":["38486990"],"is_preprint":false}],"current_model":"SAV1 (WW45/Salvador) is a scaffold/adaptor protein that promotes Hippo pathway activation through multiple mechanisms: its WW tandem domain-swapped homodimer assembles an MST1/2-SAV1 heterotetramer enabling MST trans-autophosphorylation; SAV1 directly inhibits the PP2A complex STRIPAK(SLMAP)—which otherwise dephosphorylates the MST activation loop—thereby protecting MST kinase activity; the STK25 kinase (a STRIPAK component) counters SAV1 by phosphorylating it, creating a mutual antagonism that gates Hippo initiation; SAV1 also heterodimerizes with MST1/2 via their SARAH domains (with SAV1 harboring a unique N-terminal SARAH extension that expands the interface) and is stabilized by this interaction through antagonism of the HECT ubiquitin ligase Herc4/HERC4; downstream, SAV1-mediated MST activation leads to LATS1/2-dependent YAP/TAZ phosphorylation and cytoplasmic sequestration, enforcing cell-cycle exit and apoptosis; additionally, SAV1 has Hippo-independent roles including suppression of Akt activation (by blocking Akt PH-domain membrane recruitment), inhibition of Hedgehog/Gli1 signaling (by promoting Gli1 ubiquitination), and interaction with PPARγ to regulate adipogenesis; the cell-adhesion molecule KIRREL1 recruits SAV1 to cell-cell contact sites as a feedback mechanism; and SAV1 protein stability is regulated by phosphorylation (by MST, GRK2, STK25), ubiquitination, and m6A-mediated mRNA regulation."},"narrative":{"mechanistic_narrative":"SAV1 (WW45/Salvador) is a scaffold/adaptor protein that activates the Hippo tumor-suppressor pathway to enforce cell-cycle exit, apoptosis, and terminal differentiation, restraining tissue overgrowth [PMID:12202036, PMID:18369314, PMID:20404163]. It was first defined genetically in Drosophila as a two-WW-domain protein that binds the Warts (LATS) kinase, and loss of Salvador elevates Cyclin E and the apoptosis inhibitor DIAP1 [PMID:12202036]. SAV1 functions within a Hippo (MST1/2)–Salvador–Warts (LATS) module: MST/Hippo binds a regulatory region of SAV1 through their SARAH domains, an interaction required for kinase function [PMID:14502294, PMID:14502295, PMID:29519817], and structural work shows the SAV1 SARAH domain carries a unique folded N-terminal extension that expands the MST interface [PMID:29519817]. SAV1 promotes MST activation by multiple mechanisms — a domain-swapped WW-tandem homodimer assembles an MST–SAV1 heterotetramer enabling MST trans-autophosphorylation [PMID:32905778], and SAV1 directly binds and inhibits the PP2A-containing STRIPAK(SLMAP) complex that would otherwise dephosphorylate the MST activation loop [PMID:29063833]. This protection is reciprocally antagonized by the STRIPAK kinase STK25, which phosphorylates SAV1 and blocks its inhibition of STRIPAK, gating Hippo initiation [PMID:32292165]. SAV1-mediated MST activation drives LATS1/2-dependent YAP/TAZ phosphorylation and cytoplasmic sequestration; genetic ablation of SAV1 in mouse liver and kidney elevates nuclear YAP/TAZ and causes overgrowth, hepatoma, fibrosis, and senescence-associated phenotypes [PMID:18369314, PMID:20404163, PMID:27550469, PMID:28320873]. SAV1 is an unstable protein stabilized by MST binding and by antagonism of the HECT ligase Herc4/HERC4, and its levels are further controlled by phosphorylation-coupled degradation via GRK2 [PMID:14502295, PMID:26125558, PMID:38486990]. Beyond Hippo, SAV1 has independent roles: it blocks Akt membrane recruitment by binding the Akt PH domain [PMID:30944303], promotes Gli1 ubiquitination to suppress Hedgehog signaling [PMID:27661123], stabilizes PPARγ to support adipogenesis [PMID:22292086], and with MST1/2 promotes ciliogenesis [PMID:25367221]. The adhesion molecule KIRREL1 recruits SAV1 to cell-cell contacts as a feedback input to Hippo signaling [PMID:35177623].","teleology":[{"year":2002,"claim":"Established SAV1/Salvador as a growth-suppressing adaptor by showing it binds the Warts/LATS kinase and that its loss drives proliferation and blocks apoptosis, defining the founding genetic role.","evidence":"Genetic loss-of-function screen with binding assays and in vivo phenotypes in Drosophila","pmids":["12202036"],"confidence":"High","gaps":["Did not define how Salvador couples to upstream kinases","Mammalian function not yet addressed"]},{"year":2003,"claim":"Placed Salvador in a Hippo–Salvador–Warts module by showing MST/Hippo binds Salvador via SARAH domains and directly phosphorylates it, and that Salvador is an unstable protein stabilized by Hippo binding.","evidence":"Co-IP, SARAH-domain mapping, in vitro kinase assays, genetic epistasis, and cross-species rescue in Drosophila/human cells","pmids":["14502294","14502295","12941273"],"confidence":"High","gaps":["Structural basis of the SARAH interaction not resolved","Mechanism of Salvador instability not defined"]},{"year":2007,"claim":"Showed SAV1 acts within a higher-order MST2 activation complex in human cells, linking it to RASSF1A and LATS1 and to mitotic structures, and that it promotes MST2 autophosphorylation.","evidence":"Reciprocal Co-IP, immunofluorescence localization, in vitro kinase assays, and domain-deletion mapping in human cells","pmids":["17379520"],"confidence":"High","gaps":["Stoichiometry of the complex not resolved","Did not establish how SAV1 activates MST2 mechanistically"]},{"year":2008,"claim":"Defined the mammalian physiological output: SAV1 is required for MST1 activation and LATS1/2-dependent YAP phosphorylation, driving cell-cycle exit and terminal differentiation of epithelial progenitors.","evidence":"Conditional knockout mice with pathway readouts by IF, IP, and western blot","pmids":["18369314"],"confidence":"High","gaps":["Tissue-specific contributions not fully mapped","Did not address Hippo-independent functions"]},{"year":2010,"claim":"Demonstrated SAV1 is a tumor suppressor in vivo: liver-specific loss expands oval cells, elevates nuclear YAP, and produces hepatoma.","evidence":"Liver-specific conditional knockout mice with IHC, IF, and western blot","pmids":["20404163"],"confidence":"High","gaps":["Cell-of-origin for the tumors not fully defined","Did not test reversibility upon YAP inhibition"]},{"year":2011,"claim":"Identified Hippo-independent and self-association determinants: MST2 phosphorylates SAV1 at four residues controlling dimerization and cell death, and SAV1 supports RASSF1A/p73 apoptosis without canonical MST activation.","evidence":"MS phospho-mapping, mutagenesis, Co-IP, and apoptosis/cell-cycle assays in human cells","pmids":["21944251","21489991"],"confidence":"Medium","gaps":["Single-lab phospho-site assignments","Hippo-independent apoptotic mechanism not biochemically resolved"]},{"year":2012,"claim":"Extended SAV1 function beyond growth control by showing WW-domain-mediated binding to PPARγ stabilizes it and supports adipocyte differentiation.","evidence":"Co-IP, domain mapping, siRNA, luciferase reporter, and adipogenesis assays in 3T3-L1 cells","pmids":["22292086"],"confidence":"Medium","gaps":["In vivo relevance to adipogenesis not established","Single lab"]},{"year":2013,"claim":"Revealed upstream regulation of the Hippo-Salvador interaction: Par-1 phosphorylates Hippo and disrupts Hpo-Sav association, destabilizing Salvador.","evidence":"Co-IP, in vitro kinase assay, and genetic epistasis in Drosophila with mammalian validation","pmids":["23940457"],"confidence":"High","gaps":["Conditions selecting Par-1 regulation in mammals not defined"]},{"year":2014,"claim":"Connected the MST1/2-SAV1 complex to ciliogenesis via AURKA phosphorylation and NPHP transition-zone association, broadening SAV1's organelle-level roles.","evidence":"Co-IP, in vitro kinase assay, localization, and LOF in cultured cells and zebrafish","pmids":["25367221"],"confidence":"High","gaps":["SAV1's specific contribution versus MST1/2 not separated","Link to canonical Hippo output not addressed"]},{"year":2015,"claim":"Defined a positive-feedback stability mechanism: Hippo kinase antagonizes the HECT ligase Herc4, protecting Salvador from ubiquitin-dependent degradation.","evidence":"RNAi screen, Co-IP, ubiquitylation, and genetic interaction in Drosophila","pmids":["26125558"],"confidence":"Medium","gaps":["Human HERC4 regulation of SAV1 not directly tested","Single lab, Drosophila system"]},{"year":2016,"claim":"Showed a Hippo-independent suppressive role on Hedgehog signaling: SAV1 binds Gli1 and promotes its ubiquitination to repress Gli1 target genes.","evidence":"MS interaction ID, Co-IP, ubiquitination, reporter assays, and LOF/GOF in lung cancer cells","pmids":["27661123"],"confidence":"Medium","gaps":["E3 ligase mediating Gli1 ubiquitination not identified","Single lab"]},{"year":2017,"claim":"Provided the structural and biochemical mechanism of MST activation: a SAV1 SARAH heterodimer and WW-domain-driven heterotetramer enable MST2 trans-autophosphorylation, while SAV1 directly inhibits STRIPAK(SLMAP) to protect the MST2 activation loop.","evidence":"Crystal structure, reconstitution, phosphatase assay, Co-IP, CRISPR knockout, and mutagenesis","pmids":["29063833"],"confidence":"High","gaps":["How STRIPAK recruitment is dynamically regulated in cells not resolved at the time"]},{"year":2017,"claim":"Established disease relevance of SAV1 loss in kidney: epithelial Sav1 deletion activates TAZ, TGF-β, β-catenin, Stat3, senescence, and SASP, driving tubulointerstitial fibrosis.","evidence":"Conditional knockout mice, fibrosis model, reporter assays, siRNA, and verteporfin rescue","pmids":["27550469","28320873"],"confidence":"Medium","gaps":["Direct versus indirect transcriptional effects not fully separated","Single lab per study"]},{"year":2018,"claim":"Resolved the structural basis of the Salvador-Hippo SARAH interface, showing a unique Salvador N-terminal extension expands and strengthens the interaction and competes with RassF binding.","evidence":"X-ray crystallography, cross-linked MS, co-transfection western blot, and in vitro kinase assay","pmids":["29519817"],"confidence":"High","gaps":["Reconciliation of cellular activation with in vitro inhibition by isolated SARAH not resolved"]},{"year":2019,"claim":"Defined a Hippo-independent SAV1 function in PI3K/Akt control: SAV1 binds the Akt PH domain to block membrane recruitment, with MERTK-driven Akt phosphorylation releasing SAV1.","evidence":"Co-IP, domain mapping, phospho-westerns, fractionation, mutagenesis, and cancer-mutation analysis","pmids":["30944303"],"confidence":"Medium","gaps":["Structural basis of SAV1-PH binding not solved","Single lab"]},{"year":2020,"claim":"Established mutual antagonism gating Hippo initiation: STRIPAK kinase STK25 phosphorylates SAV1 to disable its STRIPAK inhibition, balancing MST2 activation.","evidence":"In vitro kinase assay, Co-IP, siRNA, and MST2 phospho-westerns extending the prior structural study","pmids":["32292165"],"confidence":"High","gaps":["SAV1 phospho-sites targeted by STK25 not fully mapped","Single lab"]},{"year":2020,"claim":"Defined the molecular architecture of SAV1 self-association: the WW-tandem plus Pro-rich extension forms a domain-swapped homodimer required for MST/SAV1 complex assembly and kinase activation, with cancer variants disrupting the dimer.","evidence":"X-ray crystallography, binding assays, mutagenesis, Co-IP, and kinase activation assay","pmids":["32905778"],"confidence":"High","gaps":["In vivo consequences of dimer-disrupting variants not tested"]},{"year":2022,"claim":"Identified a spatial feedback input: the adhesion molecule KIRREL1 recruits SAV1 to cell-cell contacts, restraining YAP in neighboring cells and modulating liver regeneration.","evidence":"Co-IP, live-cell imaging, CRISPR KO, YAP reporter, and mouse liver regeneration model","pmids":["35177623"],"confidence":"Medium","gaps":["How KIRREL1-bound SAV1 mechanistically engages MST not defined","Single lab"]},{"year":2023,"claim":"Linked GPCR signaling to SAV1 turnover: GRK2 phosphorylates, ubiquitinates, and degrades SAV1, releasing YAP in synoviocytes and contributing to rheumatoid arthritis pathology.","evidence":"Co-IP, ubiquitination assay, siRNA, paroxetine inhibition, and rat arthritis model","pmids":["38486990"],"confidence":"Medium","gaps":["GRK2 phospho-sites on SAV1 not mapped","E3 ligase coupling not identified"]},{"year":null,"claim":"How SAV1's multiple Hippo-independent activities (Akt, Hedgehog/Gli1, PPARγ, ciliogenesis) are coordinated with its core MST-activating scaffold function, and which inputs select among them, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying mechanism integrating Hippo and non-Hippo roles","Structural models for non-Hippo partner interactions lacking","Tissue-specific partner selection undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,17,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,20]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[12]}],"complexes":["MST1/2-SAV1 complex","RASSF1A-MST2-WW45-LATS1 complex","STRIPAK (as inhibitory target)"],"partners":["MST1","MST2","LATS1","RASSF1A","SLMAP","STK25","KIRREL1","GRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H4B6","full_name":"Protein salvador homolog 1","aliases":["45 kDa WW domain protein","hWW45"],"length_aa":383,"mass_kda":44.6,"function":"Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:29063833). 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. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. SAV1 is required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle exit and terminal differentiation in developing epithelial tissues. Plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/21944251","citation_count":18,"is_preprint":false},{"pmid":"32439835","id":"PMC_32439835","title":"Correction of the tumor suppressor Salvador homolog-1 deficiency in tumors by lycorine as a new strategy in lung cancer therapy.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32439835","citation_count":18,"is_preprint":false},{"pmid":"26474762","id":"PMC_26474762","title":"Factors affecting attendance to cervical cancer screening among women in the Paracentral Region of El Salvador: a nested study within the CAPE HPV screening program.","date":"2015","source":"BMC public health","url":"https://pubmed.ncbi.nlm.nih.gov/26474762","citation_count":18,"is_preprint":false},{"pmid":"30547835","id":"PMC_30547835","title":"Genetic variability of the Aedes aegypti (Diptera: Culicidae) mosquito in El Salvador, vector of dengue, yellow fever, chikungunya and Zika.","date":"2018","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/30547835","citation_count":18,"is_preprint":false},{"pmid":"30009135","id":"PMC_30009135","title":"Occurrence of Aflatoxin M1 in cow milk in El Salvador: Results from a two-year survey.","date":"2018","source":"Toxicology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30009135","citation_count":18,"is_preprint":false},{"pmid":"30681889","id":"PMC_30681889","title":"SAV1, regulated by microRNA-21, suppresses tumor growth in colorectal cancer.","date":"2019","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/30681889","citation_count":17,"is_preprint":false},{"pmid":"33517418","id":"PMC_33517418","title":"Emergence of MDR invasive Neisseria meningitidis in El Salvador, 2017-19.","date":"2021","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/33517418","citation_count":17,"is_preprint":false},{"pmid":"20058833","id":"PMC_20058833","title":"[Assessing the insecticide resistance of an Aedes aegypti strain in El Salvador].","date":"2009","source":"Revista panamericana de salud publica = Pan American journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/20058833","citation_count":17,"is_preprint":false},{"pmid":"22109110","id":"PMC_22109110","title":"Impact of depression on quality of life in people living with human T cell lymphotropic virus type 1 (HTLV-1) in Salvador, Brazil.","date":"2011","source":"Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation","url":"https://pubmed.ncbi.nlm.nih.gov/22109110","citation_count":17,"is_preprint":false},{"pmid":"19212654","id":"PMC_19212654","title":"The human WW45 protein enhances MST1-mediated apoptosis in vivo.","date":"2009","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19212654","citation_count":16,"is_preprint":false},{"pmid":"26254690","id":"PMC_26254690","title":"Hepatitis C virus infection and spontaneous clearance in HTLV-1 and HIV co-infected patients in Salvador, Bahia, Brazil.","date":"2015","source":"The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26254690","citation_count":16,"is_preprint":false},{"pmid":"31765712","id":"PMC_31765712","title":"The cost-effectiveness of human papillomavirus self-collection among cervical cancer screening non-attenders in El Salvador.","date":"2019","source":"Preventive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31765712","citation_count":16,"is_preprint":false},{"pmid":"21439700","id":"PMC_21439700","title":"Demand for sanitation in Salvador, Brazil: a hybrid choice approach.","date":"2011","source":"Social science & medicine (1982)","url":"https://pubmed.ncbi.nlm.nih.gov/21439700","citation_count":16,"is_preprint":false},{"pmid":"29267598","id":"PMC_29267598","title":"Association between seroprevalence of IgG anti-Toxoplasma gondii and risk factors for infection among pregnant women in Climério de Oliveira Maternity, Salvador, Bahia, Brazil.","date":"2017","source":"Revista do Instituto de Medicina Tropical de Sao Paulo","url":"https://pubmed.ncbi.nlm.nih.gov/29267598","citation_count":16,"is_preprint":false},{"pmid":"38486990","id":"PMC_38486990","title":"GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis.","date":"2023","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/38486990","citation_count":15,"is_preprint":false},{"pmid":"24710534","id":"PMC_24710534","title":"Effects of mTOR Inhibitors on Components of the Salvador-Warts-Hippo Pathway.","date":"2012","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/24710534","citation_count":15,"is_preprint":false},{"pmid":"16916590","id":"PMC_16916590","title":"The genetic male legacy from El Salvador.","date":"2006","source":"Forensic science international","url":"https://pubmed.ncbi.nlm.nih.gov/16916590","citation_count":15,"is_preprint":false},{"pmid":"14636481","id":"PMC_14636481","title":"Comparative study of hepatitis C virus genotypes 1 and 3 in Salvador, Bahia Brazil.","date":"2003","source":"The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/14636481","citation_count":15,"is_preprint":false},{"pmid":"27661123","id":"PMC_27661123","title":"WW45, a Gli1 binding protein, negatively regulated Hedgehog signaling in lung cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27661123","citation_count":14,"is_preprint":false},{"pmid":"32780197","id":"PMC_32780197","title":"RNA-binding protein Musashi2 regulates Hippo signaling via SAV1 and MOB1 in pancreatic cancer.","date":"2020","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32780197","citation_count":14,"is_preprint":false},{"pmid":"29519817","id":"PMC_29519817","title":"Salvador has an extended SARAH domain that mediates binding to Hippo kinase.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29519817","citation_count":14,"is_preprint":false},{"pmid":"28968962","id":"PMC_28968962","title":"Protein salvador homolog 1 acts as a tumor suppressor and is modulated by hypermethylation in pancreatic ductal adenocarcinoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28968962","citation_count":14,"is_preprint":false},{"pmid":"23782115","id":"PMC_23782115","title":"Transmitted drug-resistance in human immunodeficiency virus-infected adult population in El Salvador, Central America.","date":"2013","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23782115","citation_count":14,"is_preprint":false},{"pmid":"17187101","id":"PMC_17187101","title":"HIV-1 seroprevalence in the general population of Salvador, Bahia State, Northeast Brazil.","date":"2007","source":"Cadernos de saude publica","url":"https://pubmed.ncbi.nlm.nih.gov/17187101","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49358,"output_tokens":6223,"usd":0.120709,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15011,"output_tokens":5748,"usd":0.109378,"stage2_stop_reason":"end_turn"},"total_usd":0.230087,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Salvador (SAV1/WW45) contains two WW domains and directly binds to the Warts (LATS) protein kinase, promoting both cell cycle exit and apoptosis in Drosophila; loss of sav results in elevated Cyclin E and DIAP1 levels.\",\n      \"method\": \"Genetic loss-of-function screen, co-immunoprecipitation/binding assay, in vivo phenotypic analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — founding paper with genetic LOF, binding assay, and phenotypic readouts; independently replicated by multiple labs in subsequent years\",\n      \"pmids\": [\"12202036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hippo (Drosophila MST1/2 ortholog) binds to a regulatory domain of Salvador (Sav) through its SARAH domain; this interaction is essential for Hippo kinase function and for the Hpo-Sav-Wts signaling module that coordinately regulates cell proliferation and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis, dominant-negative and gain-of-function experiments in Drosophila\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interaction confirmed, genetic epistasis established, replicated across two independent labs in same year (PMID 14502294 and 14502295)\",\n      \"pmids\": [\"14502294\", \"14502295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hippo (Drosophila MST1/2) phosphorylates DIAP1 in a Hpo-dependent manner in S2 cells and can phosphorylate DIAP1 in vitro; Sav is an unstable protein that is stabilized by Hpo binding.\",\n      \"method\": \"In vitro kinase assay, S2 cell phosphorylation assay, co-expression stabilization experiments\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus cell-based phosphorylation, single lab\",\n      \"pmids\": [\"14502295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hippo (Hpo) kinase phosphorylates Salvador (Sav) directly; hpo, sav, and wts define a genetic pathway that regulates diap1 at the transcriptional level; human MST2 (hpo homolog) completely rescues Drosophila hpo mutant overgrowth.\",\n      \"method\": \"In vitro kinase assay, genetic epistasis, cross-species rescue experiment\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct phosphorylation assay, genetic epistasis, and cross-species functional conservation shown\",\n      \"pmids\": [\"12941273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RASSF1A, MST2, WW45 (SAV1), and LATS1 form a complex in human cells; MST2 enhances the RASSF1A-WW45 interaction, which requires the C-terminal SARAH domain of both proteins; the complex localizes to centrosomes and spindle poles through mitosis and to the midbody during cytokinesis; RASSF1A and WW45 activate MST2 by promoting MST2 autophosphorylation and LATS1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence/subcellular localization, in vitro kinase assay, domain-deletion mapping\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP, functional kinase assays, localization studies, and domain mutagenesis in one study\",\n      \"pmids\": [\"17379520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"WW45 (SAV1) is required for MST1 activation and its translocation to the nucleus upon differentiation signal in mouse epithelial cells; WW45 mediates LATS1/2 activation downstream of MST1, leading to YAP phosphorylation and cytoplasmic translocation, resulting in cell-cycle exit and terminal differentiation of epithelial progenitors.\",\n      \"method\": \"Conditional knockout mice, immunofluorescence, immunoprecipitation, western blot for pathway activation\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular phenotype, pathway dissection with multiple orthogonal readouts\",\n      \"pmids\": [\"18369314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human WW45 (hSAV1) physically associates with MST1 (confirmed by co-immunoprecipitation and co-localization); hWW45 is present in both cytoplasm and nucleus; hWW45 enhances MST1-induced apoptosis when co-expressed, and siRNA depletion of hWW45 suppresses MST1-induced apoptosis.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown with apoptosis readout\",\n      \"journal\": \"International Journal of Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple methods (Y2H, Co-IP, localization, RNAi phenotype) in single lab\",\n      \"pmids\": [\"19212654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Liver-specific ablation of WW45 (SAV1) in mice leads to increased liver size, expansion of hepatic oval cells, and eventual hepatoma; WW45 loss increases YAP abundance and promotes its nuclear localization specifically in oval cells, driving their proliferation.\",\n      \"method\": \"Liver-specific conditional knockout mice, immunofluorescence, immunohistochemistry, western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic KO with mechanistic pathway dissection (YAP nuclear localization) and tumor phenotype\",\n      \"pmids\": [\"20404163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SAV1 (Salvador) promotes apoptosis in human cells and interacts with RASSF1A; RASSF1A requires Salvador for full apoptotic activity and to activate p73; this effect does not require direct MST kinase activation or canonical Hippo pathway signaling, indicating SAV1 has Hippo pathway-independent functions.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, apoptosis assays, cell cycle analysis, transformation assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional assays in human cells; single lab\",\n      \"pmids\": [\"21489991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MST2-mediated phosphorylation of SAV1 at Thr-26, Ser-27, Ser-36, and Ser-269 promotes cell death; mutation of all four residues (SAV1-4A) weakens SAV1 interaction with MST2, reduces SAV1 self-dimerization, and inhibits MST2- and K-RasG12V-induced cell death.\",\n      \"method\": \"Mass spectrometric phosphorylation mapping, site-directed mutagenesis, co-immunoprecipitation, cell death assays\",\n      \"journal\": \"BMB Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS-based phospho-mapping plus mutagenesis with functional readout; single lab\",\n      \"pmids\": [\"21944251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MST2 stimulates binding of SAV1 to PPARγ via the WW domains of SAV1 and PPYY motif of PPARγ; SAV1 stabilizes PPARγ protein and increases PPARγ transactivation; SAV1 knockdown decreases PPARγ levels in 3T3-L1 adipocytes and impairs adipocyte differentiation.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/mutation analysis, siRNA knockdown, luciferase reporter assay, western blot\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — binding domain mapped, functional readout (adipogenesis), multiple methods; single lab\",\n      \"pmids\": [\"22292086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Par-1 kinase physically interacts with both Hippo (Hpo) and Salvador (Sav) in Drosophila; Par-1 phosphorylates Hpo at Ser30, restricting its activity; Par-1 inhibits Hpo-Sav association, resulting in Sav dephosphorylation and destabilization; this regulation is conserved in mammalian cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, genetic epistasis, gain/loss-of-function in Drosophila, mammalian cell validation\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct kinase assay, co-IP of interaction, genetic epistasis, cross-species validation\",\n      \"pmids\": [\"23940457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The MST1/2-SAV1 complex promotes ciliogenesis: MST1 activates during ciliogenesis and localizes to the basal body; MST1/2 binds and phosphorylates Aurora kinase A (AURKA), leading to dissociation of the AURKA/HDAC6 cilia-disassembly complex; MST1/2-SAV1 also associates with the NPHP transition-zone complex promoting ciliary cargo localization; depletion of MST1/2 or SAV1 impairs ciliogenesis in cultured cells and zebrafish.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, immunofluorescence/subcellular localization, siRNA knockdown, zebrafish morpholino knockdown\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, Co-IP, localization, LOF in two systems (cells + zebrafish), multiple orthogonal methods\",\n      \"pmids\": [\"25367221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Drosophila, Hippo kinase stabilizes its adaptor Salvador by antagonizing the HECT ubiquitin ligase Herc4; Herc4 promotes Salvador ubiquitylation and degradation; Hippo reduces Salvador/Herc4 interaction in a kinase-dependent manner, creating a positive feedback loop.\",\n      \"method\": \"RNAi screen, co-immunoprecipitation, ubiquitylation assay, genetic interaction\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitylation assay, Co-IP, RNAi phenotypes; single lab, Drosophila system\",\n      \"pmids\": [\"26125558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WW45 (SAV1) interacts with Gli1; WW45 promotes Gli1 ubiquitination and inhibits expression of Gli1 target genes, thereby negatively regulating Hedgehog signaling in lung cancer cells independently of canonical Hippo pathway activity.\",\n      \"method\": \"Mass spectrometry (binding partner identification), co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, siRNA and overexpression functional studies\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MS-identified interaction, Co-IP, functional ubiquitination data; single lab\",\n      \"pmids\": [\"27661123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SAV1 promotes MST1/2 activation by directly binding to and inhibiting the PP2A complex STRIPAK(SLMAP), protecting MST2 activation-loop phosphorylation; SAV1 and MST2 heterodimerize through their SARAH domains; two SAV1-MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer enabling MST2 trans-autophosphorylation; SLMAP binds autophosphorylated MST2 linker, recruits STRIPAK, and promotes PP2A-mediated dephosphorylation of MST2 activation loop; genetic ablation of SLMAP in human cells leads to spontaneous Hippo pathway activation and alleviates the need for SAV1.\",\n      \"method\": \"Crystal structure, biochemical reconstitution, in vitro phosphatase assay, co-immunoprecipitation, CRISPR/Cas9 knockout, mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, in vitro reconstitution with mutagenesis, genetic KO validation; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"29063833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tubular epithelial cell-specific deletion of Sav1 in mice leads to tubulointerstitial fibrosis; Sav1 depletion increases TGF-β and activates β-catenin; TAZ (downstream Hippo effector) is significantly activated in Sav1-knockout mice; in vitro, TAZ directly regulates TGF-β and TGF-β receptor II expression.\",\n      \"method\": \"Conditional knockout mice, western blot, luciferase reporter assay, siRNA knockdown, in vivo fibrosis model (UUO)\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with pathway dissection, in vitro mechanistic follow-up; single lab\",\n      \"pmids\": [\"27550469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sav1 loss in mouse renal epithelium induces Stat3 activation and a senescence-associated secretory phenotype (SASP) coinciding with tubulointerstitial fibrosis; YAP inhibition with verteporfin inhibits senescence, SASP, and Stat3 activation downstream of Sav1 loss.\",\n      \"method\": \"Conditional knockout mice, western blot, pharmacological inhibition (verteporfin), gene expression analysis\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with pharmacological rescue, pathway placement; single lab\",\n      \"pmids\": [\"28320873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of Drosophila Salvador (Sav) and Hippo (Hpo) SARAH domains in complex reveals that Salvador SARAH domain has a folded N-terminal extension that expands the binding interface with Hpo and is unique to Salvador; this extension enhances binding affinity and is required for proper Hippo kinase modulation; Salvador/Sav SARAH domain interaction with Hippo/Hpo is mutually exclusive with dRassF/Hippo SARAH domain interaction; human Salvador increases MST2 autophosphorylation in cells, but isolated Salvador SARAH domain inhibits MST2 autophosphorylation in vitro.\",\n      \"method\": \"X-ray crystallography, cross-linked mass spectrometry, co-transfection with western blot, in vitro kinase assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determined and validated by cross-linked MS; in vitro kinase assay; single lab\",\n      \"pmids\": [\"29519817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SAV1 inhibits Akt activation independently of its Hippo pathway role by binding to a proline-tyrosine motif in the Akt-PH domain, blocking Akt movement to the plasma membrane; MERTK phosphorylates Akt1 at Y26, releasing SAV1 binding and enabling Akt plasma membrane recruitment and activation; cancer-associated SAV1 mutations impair SAV1-Akt binding leading to Akt hyperactivation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, phospho-specific western blot, subcellular fractionation/localization, site-directed mutagenesis, cancer mutation analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding domain mapped, localization experiment, mutation analysis; single lab\",\n      \"pmids\": [\"30944303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The GCKIII kinase STK25 (a STRIPAK component) directly phosphorylates SAV1 and diminishes SAV1's ability to inhibit STRIPAK, thereby promoting STRIPAK-mediated inhibition of MST2; depletion of STK25 enhances MST2 activation without affecting STRIPAK(SLMAP) integrity, establishing a mutual antagonism between STRIPAK and SAV1 that controls Hippo pathway initiation.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, western blot for MST2 phosphorylation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay demonstrates direct phosphorylation, siRNA with biochemical readout, mechanistically extends prior structural study (PMID 29063833); single lab\",\n      \"pmids\": [\"32292165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SAV1 WW tandem with its short Pro-rich extension (WW12ex) forms a domain-swapped homodimer; the crystal structure reveals that the Pro-rich extension of one subunit binds to both WW domains of the other subunit; SAV1 WW12ex-mediated dimerization is required for MST/SAV1 complex assembly and MST kinase activation; several cancer-related SAV1 variants disrupt dimer formation.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, mutagenesis, co-immunoprecipitation, kinase activation assay\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis validation and functional kinase assay; single rigorous study\",\n      \"pmids\": [\"32905778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The cell adhesion molecule KIRREL1 physically interacts with SAV1 and recruits SAV1 to cell-cell contact sites; KIRREL1 knockout increases YAP activity in neighboring cells; in mouse liver regeneration, KIRREL1 upregulation enhances Hippo signaling and its ablation increases hepatic YAP activity.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging/localization, CRISPR/KO, YAP reporter assay, mouse liver regeneration model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, localization to cell-cell contacts, genetic KO with pathway readout; single lab\",\n      \"pmids\": [\"35177623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GRK2 phosphorylates, ubiquitinates, and promotes degradation of SAV1 in fibroblast-like synoviocytes (FLSs); GRK2 is upregulated by GPCR agonists such as prostaglandin E2 (PGE2) in rheumatoid arthritis; SAV1 degradation by GRK2 leads to decreased YAP phosphorylation, nuclear YAP accumulation, and aberrant FLS proliferation; GRK2 depletion or inhibition with paroxetine rescues SAV1 expression and YAP phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pharmacological inhibition (paroxetine), western blot, in vivo rat arthritis model\",\n      \"journal\": \"Acta Pharmaceutica Sinica B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic and pharmacological LOF with defined molecular and cellular readouts; single lab\",\n      \"pmids\": [\"38486990\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SAV1 (WW45/Salvador) is a scaffold/adaptor protein that promotes Hippo pathway activation through multiple mechanisms: its WW tandem domain-swapped homodimer assembles an MST1/2-SAV1 heterotetramer enabling MST trans-autophosphorylation; SAV1 directly inhibits the PP2A complex STRIPAK(SLMAP)—which otherwise dephosphorylates the MST activation loop—thereby protecting MST kinase activity; the STK25 kinase (a STRIPAK component) counters SAV1 by phosphorylating it, creating a mutual antagonism that gates Hippo initiation; SAV1 also heterodimerizes with MST1/2 via their SARAH domains (with SAV1 harboring a unique N-terminal SARAH extension that expands the interface) and is stabilized by this interaction through antagonism of the HECT ubiquitin ligase Herc4/HERC4; downstream, SAV1-mediated MST activation leads to LATS1/2-dependent YAP/TAZ phosphorylation and cytoplasmic sequestration, enforcing cell-cycle exit and apoptosis; additionally, SAV1 has Hippo-independent roles including suppression of Akt activation (by blocking Akt PH-domain membrane recruitment), inhibition of Hedgehog/Gli1 signaling (by promoting Gli1 ubiquitination), and interaction with PPARγ to regulate adipogenesis; the cell-adhesion molecule KIRREL1 recruits SAV1 to cell-cell contact sites as a feedback mechanism; and SAV1 protein stability is regulated by phosphorylation (by MST, GRK2, STK25), ubiquitination, and m6A-mediated mRNA regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SAV1 (WW45/Salvador) is a scaffold/adaptor protein that activates the Hippo tumor-suppressor pathway to enforce cell-cycle exit, apoptosis, and terminal differentiation, restraining tissue overgrowth [#0, #5, #7]. It was first defined genetically in Drosophila as a two-WW-domain protein that binds the Warts (LATS) kinase, and loss of Salvador elevates Cyclin E and the apoptosis inhibitor DIAP1 [#0]. SAV1 functions within a Hippo (MST1/2)–Salvador–Warts (LATS) module: MST/Hippo binds a regulatory region of SAV1 through their SARAH domains, an interaction required for kinase function [#1, #18], and structural work shows the SAV1 SARAH domain carries a unique folded N-terminal extension that expands the MST interface [#18]. SAV1 promotes MST activation by multiple mechanisms — a domain-swapped WW-tandem homodimer assembles an MST–SAV1 heterotetramer enabling MST trans-autophosphorylation [#21], and SAV1 directly binds and inhibits the PP2A-containing STRIPAK(SLMAP) complex that would otherwise dephosphorylate the MST activation loop [#15]. This protection is reciprocally antagonized by the STRIPAK kinase STK25, which phosphorylates SAV1 and blocks its inhibition of STRIPAK, gating Hippo initiation [#20]. SAV1-mediated MST activation drives LATS1/2-dependent YAP/TAZ phosphorylation and cytoplasmic sequestration; genetic ablation of SAV1 in mouse liver and kidney elevates nuclear YAP/TAZ and causes overgrowth, hepatoma, fibrosis, and senescence-associated phenotypes [#5, #7, #16, #17]. SAV1 is an unstable protein stabilized by MST binding and by antagonism of the HECT ligase Herc4/HERC4, and its levels are further controlled by phosphorylation-coupled degradation via GRK2 [#2, #13, #23]. Beyond Hippo, SAV1 has independent roles: it blocks Akt membrane recruitment by binding the Akt PH domain [#19], promotes Gli1 ubiquitination to suppress Hedgehog signaling [#14], stabilizes PPARγ to support adipogenesis [#10], and with MST1/2 promotes ciliogenesis [#12]. The adhesion molecule KIRREL1 recruits SAV1 to cell-cell contacts as a feedback input to Hippo signaling [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SAV1/Salvador as a growth-suppressing adaptor by showing it binds the Warts/LATS kinase and that its loss drives proliferation and blocks apoptosis, defining the founding genetic role.\",\n      \"evidence\": \"Genetic loss-of-function screen with binding assays and in vivo phenotypes in Drosophila\",\n      \"pmids\": [\"12202036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how Salvador couples to upstream kinases\", \"Mammalian function not yet addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed Salvador in a Hippo–Salvador–Warts module by showing MST/Hippo binds Salvador via SARAH domains and directly phosphorylates it, and that Salvador is an unstable protein stabilized by Hippo binding.\",\n      \"evidence\": \"Co-IP, SARAH-domain mapping, in vitro kinase assays, genetic epistasis, and cross-species rescue in Drosophila/human cells\",\n      \"pmids\": [\"14502294\", \"14502295\", \"12941273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SARAH interaction not resolved\", \"Mechanism of Salvador instability not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed SAV1 acts within a higher-order MST2 activation complex in human cells, linking it to RASSF1A and LATS1 and to mitotic structures, and that it promotes MST2 autophosphorylation.\",\n      \"evidence\": \"Reciprocal Co-IP, immunofluorescence localization, in vitro kinase assays, and domain-deletion mapping in human cells\",\n      \"pmids\": [\"17379520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the complex not resolved\", \"Did not establish how SAV1 activates MST2 mechanistically\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the mammalian physiological output: SAV1 is required for MST1 activation and LATS1/2-dependent YAP phosphorylation, driving cell-cycle exit and terminal differentiation of epithelial progenitors.\",\n      \"evidence\": \"Conditional knockout mice with pathway readouts by IF, IP, and western blot\",\n      \"pmids\": [\"18369314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions not fully mapped\", \"Did not address Hippo-independent functions\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated SAV1 is a tumor suppressor in vivo: liver-specific loss expands oval cells, elevates nuclear YAP, and produces hepatoma.\",\n      \"evidence\": \"Liver-specific conditional knockout mice with IHC, IF, and western blot\",\n      \"pmids\": [\"20404163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-of-origin for the tumors not fully defined\", \"Did not test reversibility upon YAP inhibition\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Hippo-independent and self-association determinants: MST2 phosphorylates SAV1 at four residues controlling dimerization and cell death, and SAV1 supports RASSF1A/p73 apoptosis without canonical MST activation.\",\n      \"evidence\": \"MS phospho-mapping, mutagenesis, Co-IP, and apoptosis/cell-cycle assays in human cells\",\n      \"pmids\": [\"21944251\", \"21489991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab phospho-site assignments\", \"Hippo-independent apoptotic mechanism not biochemically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended SAV1 function beyond growth control by showing WW-domain-mediated binding to PPARγ stabilizes it and supports adipocyte differentiation.\",\n      \"evidence\": \"Co-IP, domain mapping, siRNA, luciferase reporter, and adipogenesis assays in 3T3-L1 cells\",\n      \"pmids\": [\"22292086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to adipogenesis not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed upstream regulation of the Hippo-Salvador interaction: Par-1 phosphorylates Hippo and disrupts Hpo-Sav association, destabilizing Salvador.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, and genetic epistasis in Drosophila with mammalian validation\",\n      \"pmids\": [\"23940457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions selecting Par-1 regulation in mammals not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected the MST1/2-SAV1 complex to ciliogenesis via AURKA phosphorylation and NPHP transition-zone association, broadening SAV1's organelle-level roles.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, localization, and LOF in cultured cells and zebrafish\",\n      \"pmids\": [\"25367221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SAV1's specific contribution versus MST1/2 not separated\", \"Link to canonical Hippo output not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a positive-feedback stability mechanism: Hippo kinase antagonizes the HECT ligase Herc4, protecting Salvador from ubiquitin-dependent degradation.\",\n      \"evidence\": \"RNAi screen, Co-IP, ubiquitylation, and genetic interaction in Drosophila\",\n      \"pmids\": [\"26125558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human HERC4 regulation of SAV1 not directly tested\", \"Single lab, Drosophila system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed a Hippo-independent suppressive role on Hedgehog signaling: SAV1 binds Gli1 and promotes its ubiquitination to repress Gli1 target genes.\",\n      \"evidence\": \"MS interaction ID, Co-IP, ubiquitination, reporter assays, and LOF/GOF in lung cancer cells\",\n      \"pmids\": [\"27661123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating Gli1 ubiquitination not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the structural and biochemical mechanism of MST activation: a SAV1 SARAH heterodimer and WW-domain-driven heterotetramer enable MST2 trans-autophosphorylation, while SAV1 directly inhibits STRIPAK(SLMAP) to protect the MST2 activation loop.\",\n      \"evidence\": \"Crystal structure, reconstitution, phosphatase assay, Co-IP, CRISPR knockout, and mutagenesis\",\n      \"pmids\": [\"29063833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STRIPAK recruitment is dynamically regulated in cells not resolved at the time\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established disease relevance of SAV1 loss in kidney: epithelial Sav1 deletion activates TAZ, TGF-β, β-catenin, Stat3, senescence, and SASP, driving tubulointerstitial fibrosis.\",\n      \"evidence\": \"Conditional knockout mice, fibrosis model, reporter assays, siRNA, and verteporfin rescue\",\n      \"pmids\": [\"27550469\", \"28320873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect transcriptional effects not fully separated\", \"Single lab per study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structural basis of the Salvador-Hippo SARAH interface, showing a unique Salvador N-terminal extension expands and strengthens the interaction and competes with RassF binding.\",\n      \"evidence\": \"X-ray crystallography, cross-linked MS, co-transfection western blot, and in vitro kinase assay\",\n      \"pmids\": [\"29519817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of cellular activation with in vitro inhibition by isolated SARAH not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a Hippo-independent SAV1 function in PI3K/Akt control: SAV1 binds the Akt PH domain to block membrane recruitment, with MERTK-driven Akt phosphorylation releasing SAV1.\",\n      \"evidence\": \"Co-IP, domain mapping, phospho-westerns, fractionation, mutagenesis, and cancer-mutation analysis\",\n      \"pmids\": [\"30944303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of SAV1-PH binding not solved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established mutual antagonism gating Hippo initiation: STRIPAK kinase STK25 phosphorylates SAV1 to disable its STRIPAK inhibition, balancing MST2 activation.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, siRNA, and MST2 phospho-westerns extending the prior structural study\",\n      \"pmids\": [\"32292165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SAV1 phospho-sites targeted by STK25 not fully mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the molecular architecture of SAV1 self-association: the WW-tandem plus Pro-rich extension forms a domain-swapped homodimer required for MST/SAV1 complex assembly and kinase activation, with cancer variants disrupting the dimer.\",\n      \"evidence\": \"X-ray crystallography, binding assays, mutagenesis, Co-IP, and kinase activation assay\",\n      \"pmids\": [\"32905778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of dimer-disrupting variants not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a spatial feedback input: the adhesion molecule KIRREL1 recruits SAV1 to cell-cell contacts, restraining YAP in neighboring cells and modulating liver regeneration.\",\n      \"evidence\": \"Co-IP, live-cell imaging, CRISPR KO, YAP reporter, and mouse liver regeneration model\",\n      \"pmids\": [\"35177623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How KIRREL1-bound SAV1 mechanistically engages MST not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked GPCR signaling to SAV1 turnover: GRK2 phosphorylates, ubiquitinates, and degrades SAV1, releasing YAP in synoviocytes and contributing to rheumatoid arthritis pathology.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA, paroxetine inhibition, and rat arthritis model\",\n      \"pmids\": [\"38486990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GRK2 phospho-sites on SAV1 not mapped\", \"E3 ligase coupling not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SAV1's multiple Hippo-independent activities (Akt, Hedgehog/Gli1, PPARγ, ciliogenesis) are coordinated with its core MST-activating scaffold function, and which inputs select among them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism integrating Hippo and non-Hippo roles\", \"Structural models for non-Hippo partner interactions lacking\", \"Tissue-specific partner selection undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 17, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"MST1/2-SAV1 complex\", \"RASSF1A-MST2-WW45-LATS1 complex\", \"STRIPAK (as inhibitory target)\"],\n    \"partners\": [\"MST1\", \"MST2\", \"LATS1\", \"RASSF1A\", \"SLMAP\", \"STK25\", \"KIRREL1\", \"GRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}