{"gene":"PTPN14","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1995,"finding":"PTPN14 (Pez) was identified as a novel non-receptor protein tyrosine phosphatase with N-terminal FERM domain homology (ezrin/band 4.1/merlin/radixin family) and a C-terminal PTP catalytic domain, encoded on chromosome 1q32.2-41.","method":"cDNA cloning, sequence analysis, Northern blot, FISH mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — original cloning paper with sequence analysis and chromosomal mapping; domain architecture established by sequence homology, single lab","pmids":["7733990"],"is_preprint":false},{"year":2000,"finding":"PTPN14 (Pez) localizes to the nucleus in proliferating/low-density endothelial cells and translocates to the cytoplasm in confluent quiescent monolayers; TGFβ inhibited nuclear translocation at wound edges, linking nuclear localization to cell proliferation.","method":"Subcellular fractionation, immunofluorescence, density manipulation, serum starvation/refeeding, wound assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional correlate (proliferation state), single lab, multiple conditions tested","pmids":["10934049"],"is_preprint":false},{"year":2003,"finding":"PTPN14 (Pez) localizes to adherens junctions in confluent epithelial cells and directly dephosphorylates β-catenin; a catalytic-domain truncation dominant-negative mutant increased tyrosine phosphorylation at adherens junctions and enhanced cell motility.","method":"Immunofluorescence, substrate-trapping approach, in vitro dephosphorylation with recombinant Pez, dominant-negative overexpression, wound motility assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro dephosphorylation with recombinant enzyme plus substrate trapping and dominant-negative functional readout; single lab but multiple orthogonal methods","pmids":["12808048"],"is_preprint":false},{"year":2007,"finding":"PTPN14 (Pez) overexpression in epithelial MDCK cells induces EMT accompanied by induction of TGFβ signaling; Pez knockdown in zebrafish disrupts organogenesis (brain, heart, pharyngeal arches, somites) and abolishes TGFβ3 expression from co-expressing tissues.","method":"Overexpression in MDCK cells (morphology, gene expression), morpholino knockdown in zebrafish, in situ hybridization","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vivo (zebrafish) and gain-of-function in vitro with defined phenotypic readouts; single lab, two model systems","pmids":["17893246"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function mutation in PTPN14 causes autosomal-recessive lymphedema-choanal atresia syndrome; Ptpn14 gene-trap mice develop lymphatic hyperplasia with lymphedema; PTPN14 biochemically interacts with VEGFR3, a receptor tyrosine kinase essential for lymphangiogenesis.","method":"Genetic linkage, Sanger sequencing, murine gene-trap model (lymphatic phenotype), co-immunoprecipitation/biochemical interaction studies","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics plus mouse KO phenotype plus biochemical interaction; multiple orthogonal methods establishing role in lymphangiogenesis","pmids":["20826270"],"is_preprint":false},{"year":2012,"finding":"PTPN14 interacts with YAP1 (via PTPN14 PPxY domain and YAP1 WW domain) and promotes nucleus-to-cytoplasm translocation of YAP1 during contact inhibition, suppressing YAP1 transcriptional activity; PTPN14 protein stability is positively regulated by cell density, and the CRL2(LRR1) E3 ubiquitin ligase complex targets PTPN14 for degradation at low cell density.","method":"shRNA screen, co-immunoprecipitation, subcellular fractionation/localization assays, luciferase reporter, ubiquitin ligase identification","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, localization, reporter, E3 identification), replicated by independent lab (PMID:22525271)","pmids":["22948661"],"is_preprint":false},{"year":2012,"finding":"PTPN14 directly interacts with YAP through the WW domain of YAP and the PPxY domain of PTPN14; YAP is a direct substrate of PTPN14 phosphatase activity; PTPN14 inhibits YAP transcriptional co-activator function and increases cytoplasmic YAP; PTPN14 knockdown induces nuclear retention of YAP and increases YAP-dependent cell migration.","method":"Co-immunoprecipitation, luciferase reporter assay, immunofluorescence, siRNA knockdown, migration assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct substrate identification, Co-IP with domain mapping, reporter assay, functional readout; independently replicated by multiple labs","pmids":["22525271"],"is_preprint":false},{"year":2012,"finding":"Drosophila Pez (ortholog of PTPN14) acts as a negative upstream regulator of Yorkie (YAP ortholog) specifically in the fly midgut epithelium by binding the upstream Hippo component Kibra; the PTP catalytic domain of Pez is dispensable for Hippo pathway activity in this context.","method":"Genetic loss-of-function in Drosophila, co-immunoprecipitation (Pez-Kibra interaction), ISC proliferation assays, PTP domain mutant analysis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — Drosophila genetic epistasis with Co-IP and domain dissection; established in vivo Hippo pathway position","pmids":["22305752"],"is_preprint":false},{"year":2013,"finding":"PTPN14 negatively regulates YAP activity by controlling its cytoplasmic localization; the WW/PPxY interaction between PTPN14 and YAP mediates their binding, but the PPxY motif and phosphatase activity of PTPN14 are dispensable for regulation of endogenous YAP; PTPN14 downregulation phenocopies YAP activation and synergizes with YAP to induce oncogenic transformation in mammary epithelial cells.","method":"Co-immunoprecipitation, immunofluorescence, domain/motif mutants, transformation assays, siRNA knockdown","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, important mechanistic dissection showing phosphatase activity dispensable; independently replicated findings","pmids":["23613971"],"is_preprint":false},{"year":2014,"finding":"PTPN14 interacts with Kibra through PTPN14's PPXY domain and Kibra's WW domain; PTPN14 and Kibra each independently and cooperatively activate LATS1 kinase (in a manner independent of MST kinases); PTPN14 increases LATS1 protein stability; Kibra overexpression rescues the increased cell migration and aberrant 3D morphogenesis caused by PTPN14 knockdown via LATS1-mediated YAP cytoplasmic sequestration.","method":"Co-immunoprecipitation, kinase activity assays, siRNA knockdown, 3D morphogenesis assay, migration assay, immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods; establishes PTPN14-Kibra-LATS1 complex and MST-independent LATS1 activation mechanism","pmids":["25023289"],"is_preprint":false},{"year":2015,"finding":"PTPN14 suppresses metastasis by reducing protein trafficking through the secretory pathway; loss of catalytically functional PTPN14 increases secretion of IL-8 and surface abundance of EGFR and FLT4/VEGFR3; PTPN14 directly binds and dephosphorylates RIN1 and PRKCD; RIN1 dephosphorylation or PRKCD loss mimics PTPN14 overexpression in restricting receptor trafficking.","method":"shRNA knockdown, mouse xenograft model, co-immunoprecipitation, substrate identification (phosphoproteomics/pulldown), phosphomutant rescue, cytokine secretion assays, EGFR/FLT4 surface abundance measurements","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple substrates identified (RIN1, PRKCD), in vivo model, mechanistic pathway placement with functional rescue; single lab but highly rigorous multi-method study","pmids":["25690013"],"is_preprint":false},{"year":2015,"finding":"Suppressor of Deltex (Su(dx)) E3 ubiquitin ligase targets Drosophila Pez (PTPN14 ortholog) for degradation via WW domain–PY/PPxY motif interactions; Kibra stabilizes Pez through the same WW-PY/PPxY interaction; the mammalian Su(dx) homolog WWP1 similarly degrades PTPN14 in mammalian cells.","method":"In vitro and in vivo degradation assays in Drosophila, co-immunoprecipitation (WW-PPxY interaction), overexpression rescue experiments, mammalian cell WWP1 overexpression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo degradation assays, domain interaction mapping, conserved in mammalian cells; multiple orthogonal methods","pmids":["25814387"],"is_preprint":false},{"year":2016,"finding":"High-risk HPV E7 proteins target PTPN14 for proteasome-mediated degradation; this requires the E3 ubiquitin ligase UBR4; residues in the C-terminus of E7 interact with the C-terminal phosphatase domain of PTPN14; PTPN14 degradation correlates with retinoblastoma-independent transforming activity of high-risk HPV E7.","method":"Co-immunoprecipitation, proteasome inhibitor assays, UBR4 siRNA knockdown, domain mapping, transformation assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — E3 ligase identification, domain mapping, degradation mechanism established; independently replicated by Banks lab (PMID:28100625)","pmids":["27651363"],"is_preprint":false},{"year":2017,"finding":"High-risk HPV E7-mediated PTPN14 degradation (proteasome-dependent, via UBR4/p600 ubiquitin ligase) impairs keratinocyte differentiation; using an HPV16 E7 variant that degrades pRb but cannot degrade PTPN14, PTPN14 degradation was shown to contribute to HPV E6/E7-mediated keratinocyte immortalization and anoikis resistance independent of RB1 inactivation.","method":"E7 variant with separated RB1/PTPN14 activities, CRISPR/primary keratinocyte culture, differentiation gene expression, anoikis/detachment survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic separation of E7 activities with defined functional readouts; multiple independent experiments establishing PTPN14-specific contribution","pmids":["30894485"],"is_preprint":false},{"year":2017,"finding":"The p53-target gene Ptpn14 is necessary and sufficient for pancreatic cancer suppression downstream of p53; Ptpn14 negatively regulates the Yap oncoprotein; PTPN14 and TP53 mutations are mutually exclusive in human cancers, establishing a p53-Ptpn14-Yap pathway.","method":"Mouse pancreatic cancer model (p53 TAD mutants), shRNA knockdown, overexpression studies, analysis of human cancer mutation databases","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with genetic necessity/sufficiency tests, human cancer mutual exclusivity; multiple orthogonal methods","pmids":["29017057"],"is_preprint":false},{"year":2017,"finding":"PTPN14 interacts with HPV E7 C-terminal region independently of pRb; high-risk E7 induces proteasome-mediated PTPN14 degradation (via UBR4/p600, independent of cullin-1/cullin-2) in cervical cancer cells; PTPN14 overexpression decreases the ability of HPV-16 E7 to cooperate with activated EJ-ras in primary cell transformation.","method":"Co-immunoprecipitation, proteasome inhibitor and cullin knockdown assays, transformation/focus formation assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection of degradation pathway with multiple knockdowns, independent replication of E7-PTPN14 degradation findings","pmids":["28100625"],"is_preprint":false},{"year":2018,"finding":"PTPN14 specifically interacts with the mRNA decay factor Roquin2 through its phosphatase domain and dephosphorylates Roquin2 at tyrosine 691; this dephosphorylation restores the Roquin2-KLHL6 E3 ligase interaction, promoting Roquin2 proteasomal degradation.","method":"Co-immunoprecipitation, mass spectrometry identification, phospho-site mapping, in vivo phosphorylation assays, overexpression of PTPN14, KLHL6-dependent degradation assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification and dephosphorylation with defined downstream consequence; single lab, multiple methods but limited independent replication","pmids":["30209976"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of HPV18 E7 C-terminal domain bound to PTPN14 catalytic domain was solved; the interaction has a Kd of 18.2 nM; structure-based mutagenesis of the binding interface impaired E7-promoted keratinocyte proliferation/migration and rendered PTPN14 resistant to proteasomal degradation; E7-binding-defective PTPN14 more effectively inhibited Hippo signaling downstream effectors.","method":"X-ray crystallography, surface plasmon resonance (binding affinity), structure-guided mutagenesis, cell proliferation/migration/invasion assays, immunoblot for Hippo signaling","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus structure-based mutagenesis with functional validation; rigorous single study with multiple orthogonal methods","pmids":["31323018"],"is_preprint":false},{"year":2019,"finding":"In rheumatoid arthritis fibroblast-like synoviocytes (FLS), PTPN14 forms a complex with YAP and promotes nuclear localization of SMAD3 and TGFβ signaling (MMP13 expression, TNF potentiation); a non-YAP-interacting PTPN14 mutant fails to enhance SMAD reporter activity, indicating the PTPN14-YAP interaction is required for this function.","method":"Co-immunoprecipitation, antisense oligonucleotide knockdown, immunofluorescence, SMAD luciferase reporter, RA FLS-cartilage co-implantation model","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assay, in vivo model, mutant analysis; single lab but multiple orthogonal methods in disease-relevant context","pmids":["30808624"],"is_preprint":false},{"year":2020,"finding":"A conserved C-terminal arginine in diverse HPV E7 proteins mediates the interaction with PTPN14; mutation of this arginine prevents PTPN14 binding and degradation (via UBR4), renders HPV16 and HPV18 E7 unable to repress keratinocyte differentiation gene expression, and prevents HPV18 E7 from extending keratinocyte lifespan; PTPN14 CRISPR knockout rescued keratinocyte lifespan in cells expressing the PTPN14-binding-deficient E7 variant.","method":"E7 arginine mutant analysis, Co-immunoprecipitation, CRISPR/Cas9 knockout rescue experiment, differentiation gene expression assays, keratinocyte lifespan assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue experiment, domain mapping, multiple functional readouts; stringent mechanistic dissection with CRISPR rescue","pmids":["32581101"],"is_preprint":false},{"year":2020,"finding":"PLD2-generated phosphatidic acid promotes PTPN14 activity; PTPN14, VE-cadherin, and PLD2 form a complex at adherens junctions after thrombin stimulation; PTPN14 dephosphorylates VE-cadherin at Tyr-658, enabling VE-cadherin recycling and endothelial barrier recovery after edemagenic insult.","method":"Co-immunoprecipitation, VE-cadherin phospho-site specific antibodies, siRNA knockdown, PLD2 inhibitor/deletion, in vivo lung permeability model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate (VE-cadherin Tyr-658) identified with phospho-site specificity, complex characterized by Co-IP, in vivo validation; multiple orthogonal methods","pmids":["32327488"],"is_preprint":false},{"year":2020,"finding":"PTPN14 interacts with SOCS7 and promotes its degradation via ubiquitination at K11 and K48 linkages, reducing SOCS7 protein levels; SOCS7 blocks NF-κB signaling by inhibiting IKK complex activity; PTPN14 deficiency reduces inflammation in LPS+D-GalN-induced acute liver failure via the PTPN14-SOCS7-NF-κB axis.","method":"Co-immunoprecipitation, ubiquitination assays (K11/K48 linkage-specific), PTPN14 knockout mouse model, NF-κB signaling assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination site identification, mouse KO model; single lab, multiple methods","pmids":["32978373"],"is_preprint":false},{"year":2022,"finding":"Hypoxia-induced nuclear translocation of PTPN14 in hepatocellular carcinoma causes resistance to sorafenib; NPM1 regulates PTPN14 localization under hypoxia, retaining it in the nucleus and thereby releasing YAP from PTPN14-mediated cytoplasmic sequestration.","method":"Immunofluorescence/subcellular fractionation, siRNA knockdown, hypoxia treatment, co-immunoprecipitation (NPM1-PTPN14), HCC cell functional assays and xenograft","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization experiments with functional consequence, Co-IP establishing NPM1-PTPN14 interaction; single lab, moderate evidence","pmids":["35135548"],"is_preprint":false},{"year":2024,"finding":"PTPN14 interacts with intracellular region of PDGFRβ and dephosphorylates it at Y692; phosphorylation of PDGFRβ Y692 negatively regulates PDGFRβ signaling; PTPN14 overexpression (phosphatase activity-dependent) exacerbates neointimal hyperplasia in mice by boosting PDGFRβ signaling-induced smooth muscle cell phenotypic modulation, while SMC-specific PTPN14 deletion mitigates it.","method":"Co-immunoprecipitation, phospho-site specific antibodies (Y692), SMC-specific conditional KO mouse (neointima model), RNA-seq, overexpression studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — substrate (PDGFRβ Y692) identified biochemically, in vivo KO and OE mouse models, phosphatase activity-dependence confirmed; multiple orthogonal methods","pmids":["39191789"],"is_preprint":false},{"year":2024,"finding":"PTPN14 is identified as a key regulator of anoikis resistance in triple-negative breast cancer; PTPN14 dephosphorylates BCAR3 (breast cancer antiestrogen resistance 3), leading to inhibition of PI3K/AKT and ERK signaling; PTPN14 mRNA-LNP delivery inhibited TNBC tumor growth and metastasis in vivo.","method":"Genome-wide CRISPR/Cas9 knockout screen, substrate identification (BCAR3 dephosphorylation), PI3K/AKT/ERK signaling assays, mRNA-LNP mouse xenograft","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen with substrate validation, in vivo model; single lab, moderate mechanistic depth in abstract","pmids":["39189475"],"is_preprint":false},{"year":2024,"finding":"PTPN14 knockout or HPV18 E7-mediated PTPN14 degradation decreases phosphorylation of LATS1 at T1079 and YAP1 at S127 in human keratinocytes; PTPN14-dependent differentiation requires LATS kinases and specific PPxY motifs in PTPN14 but not MST1/2 kinases or the PTPN14 phosphatase active site, placing PTPN14 as a scaffold regulator of LATS1 upstream of YAP1.","method":"PTPN14 CRISPR knockout, phospho-specific immunoblots (LATS1 T1079, YAP1 S127), LATS1/2 double knockout, PPxY motif mutants, phosphatase active-site mutants, keratinocyte differentiation assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic dissection with KO, phospho-site analysis, domain mutants, active-site mutants; multiple orthogonal methods establishing scaffold (not phosphatase) mechanism for LATS1 activation","pmids":["39248565"],"is_preprint":false},{"year":2025,"finding":"PTPN14 knockout mice develop corneal lesions, hydrometra, heart and kidney abnormalities with only ~60% postnatal survival; the cornea shows impaired injury response and both cornea and uterus exhibit dysregulated YAP signaling; phenotypes are female-specific, revealing sexually dimorphic Hippo pathway function.","method":"Ptpn14 constitutive knockout mouse generation, histopathology, immunofluorescence for YAP, corneal injury assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse model with multiple defined tissue phenotypes and YAP signaling readouts; peer-reviewed with preprint version also available","pmids":["40533389"],"is_preprint":false},{"year":2025,"finding":"Fenofibrate directly binds the PPxY motif of PTPN14, facilitating formation of a PTPN14/LATS1/MARK3 complex that promotes cytoplasmic sequestration of YAP; PTPN14 knockdown or MARK3 inhibition abolished fenofibrate-mediated suppression of cancer cell malignant phenotypes.","method":"Direct binding assay (PPxY motif), co-immunoprecipitation (PTPN14/LATS1/MARK3 complex), siRNA knockdown, YAP localization assays, cancer cell functional assays","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and complex formation with functional knockdown rescue; single lab, limited independent replication","pmids":["40858196"],"is_preprint":false},{"year":2025,"finding":"Inactivation of both RB1 and PTPN14 is required for high-risk HPV E7-mediated keratinocyte immortalization; neither RB1-binding-deficient nor PTPN14-binding-deficient E7 mutant alone could extend keratinocyte lifespan, but together they reconstituted wild-type E7 activity; PTPN14 depletion and RB1 inactivation act synergistically to induce cell cycle regulatory gene expression.","method":"Genetic complementation with E7 separation-of-function mutants (RB1-binding-deficient and PTPN14-binding-deficient), primary keratinocyte lifespan assay, gene expression analysis","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic complementation experiment; preprint, single lab, but rigorous separation-of-function approach","pmids":["41890011"],"is_preprint":true}],"current_model":"PTPN14 is an evolutionarily conserved FERM domain-containing non-receptor tyrosine phosphatase that functions primarily as a scaffold/adaptor to activate LATS1 kinase (independent of MST1/2 and its own phosphatase activity), thereby driving YAP1 phosphorylation and cytoplasmic sequestration; it also acts as a direct phosphatase for substrates including β-catenin (at adherens junctions), VE-cadherin (Tyr-658, restoring endothelial barrier function), PDGFRβ (Tyr-692, a self-inhibitory site controlling SMC phenotypic switching), RIN1 and PRKCD (restricting secretory trafficking), BCAR3 (suppressing PI3K/AKT and ERK), STAT3, and Roquin2 (Tyr-691, controlling its E3 ligase interaction); its subcellular localization switches between cytoplasm (in confluent cells, where it retains YAP in the cytoplasm) and nucleus (in proliferating cells or under hypoxia, where NPM1 retains it and YAP is released); PTPN14 protein stability is density-dependent, being degraded by CRL2(LRR1) at low density and by the WWP1/Su(dx) E3 ligases via its PPxY motifs; high-risk HPV E7 oncoproteins target PTPN14 for UBR4-mediated proteasomal degradation through a C-terminal arginine-mediated interaction, thereby inhibiting keratinocyte differentiation and—cooperatively with RB1 inactivation—immortalizing keratinocytes; PTPN14 loss-of-function in vivo causes lymphatic hyperplasia, female-specific corneal and uterine defects, and pancreatic cancer susceptibility."},"narrative":{"mechanistic_narrative":"PTPN14 is an evolutionarily conserved FERM domain–containing non-receptor protein tyrosine phosphatase that acts as a central negative regulator of the Hippo pathway effector YAP, coupling cell-density and growth-state cues to growth suppression [PMID:7733990, PMID:22948661, PMID:22525271]. Its dominant mechanism is non-catalytic: PTPN14 binds YAP through reciprocal PPxY–WW interactions and, by binding the upstream component Kibra, cooperatively activates and stabilizes LATS1 kinase independently of MST1/2, driving LATS1-dependent YAP phosphorylation (YAP1 S127), cytoplasmic sequestration, and loss of YAP transcriptional output [PMID:22948661, PMID:22525271, PMID:25023289, PMID:39248565]. This scaffold function requires PTPN14's PPxY motifs but not its phosphatase active site [PMID:23613971, PMID:39248565]. PTPN14 localization is growth-state-dependent, residing in the nucleus in proliferating/low-density cells and at the cytoplasm/adherens junctions in confluent monolayers, with NPM1 retaining it in the nucleus under hypoxia to release YAP [PMID:10934049, PMID:12808048, PMID:35135548]. In parallel, PTPN14 acts as a bona fide tyrosine phosphatase on multiple substrates, dephosphorylating β-catenin at adherens junctions [PMID:12808048], VE-cadherin at Tyr-658 to restore endothelial barrier function [PMID:32327488], PDGFRβ at Tyr-692 to restrain smooth-muscle phenotypic switching [PMID:39191789], RIN1 and PRKCD to limit secretory trafficking and metastasis [PMID:25690013], and BCAR3 to suppress PI3K/AKT and ERK signaling [PMID:39189475]. PTPN14 protein levels are tightly controlled by ubiquitin ligases—CRL2(LRR1) at low density and WWP1/Su(dx) via its PPxY motifs—while high-risk HPV E7 oncoproteins co-opt UBR4 to degrade PTPN14 through a high-affinity C-terminal interaction with the phosphatase domain, impairing keratinocyte differentiation and, together with RB1 inactivation, immortalizing keratinocytes [PMID:22948661, PMID:25814387, PMID:27651363, PMID:31323018, PMID:41890011]. Loss-of-function mutations in PTPN14 cause autosomal-recessive lymphedema-choanal atresia syndrome, and PTPN14 is a p53-induced tumor suppressor of pancreatic cancer acting through YAP [PMID:20826270, PMID:29017057].","teleology":[{"year":1995,"claim":"Establishing PTPN14's domain architecture defined it as a candidate cytoskeleton/membrane-associated phosphatase, framing all later mechanistic work.","evidence":"cDNA cloning, sequence analysis and FISH mapping of a FERM-PTP protein","pmids":["7733990"],"confidence":"Medium","gaps":["No substrate or pathway assigned at this stage","FERM-domain binding partners not identified"]},{"year":2000,"claim":"Linking PTPN14 localization to proliferation state revealed that its function is regulated by a nuclear-cytoplasmic switch tied to cell density.","evidence":"Subcellular fractionation, immunofluorescence and density/wound assays in endothelial cells","pmids":["10934049"],"confidence":"Medium","gaps":["Molecular driver of the localization switch unknown","Functional output of localization not defined"]},{"year":2003,"claim":"Identifying β-catenin as a direct substrate at adherens junctions provided the first catalytic substrate and connected PTPN14 to junctional integrity and motility.","evidence":"Substrate trapping, in vitro dephosphorylation with recombinant enzyme, dominant-negative motility assay","pmids":["12808048"],"confidence":"High","gaps":["Did not address Hippo/YAP regulation","In vivo relevance not tested"]},{"year":2007,"claim":"Demonstrating that PTPN14 perturbation drives EMT and organogenesis defects established it as a developmental regulator linked to TGFβ signaling.","evidence":"Overexpression in MDCK cells and morpholino knockdown in zebrafish","pmids":["17893246"],"confidence":"Medium","gaps":["Mechanism connecting PTPN14 to TGFβ unresolved","No molecular substrate linked to the phenotype"]},{"year":2010,"claim":"Human genetics and mouse models tied PTPN14 loss to lymphedema-choanal atresia and lymphatic hyperplasia, with a VEGFR3 interaction giving a candidate mechanism.","evidence":"Genetic linkage/sequencing, gene-trap mouse, co-immunoprecipitation","pmids":["20826270"],"confidence":"High","gaps":["Whether VEGFR3 is a phosphatase substrate not established","Causal pathway from interaction to lymphatic phenotype incomplete"]},{"year":2012,"claim":"Convergent studies placed PTPN14 as a YAP-binding negative regulator that promotes YAP cytoplasmic localization during contact inhibition, with density-dependent stability controlled by CRL2(LRR1).","evidence":"shRNA screen, Co-IP with domain mapping, fractionation, luciferase reporter and E3 ligase identification across multiple labs","pmids":["22948661","22525271","22305752"],"confidence":"High","gaps":["Whether YAP regulation requires phosphatase catalysis was disputed","Upstream kinase mediating the effect not yet defined"]},{"year":2013,"claim":"Showing that the PPxY motif and phosphatase activity are dispensable for endogenous YAP regulation reframed PTPN14 as a scaffold rather than a YAP-directed enzyme.","evidence":"Domain/motif and active-site mutants, transformation assays, siRNA in mammary epithelial cells","pmids":["23613971"],"confidence":"High","gaps":["Identity of the activated kinase still unknown at this point","Reconciliation with earlier direct-substrate claims left open"]},{"year":2014,"claim":"Identifying the PTPN14-Kibra-LATS1 axis explained how PTPN14 represses YAP without MST kinases, by cooperatively activating and stabilizing LATS1.","evidence":"Co-IP, kinase activity assays, 3D morphogenesis and migration rescue with Kibra","pmids":["25023289"],"confidence":"High","gaps":["Structural basis of LATS1 activation not resolved","Quantitative contribution of scaffolding vs. stability unclear"]},{"year":2015,"claim":"Two studies defined PTPN14 stability control by WWP1/Su(dx) via PPxY motifs and revealed catalytic suppression of secretory trafficking through RIN1 and PRKCD dephosphorylation.","evidence":"Degradation assays with domain mapping in Drosophila/mammalian cells; substrate identification, phosphomutant rescue, xenografts","pmids":["25814387","25690013"],"confidence":"High","gaps":["Coordination between scaffold and catalytic functions not integrated","How trafficking substrates relate to YAP control unaddressed"]},{"year":2017,"claim":"High-risk HPV E7 was shown to drive UBR4-dependent PTPN14 degradation via a C-terminal E7–phosphatase-domain interaction, establishing PTPN14 as an RB1-independent E7 target controlling differentiation and immortalization, and p53 was shown to act through Ptpn14 to suppress pancreatic cancer.","evidence":"Co-IP, proteasome/cullin and UBR4 knockdown, E7 separation-of-function variants, p53 mouse cancer model and human mutual-exclusivity analysis","pmids":["27651363","30894485","28100625","29017057"],"confidence":"High","gaps":["Whether PTPN14 catalytic activity matters for the HPV phenotypes not yet pinned down","Downstream effectors of the p53-PTPN14-YAP axis incompletely mapped"]},{"year":2018,"claim":"Identifying Roquin2 Tyr-691 as a catalytic substrate linked PTPN14 dephosphorylation to control of an mRNA-decay factor via its E3 ligase interaction.","evidence":"Co-IP, mass spectrometry, phospho-site mapping, KLHL6-dependent degradation assay","pmids":["30209976"],"confidence":"Medium","gaps":["Single lab, limited independent replication","Physiological context of Roquin2 regulation not established"]},{"year":2019,"claim":"A crystal structure of HPV18 E7 bound to the PTPN14 phosphatase domain (Kd 18.2 nM) defined the degradation interface and enabled separation-of-function mutants showing E7-resistant PTPN14 better inhibits Hippo effectors; a parallel study placed PTPN14-YAP upstream of SMAD3/TGFβ signaling in synoviocytes.","evidence":"X-ray crystallography, SPR, structure-guided mutagenesis; Co-IP, SMAD reporter and disease model with non-YAP-binding mutant","pmids":["31323018","30808624"],"confidence":"High","gaps":["How E7 binding to the catalytic domain alters phosphatase function not detailed","TGFβ/SMAD link mechanistically shallow"]},{"year":2020,"claim":"Multiple substrates and partners were established, defining PTPN14 catalytic roles in endothelial barrier recovery (VE-cadherin Tyr-658), an NPM1-driven nuclear retention mechanism under hypoxia that releases YAP, an inflammatory PTPN14-SOCS7-NF-κB axis, and a conserved C-terminal arginine in E7 required for PTPN14 binding/degradation.","evidence":"Phospho-site-specific antibodies, Co-IP, PLD2 manipulation, in vivo permeability/liver-failure models, E7 arginine mutants with CRISPR rescue","pmids":["32327488","32978373","35135548","32581101"],"confidence":"High","gaps":["Whether SOCS7 ubiquitination is direct vs. indirect unclear","Integration of catalytic substrate roles with scaffold-YAP role incomplete"]},{"year":2024,"claim":"New substrates (PDGFRβ Tyr-692, BCAR3) and a definitive scaffold-mechanism study clarified that PTPN14 controls keratinocyte differentiation through LATS1-dependent YAP phosphorylation requiring its PPxY motifs but not its catalytic site, while also using catalysis to restrain SMC switching and anoikis resistance.","evidence":"Phospho-site antibodies, SMC conditional KO/OE mice, genome-wide CRISPR screen, LATS1/2 KO and active-site/PPxY mutants in keratinocytes","pmids":["39191789","39189475","39248565"],"confidence":"High","gaps":["What dictates choice between scaffold vs. catalytic mode in a given tissue","Mechanism of LATS1 phosphorylation by the scaffold not resolved"]},{"year":2025,"claim":"In vivo knockout revealed sexually dimorphic, YAP-dependent tissue phenotypes; small-molecule (fenofibrate) engagement of the PPxY motif assembling a PTPN14/LATS1/MARK3 complex demonstrated pharmacological exploitability; RB1 and PTPN14 inactivation were shown to be jointly required for HPV E7 immortalization.","evidence":"Constitutive KO mouse histopathology/YAP IF; direct PPxY binding and complex Co-IP with functional knockdown; E7 separation-of-function complementation (preprint)","pmids":["40533389","40858196","41890011"],"confidence":"High","gaps":["Basis of female-specific phenotypes unexplained","Role of MARK3 in physiological PTPN14-LATS1 signaling not defined"]},{"year":null,"claim":"How PTPN14's scaffold (LATS1-activating) and catalytic (multi-substrate) functions are selected and integrated within a given cell, and what determines its nuclear-cytoplasmic partitioning beyond density and hypoxia, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling localization to catalytic vs. scaffold output","Structural mechanism of LATS1 activation by the PTPN14-Kibra scaffold unknown","Tissue determinants of substrate selection uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,10,16,20,23,24]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,20,23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,9,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,5,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,9,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,14,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,26]}],"complexes":["PTPN14-Kibra-LATS1 complex","PTPN14/LATS1/MARK3 complex","PTPN14-VE-cadherin-PLD2 junctional complex"],"partners":["YAP1","WWBP2/KIBRA","LATS1","VEGFR3","NPM1","RIN1","PRKCD","PDGFRB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15678","full_name":"Tyrosine-protein phosphatase non-receptor type 14","aliases":["Protein-tyrosine phosphatase pez"],"length_aa":1187,"mass_kda":135.3,"function":"Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mesenchymal transition. 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Version","date":"2024-07-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.03.24309734","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32050,"output_tokens":8006,"usd":0.10812,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17349,"output_tokens":5395,"usd":0.11081,"stage2_stop_reason":"end_turn"},"total_usd":0.21893,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"PTPN14 (Pez) was identified as a novel non-receptor protein tyrosine phosphatase with N-terminal FERM domain homology (ezrin/band 4.1/merlin/radixin family) and a C-terminal PTP catalytic domain, encoded on chromosome 1q32.2-41.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blot, FISH mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — original cloning paper with sequence analysis and chromosomal mapping; domain architecture established by sequence homology, single lab\",\n      \"pmids\": [\"7733990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTPN14 (Pez) localizes to the nucleus in proliferating/low-density endothelial cells and translocates to the cytoplasm in confluent quiescent monolayers; TGFβ inhibited nuclear translocation at wound edges, linking nuclear localization to cell proliferation.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, density manipulation, serum starvation/refeeding, wound assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional correlate (proliferation state), single lab, multiple conditions tested\",\n      \"pmids\": [\"10934049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTPN14 (Pez) localizes to adherens junctions in confluent epithelial cells and directly dephosphorylates β-catenin; a catalytic-domain truncation dominant-negative mutant increased tyrosine phosphorylation at adherens junctions and enhanced cell motility.\",\n      \"method\": \"Immunofluorescence, substrate-trapping approach, in vitro dephosphorylation with recombinant Pez, dominant-negative overexpression, wound motility assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro dephosphorylation with recombinant enzyme plus substrate trapping and dominant-negative functional readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12808048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN14 (Pez) overexpression in epithelial MDCK cells induces EMT accompanied by induction of TGFβ signaling; Pez knockdown in zebrafish disrupts organogenesis (brain, heart, pharyngeal arches, somites) and abolishes TGFβ3 expression from co-expressing tissues.\",\n      \"method\": \"Overexpression in MDCK cells (morphology, gene expression), morpholino knockdown in zebrafish, in situ hybridization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vivo (zebrafish) and gain-of-function in vitro with defined phenotypic readouts; single lab, two model systems\",\n      \"pmids\": [\"17893246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function mutation in PTPN14 causes autosomal-recessive lymphedema-choanal atresia syndrome; Ptpn14 gene-trap mice develop lymphatic hyperplasia with lymphedema; PTPN14 biochemically interacts with VEGFR3, a receptor tyrosine kinase essential for lymphangiogenesis.\",\n      \"method\": \"Genetic linkage, Sanger sequencing, murine gene-trap model (lymphatic phenotype), co-immunoprecipitation/biochemical interaction studies\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics plus mouse KO phenotype plus biochemical interaction; multiple orthogonal methods establishing role in lymphangiogenesis\",\n      \"pmids\": [\"20826270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPN14 interacts with YAP1 (via PTPN14 PPxY domain and YAP1 WW domain) and promotes nucleus-to-cytoplasm translocation of YAP1 during contact inhibition, suppressing YAP1 transcriptional activity; PTPN14 protein stability is positively regulated by cell density, and the CRL2(LRR1) E3 ubiquitin ligase complex targets PTPN14 for degradation at low cell density.\",\n      \"method\": \"shRNA screen, co-immunoprecipitation, subcellular fractionation/localization assays, luciferase reporter, ubiquitin ligase identification\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, localization, reporter, E3 identification), replicated by independent lab (PMID:22525271)\",\n      \"pmids\": [\"22948661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPN14 directly interacts with YAP through the WW domain of YAP and the PPxY domain of PTPN14; YAP is a direct substrate of PTPN14 phosphatase activity; PTPN14 inhibits YAP transcriptional co-activator function and increases cytoplasmic YAP; PTPN14 knockdown induces nuclear retention of YAP and increases YAP-dependent cell migration.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, immunofluorescence, siRNA knockdown, migration assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct substrate identification, Co-IP with domain mapping, reporter assay, functional readout; independently replicated by multiple labs\",\n      \"pmids\": [\"22525271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila Pez (ortholog of PTPN14) acts as a negative upstream regulator of Yorkie (YAP ortholog) specifically in the fly midgut epithelium by binding the upstream Hippo component Kibra; the PTP catalytic domain of Pez is dispensable for Hippo pathway activity in this context.\",\n      \"method\": \"Genetic loss-of-function in Drosophila, co-immunoprecipitation (Pez-Kibra interaction), ISC proliferation assays, PTP domain mutant analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Drosophila genetic epistasis with Co-IP and domain dissection; established in vivo Hippo pathway position\",\n      \"pmids\": [\"22305752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTPN14 negatively regulates YAP activity by controlling its cytoplasmic localization; the WW/PPxY interaction between PTPN14 and YAP mediates their binding, but the PPxY motif and phosphatase activity of PTPN14 are dispensable for regulation of endogenous YAP; PTPN14 downregulation phenocopies YAP activation and synergizes with YAP to induce oncogenic transformation in mammary epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, domain/motif mutants, transformation assays, siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, important mechanistic dissection showing phosphatase activity dispensable; independently replicated findings\",\n      \"pmids\": [\"23613971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPN14 interacts with Kibra through PTPN14's PPXY domain and Kibra's WW domain; PTPN14 and Kibra each independently and cooperatively activate LATS1 kinase (in a manner independent of MST kinases); PTPN14 increases LATS1 protein stability; Kibra overexpression rescues the increased cell migration and aberrant 3D morphogenesis caused by PTPN14 knockdown via LATS1-mediated YAP cytoplasmic sequestration.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, siRNA knockdown, 3D morphogenesis assay, migration assay, immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods; establishes PTPN14-Kibra-LATS1 complex and MST-independent LATS1 activation mechanism\",\n      \"pmids\": [\"25023289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPN14 suppresses metastasis by reducing protein trafficking through the secretory pathway; loss of catalytically functional PTPN14 increases secretion of IL-8 and surface abundance of EGFR and FLT4/VEGFR3; PTPN14 directly binds and dephosphorylates RIN1 and PRKCD; RIN1 dephosphorylation or PRKCD loss mimics PTPN14 overexpression in restricting receptor trafficking.\",\n      \"method\": \"shRNA knockdown, mouse xenograft model, co-immunoprecipitation, substrate identification (phosphoproteomics/pulldown), phosphomutant rescue, cytokine secretion assays, EGFR/FLT4 surface abundance measurements\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple substrates identified (RIN1, PRKCD), in vivo model, mechanistic pathway placement with functional rescue; single lab but highly rigorous multi-method study\",\n      \"pmids\": [\"25690013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Suppressor of Deltex (Su(dx)) E3 ubiquitin ligase targets Drosophila Pez (PTPN14 ortholog) for degradation via WW domain–PY/PPxY motif interactions; Kibra stabilizes Pez through the same WW-PY/PPxY interaction; the mammalian Su(dx) homolog WWP1 similarly degrades PTPN14 in mammalian cells.\",\n      \"method\": \"In vitro and in vivo degradation assays in Drosophila, co-immunoprecipitation (WW-PPxY interaction), overexpression rescue experiments, mammalian cell WWP1 overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo degradation assays, domain interaction mapping, conserved in mammalian cells; multiple orthogonal methods\",\n      \"pmids\": [\"25814387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"High-risk HPV E7 proteins target PTPN14 for proteasome-mediated degradation; this requires the E3 ubiquitin ligase UBR4; residues in the C-terminus of E7 interact with the C-terminal phosphatase domain of PTPN14; PTPN14 degradation correlates with retinoblastoma-independent transforming activity of high-risk HPV E7.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor assays, UBR4 siRNA knockdown, domain mapping, transformation assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — E3 ligase identification, domain mapping, degradation mechanism established; independently replicated by Banks lab (PMID:28100625)\",\n      \"pmids\": [\"27651363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"High-risk HPV E7-mediated PTPN14 degradation (proteasome-dependent, via UBR4/p600 ubiquitin ligase) impairs keratinocyte differentiation; using an HPV16 E7 variant that degrades pRb but cannot degrade PTPN14, PTPN14 degradation was shown to contribute to HPV E6/E7-mediated keratinocyte immortalization and anoikis resistance independent of RB1 inactivation.\",\n      \"method\": \"E7 variant with separated RB1/PTPN14 activities, CRISPR/primary keratinocyte culture, differentiation gene expression, anoikis/detachment survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic separation of E7 activities with defined functional readouts; multiple independent experiments establishing PTPN14-specific contribution\",\n      \"pmids\": [\"30894485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The p53-target gene Ptpn14 is necessary and sufficient for pancreatic cancer suppression downstream of p53; Ptpn14 negatively regulates the Yap oncoprotein; PTPN14 and TP53 mutations are mutually exclusive in human cancers, establishing a p53-Ptpn14-Yap pathway.\",\n      \"method\": \"Mouse pancreatic cancer model (p53 TAD mutants), shRNA knockdown, overexpression studies, analysis of human cancer mutation databases\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with genetic necessity/sufficiency tests, human cancer mutual exclusivity; multiple orthogonal methods\",\n      \"pmids\": [\"29017057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPN14 interacts with HPV E7 C-terminal region independently of pRb; high-risk E7 induces proteasome-mediated PTPN14 degradation (via UBR4/p600, independent of cullin-1/cullin-2) in cervical cancer cells; PTPN14 overexpression decreases the ability of HPV-16 E7 to cooperate with activated EJ-ras in primary cell transformation.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor and cullin knockdown assays, transformation/focus formation assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection of degradation pathway with multiple knockdowns, independent replication of E7-PTPN14 degradation findings\",\n      \"pmids\": [\"28100625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPN14 specifically interacts with the mRNA decay factor Roquin2 through its phosphatase domain and dephosphorylates Roquin2 at tyrosine 691; this dephosphorylation restores the Roquin2-KLHL6 E3 ligase interaction, promoting Roquin2 proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry identification, phospho-site mapping, in vivo phosphorylation assays, overexpression of PTPN14, KLHL6-dependent degradation assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification and dephosphorylation with defined downstream consequence; single lab, multiple methods but limited independent replication\",\n      \"pmids\": [\"30209976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of HPV18 E7 C-terminal domain bound to PTPN14 catalytic domain was solved; the interaction has a Kd of 18.2 nM; structure-based mutagenesis of the binding interface impaired E7-promoted keratinocyte proliferation/migration and rendered PTPN14 resistant to proteasomal degradation; E7-binding-defective PTPN14 more effectively inhibited Hippo signaling downstream effectors.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance (binding affinity), structure-guided mutagenesis, cell proliferation/migration/invasion assays, immunoblot for Hippo signaling\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus structure-based mutagenesis with functional validation; rigorous single study with multiple orthogonal methods\",\n      \"pmids\": [\"31323018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In rheumatoid arthritis fibroblast-like synoviocytes (FLS), PTPN14 forms a complex with YAP and promotes nuclear localization of SMAD3 and TGFβ signaling (MMP13 expression, TNF potentiation); a non-YAP-interacting PTPN14 mutant fails to enhance SMAD reporter activity, indicating the PTPN14-YAP interaction is required for this function.\",\n      \"method\": \"Co-immunoprecipitation, antisense oligonucleotide knockdown, immunofluorescence, SMAD luciferase reporter, RA FLS-cartilage co-implantation model\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assay, in vivo model, mutant analysis; single lab but multiple orthogonal methods in disease-relevant context\",\n      \"pmids\": [\"30808624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A conserved C-terminal arginine in diverse HPV E7 proteins mediates the interaction with PTPN14; mutation of this arginine prevents PTPN14 binding and degradation (via UBR4), renders HPV16 and HPV18 E7 unable to repress keratinocyte differentiation gene expression, and prevents HPV18 E7 from extending keratinocyte lifespan; PTPN14 CRISPR knockout rescued keratinocyte lifespan in cells expressing the PTPN14-binding-deficient E7 variant.\",\n      \"method\": \"E7 arginine mutant analysis, Co-immunoprecipitation, CRISPR/Cas9 knockout rescue experiment, differentiation gene expression assays, keratinocyte lifespan assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiment, domain mapping, multiple functional readouts; stringent mechanistic dissection with CRISPR rescue\",\n      \"pmids\": [\"32581101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLD2-generated phosphatidic acid promotes PTPN14 activity; PTPN14, VE-cadherin, and PLD2 form a complex at adherens junctions after thrombin stimulation; PTPN14 dephosphorylates VE-cadherin at Tyr-658, enabling VE-cadherin recycling and endothelial barrier recovery after edemagenic insult.\",\n      \"method\": \"Co-immunoprecipitation, VE-cadherin phospho-site specific antibodies, siRNA knockdown, PLD2 inhibitor/deletion, in vivo lung permeability model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate (VE-cadherin Tyr-658) identified with phospho-site specificity, complex characterized by Co-IP, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"32327488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPN14 interacts with SOCS7 and promotes its degradation via ubiquitination at K11 and K48 linkages, reducing SOCS7 protein levels; SOCS7 blocks NF-κB signaling by inhibiting IKK complex activity; PTPN14 deficiency reduces inflammation in LPS+D-GalN-induced acute liver failure via the PTPN14-SOCS7-NF-κB axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K11/K48 linkage-specific), PTPN14 knockout mouse model, NF-κB signaling assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination site identification, mouse KO model; single lab, multiple methods\",\n      \"pmids\": [\"32978373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hypoxia-induced nuclear translocation of PTPN14 in hepatocellular carcinoma causes resistance to sorafenib; NPM1 regulates PTPN14 localization under hypoxia, retaining it in the nucleus and thereby releasing YAP from PTPN14-mediated cytoplasmic sequestration.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation, siRNA knockdown, hypoxia treatment, co-immunoprecipitation (NPM1-PTPN14), HCC cell functional assays and xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization experiments with functional consequence, Co-IP establishing NPM1-PTPN14 interaction; single lab, moderate evidence\",\n      \"pmids\": [\"35135548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPN14 interacts with intracellular region of PDGFRβ and dephosphorylates it at Y692; phosphorylation of PDGFRβ Y692 negatively regulates PDGFRβ signaling; PTPN14 overexpression (phosphatase activity-dependent) exacerbates neointimal hyperplasia in mice by boosting PDGFRβ signaling-induced smooth muscle cell phenotypic modulation, while SMC-specific PTPN14 deletion mitigates it.\",\n      \"method\": \"Co-immunoprecipitation, phospho-site specific antibodies (Y692), SMC-specific conditional KO mouse (neointima model), RNA-seq, overexpression studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — substrate (PDGFRβ Y692) identified biochemically, in vivo KO and OE mouse models, phosphatase activity-dependence confirmed; multiple orthogonal methods\",\n      \"pmids\": [\"39191789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPN14 is identified as a key regulator of anoikis resistance in triple-negative breast cancer; PTPN14 dephosphorylates BCAR3 (breast cancer antiestrogen resistance 3), leading to inhibition of PI3K/AKT and ERK signaling; PTPN14 mRNA-LNP delivery inhibited TNBC tumor growth and metastasis in vivo.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 knockout screen, substrate identification (BCAR3 dephosphorylation), PI3K/AKT/ERK signaling assays, mRNA-LNP mouse xenograft\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen with substrate validation, in vivo model; single lab, moderate mechanistic depth in abstract\",\n      \"pmids\": [\"39189475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPN14 knockout or HPV18 E7-mediated PTPN14 degradation decreases phosphorylation of LATS1 at T1079 and YAP1 at S127 in human keratinocytes; PTPN14-dependent differentiation requires LATS kinases and specific PPxY motifs in PTPN14 but not MST1/2 kinases or the PTPN14 phosphatase active site, placing PTPN14 as a scaffold regulator of LATS1 upstream of YAP1.\",\n      \"method\": \"PTPN14 CRISPR knockout, phospho-specific immunoblots (LATS1 T1079, YAP1 S127), LATS1/2 double knockout, PPxY motif mutants, phosphatase active-site mutants, keratinocyte differentiation assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic dissection with KO, phospho-site analysis, domain mutants, active-site mutants; multiple orthogonal methods establishing scaffold (not phosphatase) mechanism for LATS1 activation\",\n      \"pmids\": [\"39248565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPN14 knockout mice develop corneal lesions, hydrometra, heart and kidney abnormalities with only ~60% postnatal survival; the cornea shows impaired injury response and both cornea and uterus exhibit dysregulated YAP signaling; phenotypes are female-specific, revealing sexually dimorphic Hippo pathway function.\",\n      \"method\": \"Ptpn14 constitutive knockout mouse generation, histopathology, immunofluorescence for YAP, corneal injury assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse model with multiple defined tissue phenotypes and YAP signaling readouts; peer-reviewed with preprint version also available\",\n      \"pmids\": [\"40533389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fenofibrate directly binds the PPxY motif of PTPN14, facilitating formation of a PTPN14/LATS1/MARK3 complex that promotes cytoplasmic sequestration of YAP; PTPN14 knockdown or MARK3 inhibition abolished fenofibrate-mediated suppression of cancer cell malignant phenotypes.\",\n      \"method\": \"Direct binding assay (PPxY motif), co-immunoprecipitation (PTPN14/LATS1/MARK3 complex), siRNA knockdown, YAP localization assays, cancer cell functional assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and complex formation with functional knockdown rescue; single lab, limited independent replication\",\n      \"pmids\": [\"40858196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Inactivation of both RB1 and PTPN14 is required for high-risk HPV E7-mediated keratinocyte immortalization; neither RB1-binding-deficient nor PTPN14-binding-deficient E7 mutant alone could extend keratinocyte lifespan, but together they reconstituted wild-type E7 activity; PTPN14 depletion and RB1 inactivation act synergistically to induce cell cycle regulatory gene expression.\",\n      \"method\": \"Genetic complementation with E7 separation-of-function mutants (RB1-binding-deficient and PTPN14-binding-deficient), primary keratinocyte lifespan assay, gene expression analysis\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic complementation experiment; preprint, single lab, but rigorous separation-of-function approach\",\n      \"pmids\": [\"41890011\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PTPN14 is an evolutionarily conserved FERM domain-containing non-receptor tyrosine phosphatase that functions primarily as a scaffold/adaptor to activate LATS1 kinase (independent of MST1/2 and its own phosphatase activity), thereby driving YAP1 phosphorylation and cytoplasmic sequestration; it also acts as a direct phosphatase for substrates including β-catenin (at adherens junctions), VE-cadherin (Tyr-658, restoring endothelial barrier function), PDGFRβ (Tyr-692, a self-inhibitory site controlling SMC phenotypic switching), RIN1 and PRKCD (restricting secretory trafficking), BCAR3 (suppressing PI3K/AKT and ERK), STAT3, and Roquin2 (Tyr-691, controlling its E3 ligase interaction); its subcellular localization switches between cytoplasm (in confluent cells, where it retains YAP in the cytoplasm) and nucleus (in proliferating cells or under hypoxia, where NPM1 retains it and YAP is released); PTPN14 protein stability is density-dependent, being degraded by CRL2(LRR1) at low density and by the WWP1/Su(dx) E3 ligases via its PPxY motifs; high-risk HPV E7 oncoproteins target PTPN14 for UBR4-mediated proteasomal degradation through a C-terminal arginine-mediated interaction, thereby inhibiting keratinocyte differentiation and—cooperatively with RB1 inactivation—immortalizing keratinocytes; PTPN14 loss-of-function in vivo causes lymphatic hyperplasia, female-specific corneal and uterine defects, and pancreatic cancer susceptibility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPN14 is an evolutionarily conserved FERM domain–containing non-receptor protein tyrosine phosphatase that acts as a central negative regulator of the Hippo pathway effector YAP, coupling cell-density and growth-state cues to growth suppression [#0, #5, #6]. Its dominant mechanism is non-catalytic: PTPN14 binds YAP through reciprocal PPxY–WW interactions and, by binding the upstream component Kibra, cooperatively activates and stabilizes LATS1 kinase independently of MST1/2, driving LATS1-dependent YAP phosphorylation (YAP1 S127), cytoplasmic sequestration, and loss of YAP transcriptional output [#5, #6, #9, #25]. This scaffold function requires PTPN14's PPxY motifs but not its phosphatase active site [#8, #25]. PTPN14 localization is growth-state-dependent, residing in the nucleus in proliferating/low-density cells and at the cytoplasm/adherens junctions in confluent monolayers, with NPM1 retaining it in the nucleus under hypoxia to release YAP [#1, #2, #22]. In parallel, PTPN14 acts as a bona fide tyrosine phosphatase on multiple substrates, dephosphorylating β-catenin at adherens junctions [#2], VE-cadherin at Tyr-658 to restore endothelial barrier function [#20], PDGFRβ at Tyr-692 to restrain smooth-muscle phenotypic switching [#23], RIN1 and PRKCD to limit secretory trafficking and metastasis [#10], and BCAR3 to suppress PI3K/AKT and ERK signaling [#24]. PTPN14 protein levels are tightly controlled by ubiquitin ligases—CRL2(LRR1) at low density and WWP1/Su(dx) via its PPxY motifs—while high-risk HPV E7 oncoproteins co-opt UBR4 to degrade PTPN14 through a high-affinity C-terminal interaction with the phosphatase domain, impairing keratinocyte differentiation and, together with RB1 inactivation, immortalizing keratinocytes [#5, #11, #12, #17, #28]. Loss-of-function mutations in PTPN14 cause autosomal-recessive lymphedema-choanal atresia syndrome, and PTPN14 is a p53-induced tumor suppressor of pancreatic cancer acting through YAP [#4, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing PTPN14's domain architecture defined it as a candidate cytoskeleton/membrane-associated phosphatase, framing all later mechanistic work.\",\n      \"evidence\": \"cDNA cloning, sequence analysis and FISH mapping of a FERM-PTP protein\",\n      \"pmids\": [\"7733990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate or pathway assigned at this stage\", \"FERM-domain binding partners not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linking PTPN14 localization to proliferation state revealed that its function is regulated by a nuclear-cytoplasmic switch tied to cell density.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence and density/wound assays in endothelial cells\",\n      \"pmids\": [\"10934049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular driver of the localization switch unknown\", \"Functional output of localization not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying β-catenin as a direct substrate at adherens junctions provided the first catalytic substrate and connected PTPN14 to junctional integrity and motility.\",\n      \"evidence\": \"Substrate trapping, in vitro dephosphorylation with recombinant enzyme, dominant-negative motility assay\",\n      \"pmids\": [\"12808048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address Hippo/YAP regulation\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that PTPN14 perturbation drives EMT and organogenesis defects established it as a developmental regulator linked to TGFβ signaling.\",\n      \"evidence\": \"Overexpression in MDCK cells and morpholino knockdown in zebrafish\",\n      \"pmids\": [\"17893246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting PTPN14 to TGFβ unresolved\", \"No molecular substrate linked to the phenotype\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Human genetics and mouse models tied PTPN14 loss to lymphedema-choanal atresia and lymphatic hyperplasia, with a VEGFR3 interaction giving a candidate mechanism.\",\n      \"evidence\": \"Genetic linkage/sequencing, gene-trap mouse, co-immunoprecipitation\",\n      \"pmids\": [\"20826270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VEGFR3 is a phosphatase substrate not established\", \"Causal pathway from interaction to lymphatic phenotype incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Convergent studies placed PTPN14 as a YAP-binding negative regulator that promotes YAP cytoplasmic localization during contact inhibition, with density-dependent stability controlled by CRL2(LRR1).\",\n      \"evidence\": \"shRNA screen, Co-IP with domain mapping, fractionation, luciferase reporter and E3 ligase identification across multiple labs\",\n      \"pmids\": [\"22948661\", \"22525271\", \"22305752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YAP regulation requires phosphatase catalysis was disputed\", \"Upstream kinase mediating the effect not yet defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that the PPxY motif and phosphatase activity are dispensable for endogenous YAP regulation reframed PTPN14 as a scaffold rather than a YAP-directed enzyme.\",\n      \"evidence\": \"Domain/motif and active-site mutants, transformation assays, siRNA in mammary epithelial cells\",\n      \"pmids\": [\"23613971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the activated kinase still unknown at this point\", \"Reconciliation with earlier direct-substrate claims left open\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying the PTPN14-Kibra-LATS1 axis explained how PTPN14 represses YAP without MST kinases, by cooperatively activating and stabilizing LATS1.\",\n      \"evidence\": \"Co-IP, kinase activity assays, 3D morphogenesis and migration rescue with Kibra\",\n      \"pmids\": [\"25023289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LATS1 activation not resolved\", \"Quantitative contribution of scaffolding vs. stability unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two studies defined PTPN14 stability control by WWP1/Su(dx) via PPxY motifs and revealed catalytic suppression of secretory trafficking through RIN1 and PRKCD dephosphorylation.\",\n      \"evidence\": \"Degradation assays with domain mapping in Drosophila/mammalian cells; substrate identification, phosphomutant rescue, xenografts\",\n      \"pmids\": [\"25814387\", \"25690013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between scaffold and catalytic functions not integrated\", \"How trafficking substrates relate to YAP control unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"High-risk HPV E7 was shown to drive UBR4-dependent PTPN14 degradation via a C-terminal E7–phosphatase-domain interaction, establishing PTPN14 as an RB1-independent E7 target controlling differentiation and immortalization, and p53 was shown to act through Ptpn14 to suppress pancreatic cancer.\",\n      \"evidence\": \"Co-IP, proteasome/cullin and UBR4 knockdown, E7 separation-of-function variants, p53 mouse cancer model and human mutual-exclusivity analysis\",\n      \"pmids\": [\"27651363\", \"30894485\", \"28100625\", \"29017057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PTPN14 catalytic activity matters for the HPV phenotypes not yet pinned down\", \"Downstream effectors of the p53-PTPN14-YAP axis incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying Roquin2 Tyr-691 as a catalytic substrate linked PTPN14 dephosphorylation to control of an mRNA-decay factor via its E3 ligase interaction.\",\n      \"evidence\": \"Co-IP, mass spectrometry, phospho-site mapping, KLHL6-dependent degradation assay\",\n      \"pmids\": [\"30209976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, limited independent replication\", \"Physiological context of Roquin2 regulation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A crystal structure of HPV18 E7 bound to the PTPN14 phosphatase domain (Kd 18.2 nM) defined the degradation interface and enabled separation-of-function mutants showing E7-resistant PTPN14 better inhibits Hippo effectors; a parallel study placed PTPN14-YAP upstream of SMAD3/TGFβ signaling in synoviocytes.\",\n      \"evidence\": \"X-ray crystallography, SPR, structure-guided mutagenesis; Co-IP, SMAD reporter and disease model with non-YAP-binding mutant\",\n      \"pmids\": [\"31323018\", \"30808624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How E7 binding to the catalytic domain alters phosphatase function not detailed\", \"TGFβ/SMAD link mechanistically shallow\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple substrates and partners were established, defining PTPN14 catalytic roles in endothelial barrier recovery (VE-cadherin Tyr-658), an NPM1-driven nuclear retention mechanism under hypoxia that releases YAP, an inflammatory PTPN14-SOCS7-NF-κB axis, and a conserved C-terminal arginine in E7 required for PTPN14 binding/degradation.\",\n      \"evidence\": \"Phospho-site-specific antibodies, Co-IP, PLD2 manipulation, in vivo permeability/liver-failure models, E7 arginine mutants with CRISPR rescue\",\n      \"pmids\": [\"32327488\", \"32978373\", \"35135548\", \"32581101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SOCS7 ubiquitination is direct vs. indirect unclear\", \"Integration of catalytic substrate roles with scaffold-YAP role incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"New substrates (PDGFRβ Tyr-692, BCAR3) and a definitive scaffold-mechanism study clarified that PTPN14 controls keratinocyte differentiation through LATS1-dependent YAP phosphorylation requiring its PPxY motifs but not its catalytic site, while also using catalysis to restrain SMC switching and anoikis resistance.\",\n      \"evidence\": \"Phospho-site antibodies, SMC conditional KO/OE mice, genome-wide CRISPR screen, LATS1/2 KO and active-site/PPxY mutants in keratinocytes\",\n      \"pmids\": [\"39191789\", \"39189475\", \"39248565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates choice between scaffold vs. catalytic mode in a given tissue\", \"Mechanism of LATS1 phosphorylation by the scaffold not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In vivo knockout revealed sexually dimorphic, YAP-dependent tissue phenotypes; small-molecule (fenofibrate) engagement of the PPxY motif assembling a PTPN14/LATS1/MARK3 complex demonstrated pharmacological exploitability; RB1 and PTPN14 inactivation were shown to be jointly required for HPV E7 immortalization.\",\n      \"evidence\": \"Constitutive KO mouse histopathology/YAP IF; direct PPxY binding and complex Co-IP with functional knockdown; E7 separation-of-function complementation (preprint)\",\n      \"pmids\": [\"40533389\", \"40858196\", \"41890011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of female-specific phenotypes unexplained\", \"Role of MARK3 in physiological PTPN14-LATS1 signaling not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPN14's scaffold (LATS1-activating) and catalytic (multi-substrate) functions are selected and integrated within a given cell, and what determines its nuclear-cytoplasmic partitioning beyond density and hypoxia, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling localization to catalytic vs. scaffold output\", \"Structural mechanism of LATS1 activation by the PTPN14-Kibra scaffold unknown\", \"Tissue determinants of substrate selection uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 10, 16, 20, 23, 24]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 20, 23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 9, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 9, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 14, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 26]}\n    ],\n    \"complexes\": [\n      \"PTPN14-Kibra-LATS1 complex\",\n      \"PTPN14/LATS1/MARK3 complex\",\n      \"PTPN14-VE-cadherin-PLD2 junctional complex\"\n    ],\n    \"partners\": [\n      \"YAP1\",\n      \"WWBP2/KIBRA\",\n      \"LATS1\",\n      \"VEGFR3\",\n      \"NPM1\",\n      \"RIN1\",\n      \"PRKCD\",\n      \"PDGFRB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}