{"gene":"PEAK1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2017,"finding":"X-ray crystal structure of the PEAK1 pseudokinase domain (2.3 Å resolution) revealed a closed nucleotide-binding cleft that may preclude nucleotide binding, and identified N- and C-terminal extensions forming an all α-helical split-helical dimerization (SHED) region that mediates dimerization conserved between PEAK1 and pragmin (SgK223).","method":"X-ray crystallography, sequence conservation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.3 Å resolution with structural and sequence-based functional validation in a single rigorous study","pmids":["29212708"],"is_preprint":false},{"year":2012,"finding":"PEAK1 localizes to the actin cytoskeleton and focal adhesions in migrating cells; phosphorylation of Tyr-665 (by Src family kinases) is required for normal PEAK1 localization and regulation of focal adhesion assembly and disassembly kinetics; constitutive phosphorylation at Tyr-665 is also disruptive, indicating a requirement for dynamic, spatiotemporally precise regulation.","method":"PEAK1 knockdown, phospho-site mutagenesis (Y665F and phosphomimetic), live-cell focal adhesion imaging, Src inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, mutagenesis, live-cell imaging, kinase inhibition), replicated across contexts in one rigorous study","pmids":["23105102"],"is_preprint":false},{"year":2012,"finding":"Oncogenic KRas induces a kinase amplification loop involving Src, PEAK1, and ErbB2 in pancreatic cancer cells; blockade of ErbB2 increased Src-dependent PEAK1 expression and PEAK1-dependent Src activation, suggesting PEAK1 mediates ErbB2-inhibitor resistance.","method":"In vivo tumor models, RNAi knockdown, pathway epistasis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD experiments with defined signaling epistasis, single lab","pmids":["22589274"],"is_preprint":false},{"year":2013,"finding":"The Src family kinase Lyn directly phosphorylates PEAK1 (SgK269) in basal breast cancer cells; Tyr-635 is a major Lyn phosphorylation site on PEAK1 and serves as a Grb2-binding site that promotes Stat3 and Erk activation; mutation Y635F abrogates enhanced acinar size and cellular invasion.","method":"Phosphoproteomics (Lyn substrate identification), Co-IP, Y635F mutagenesis, 3D culture invasion assays, RNAi","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphoproteomic identification, mutagenesis, and functional validation with multiple orthogonal assays in one study","pmids":["23378338"],"is_preprint":false},{"year":2016,"finding":"PEAK1 (SgK269) undergoes homotypic self-association and heterotypic association with the related pseudokinase SgK223; both associations require the CH (coiled-helix) and PK (pseudokinase) domains of both proteins; SgK269 bridges SgK223 to Grb2 but cannot activate Stat3 or efficiently enhance migration in SgK223 knockout cells, demonstrating that SgK223 is required for full SgK269 signaling output.","method":"Mass spectrometry-based interactomics, pulldowns, size-exclusion chromatography, CRISPR/Cas9 SgK223 KO, migration and Stat3 activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods plus genetic KO with defined functional readouts in one study","pmids":["27531744"],"is_preprint":false},{"year":2020,"finding":"AXL phosphorylates NEDD9, leading to NEDD9 binding to CRKII, which in turn associates with PEAK1; PEAK1 forms a complex with the tyrosine kinase CSK to mediate phosphorylation of PAXILLIN, thereby driving focal adhesion disassembly, cell migration and invasion downstream of AXL.","method":"Phosphoproteomics, Co-IP, proximity labeling, RNAi knockdown, in vivo metastasis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphoproteomic mapping combined with Co-IP complex validation and in vivo functional confirmation, multiple orthogonal methods","pmids":["32681075"],"is_preprint":false},{"year":2022,"finding":"PEAK1 interacts indirectly with RGD-binding integrins (α5β1, αVβ3, αVβ5) in focal adhesions through Tensin3; the SH2 domain of Tensin3 binds phosphorylated Tyr-635 on PEAK1 (phosphorylated by Src), and both the integrin β-tail NPxY motif and PEAK1 pY635 are required for this interaction; additionally, phosphorylated Tyr-1188 on PEAK1 recruits Shc1 to focal adhesions, linking PEAK1 to late EGFR/Shc1 signaling.","method":"BioID proximity labeling of β1/β3 integrins, Co-IP, mutagenesis (Y635, NPxY), cell migration assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — BioID plus mutagenesis of multiple sites plus Co-IP validation, multiple orthogonal methods in one rigorous study","pmids":["35687021"],"is_preprint":false},{"year":2015,"finding":"PEAK1 mediates signaling cross talk between TGFβ receptors and integrin/Src/MAPK pathways; in the context of fibronectin, high PEAK1 expression switches TGFβ signaling from canonical Smad2/3 to non-canonical Src and MAPK pathways, promoting EMT, proliferation and metastasis; PEAK1 is necessary for TGFβ to induce ZEB1-mediated EMT.","method":"PEAK1 knockdown/overexpression, Smad2/3 and Src/MAPK pathway reporter assays, fibronectin/ITGB3 manipulation, in vivo metastasis models","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined signaling pathway switching and in vivo validation, single lab","pmids":["26267863"],"is_preprint":false},{"year":2015,"finding":"PEAK1 is necessary for TGFβ-induced ZEB1 expression and ZEB1-mediated EMT in oncogene-transformed mammary epithelial cells and triple-negative breast cancer cells, specifically in the context of fibronectin/ITGB3 activation.","method":"RNAi knockdown, fibronectin/integrin β3 manipulation, ZEB1 Western blot, EMT marker analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular target (ZEB1) in contextual signaling setting, single lab","pmids":["26297948"],"is_preprint":false},{"year":2014,"finding":"eIF5A proteins regulate PDAC cell growth by modulating PEAK1 expression; hypusination of eIF5A (catalyzed by DHPS and DOHH) is required for this regulation, and pharmacologic inhibition of eIF5A hypusination suppresses PEAK1 levels and PDAC cell growth.","method":"eIF5A knockdown/overexpression, DHPS/DOHH inhibitors, orthotopic tumor models, Western blot for PEAK1","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacologic perturbation of upstream regulator with PEAK1 as defined downstream effector, single lab","pmids":["25261239"],"is_preprint":false},{"year":2021,"finding":"PEAK1 is identified by BioID as a component of the ALK proximitome in neuroblastoma cells; PEAK1 was validated as an ALK interactor in NB cells; interaction was dependent on ALK kinase activity (blocked by lorlatinib).","method":"BioID proximity labeling, LC/MS-MS, validation Co-IP/pulldown with ALK TKI lorlatinib","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID discovery plus ALK-activity-dependent interaction validated biochemically, single lab","pmids":["34273398"],"is_preprint":false},{"year":2025,"finding":"PEAK1 interacts with ZO-1 via a conserved region (amino acids 714–731), masking the LC3-interacting region on ZO-1 and preventing autophagy-mediated ZO-1 degradation; Src-mediated phosphorylation of PEAK1 at Y724 promotes the PEAK1–ZO-1 interaction; PEAK1 also binds CSK to positively regulate Src activity; loss of PEAK1 in intestinal epithelial cells reduces Src activity and ZO-1 levels, disrupting tight junctions and increasing intestinal permeability in vivo.","method":"Co-IP, mutagenesis (Y724), domain mapping (aa 714–731), autophagy assays, PEAK1 conditional KO mice, colitis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, mutagenesis, domain mapping, and in vivo KO with defined mechanistic readouts across multiple orthogonal methods","pmids":["40707483"],"is_preprint":false},{"year":2025,"finding":"PEAK1 promotes CAMK2D and CAMK2G activation in TNBC cells via PLCγ1/Ca2+ signaling and direct binding to CAMK2 through a consensus CAMK2 interaction motif in the PEAK1 N-terminus; in turn, CAMK2 phosphorylates PEAK1 to enhance its association with PEAK2, which is critical for PEAK1 oncogenic signaling.","method":"Affinity purification-mass spectrometry, Co-IP, CAMK2 inhibitor (RA306), CRISPR PEAK1 ablation, TNBC xenograft/metastasis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — AP-MS identification plus Co-IP, pharmacologic and genetic perturbation, in vivo validation — multiple orthogonal methods","pmids":["39984440"],"is_preprint":false},{"year":2021,"finding":"In HER2-positive breast cancer, PEAK1 in mesenchymal stem cells (MSCs) mediates secretion of INHBA/activin-A, which promotes lapatinib resistance in co-cultured breast cancer cells; SNAI2 is an upstream transcriptional regulator of PEAK1 in stromal cells.","method":"MSC-tumor cell co-culture, PEAK1 knockdown in MSCs, conditioned media experiments, single-cell CycIF, INHBA neutralization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-culture loss-of-function with identified secreted factor (INHBA) as mechanism, single lab","pmids":["34239043"],"is_preprint":false},{"year":2021,"finding":"CDC5L protein binds directly to the PEAK1 gene promoter to promote PEAK1 transcription in ovarian cancer cells; PEAK1 overexpression in turn activates ERK1/2 and JAK2 signaling pathways.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, Western blot for ERK1/2 and JAK2 phosphorylation","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, single lab with orthogonal reporter assay","pmids":["32167655"],"is_preprint":false},{"year":2018,"finding":"PEAK1 promotes lung cancer EMT and metastasis by enhancing activation of ERK1/2 and JAK2 signaling pathways; combined inhibition of ERK1/2 (PD98059) and JAK2 (AZD1480) reverses PEAK1-induced EMT, migration and invasion.","method":"PEAK1 overexpression/KO, Western blot for p-ERK1/2 and p-JAK2, pharmacologic inhibitors, in vivo metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/OE plus pharmacologic epistasis with defined pathway readouts, single lab","pmids":["30038287"],"is_preprint":false},{"year":2018,"finding":"PEAK1 forms a complex with PPP1R12B (protein phosphatase 1 regulatory subunit 12B) in colorectal cancer cells; this axis suppresses activation of the Grb2/PI3K/Akt pathway; PI3K/Akt inhibitors reverse the effects of PEAK1 loss on cell proliferation, migration and invasion.","method":"Co-IP, PPP1R12B KD/OE, PI3K/Akt inhibitors, in vitro and in vivo tumor models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic and pharmacologic epistasis, single lab","pmids":["30472186"],"is_preprint":false},{"year":2025,"finding":"RHOV (an atypical Rho GTPase) directly interacts with PEAK1 as identified by immunoprecipitation coupled with LC-MS; the RHOV-PEAK1 complex is required for MYC upregulation and PI3K/MAPK signaling in NSCLC; PEAK1 depletion abolishes RHOV-driven MYC upregulation; additionally, PEAK1 maintains RHOV expression by inhibiting TGF-β signaling, establishing a negative feedback loop.","method":"Co-IP/LC-MS, PEAK1 and RHOV siRNA knockdown, Western blot for MYC/PI3K/MAPK, RNA-seq","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, Co-IP/LC-MS with KD epistasis but no structural or reconstitution validation","pmids":["bio_10.1101_2025.04.18.649622"],"is_preprint":true},{"year":2024,"finding":"PEAK1 ablation in CRC mouse models driven by Apc loss (with or without oncogenic Kras or Pten loss) does not significantly contribute to tumor formation in vivo, although PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization/lumenization in vitro.","method":"CRISPR/Cas9 PEAK1 KO, in vivo CRC mouse models (Apc, Kras, Pten), in vitro proliferation assays, 3D spheroid culture","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous in vivo genetic models; negative result for tumor formation but positive result for EGF-proliferation signaling in vitro","pmids":["39532961"],"is_preprint":false}],"current_model":"PEAK1 is a pseudokinase scaffold protein that localizes to focal adhesions and the actin cytoskeleton, where it integrates signals from receptor tyrosine kinases (ErbB2, AXL, ALK, EGFR), Src-family kinases (Lyn, Src), and integrins (via Tensin3) by serving as a phosphorylation-regulated assembly platform; Src phosphorylates PEAK1 at Y635 (promoting Grb2, Tensin3, and integrin binding) and Y724 (promoting ZO-1 binding to protect tight junctions from autophagy), while PEAK1 reciprocally activates Src through CSK binding; PEAK1 dimerizes with itself and heterodimerizes with the related pseudokinase SgK223 through a SHED domain, controlling signal output to Grb2/Stat3/ERK/PI3K-Akt/JAK2 pathways; PEAK1 also activates CAMK2D/G via PLCγ1/Ca²⁺ signaling and direct binding, with CAMK2 phosphorylating PEAK1 to enhance its association with PEAK2, completing a feed-forward oncogenic loop in triple-negative breast cancer."},"narrative":{"mechanistic_narrative":"PEAK1 is a pseudokinase scaffold that localizes to focal adhesions and the actin cytoskeleton, where it acts as a phosphorylation-regulated assembly platform integrating signals from receptor tyrosine kinases, Src-family kinases, and integrins to control cell migration, adhesion dynamics, and epithelial-mesenchymal transition [PMID:23105102, PMID:35687021]. Its pseudokinase domain adopts a closed nucleotide-binding cleft and is flanked by N- and C-terminal helical extensions that form a split-helical dimerization (SHED) region, enabling PEAK1 self-association and heterodimerization with the related pseudokinase SgK223; this dimerization is required for full signaling output to Grb2/Stat3 and for efficient migration [PMID:29212708, PMID:27531744]. PEAK1 function is gated by Src-family phosphorylation: phosphorylation at Tyr-665 governs proper focal-adhesion localization and the kinetics of adhesion assembly/disassembly, while Lyn/Src phosphorylation of Tyr-635 creates a docking site that recruits Grb2 to drive Stat3 and ERK activation and recruits the Tensin3 SH2 domain to couple PEAK1 to RGD-binding integrins [PMID:23105102, PMID:23378338, PMID:35687021]. Additional phosphosites extend its interactome — pY1188 recruits Shc1 to link PEAK1 to EGFR signaling, and Src-dependent pY724 promotes binding to ZO-1, masking its LC3-interacting region to protect tight junctions from autophagic degradation [PMID:35687021, PMID:40707483]. PEAK1 reciprocally activates Src through CSK binding and assembles adhesion-remodeling complexes such as the AXL–NEDD9–CRKII–PEAK1–CSK module that phosphorylates Paxillin to drive focal-adhesion disassembly and invasion [PMID:32681075, PMID:40707483]. Through these activities PEAK1 promotes oncogenic signaling and metastasis across multiple tumor contexts, including a CAMK2–PEAK1–PEAK2 feed-forward loop in triple-negative breast cancer and switching of TGFβ signaling toward non-canonical Src/MAPK and ZEB1-driven EMT [PMID:26267863, PMID:39984440]. In intestinal epithelium, PEAK1 loss in vivo reduces Src activity and ZO-1 levels, disrupting tight junctions and increasing intestinal permeability [PMID:40707483].","teleology":[{"year":2012,"claim":"Established that PEAK1 is a focal-adhesion and actin-cytoskeleton protein whose function depends on dynamic Src-family phosphorylation, defining it as a spatiotemporally regulated adhesion scaffold rather than a static structural component.","evidence":"PEAK1 knockdown, Y665F and phosphomimetic mutagenesis, live-cell focal adhesion imaging, and Src inhibition in migrating cells","pmids":["23105102"],"confidence":"High","gaps":["Did not identify the direct partners recruited to pY665","Mechanism linking phosphorylation to adhesion turnover kinetics unresolved"]},{"year":2012,"claim":"Placed PEAK1 within an oncogenic KRas-driven Src/ErbB2 amplification loop, linking it to receptor-tyrosine-kinase-inhibitor resistance in pancreatic cancer.","evidence":"In vivo tumor models with RNAi knockdown and pathway epistasis between Src, PEAK1, and ErbB2","pmids":["22589274"],"confidence":"Medium","gaps":["Direct biochemical interactions among the loop components not mapped","Single-lab in vivo epistasis"]},{"year":2013,"claim":"Identified Tyr-635 as a major Lyn/Src phosphosite that functions as a Grb2-docking site coupling PEAK1 to Stat3 and ERK activation, providing the first defined molecular output of PEAK1 phosphorylation.","evidence":"Lyn substrate phosphoproteomics, Co-IP, Y635F mutagenesis, and 3D culture invasion assays","pmids":["23378338"],"confidence":"High","gaps":["Whether Grb2 recruitment is direct to pY635 versus bridged not fully resolved","Quantitative contribution of Stat3 vs ERK arms not separated"]},{"year":2014,"claim":"Showed PEAK1 expression is controlled by hypusinated eIF5A, positioning PEAK1 as a translationally regulated effector in pancreatic cancer growth.","evidence":"eIF5A knockdown/overexpression, DHPS/DOHH inhibitors, and orthotopic tumor models with PEAK1 Western blot","pmids":["25261239"],"confidence":"Medium","gaps":["Direct vs indirect regulation of PEAK1 translation not distinguished","Single lab"]},{"year":2015,"claim":"Defined PEAK1 as a switch that reroutes TGFβ signaling from canonical Smad2/3 to non-canonical Src/MAPK and ZEB1-driven EMT in a fibronectin/integrin context.","evidence":"PEAK1 knockdown/overexpression, pathway reporter assays, fibronectin/ITGB3 manipulation, ZEB1 analysis, and in vivo metastasis models","pmids":["26267863","26297948"],"confidence":"Medium","gaps":["Molecular basis of the Smad-to-Src/MAPK switch unresolved","Single-lab findings"]},{"year":2016,"claim":"Demonstrated that PEAK1 homo- and heterodimerizes with SgK223 via CH and PK domains, and that SgK223 is required for full PEAK1 signaling output, establishing dimerization as a determinant of scaffold activity.","evidence":"Mass spectrometry interactomics, pulldowns, size-exclusion chromatography, CRISPR SgK223 knockout, and migration/Stat3 assays","pmids":["27531744"],"confidence":"High","gaps":["Stoichiometry and architecture of the heterodimer not structurally defined","How dimerization gates downstream signaling mechanistically unclear"]},{"year":2017,"claim":"Provided the structural basis for PEAK1 as a pseudokinase, showing a closed nucleotide-binding cleft and a SHED dimerization region conserved with pragmin/SgK223.","evidence":"X-ray crystallography of the PEAK1 pseudokinase domain at 2.3 Å with sequence conservation analysis","pmids":["29212708"],"confidence":"High","gaps":["Full-length structure including N-terminal regulatory regions not determined","Whether any nucleotide or small molecule can engage the cleft unknown"]},{"year":2018,"claim":"Connected PEAK1 to ERK1/2 and JAK2 activation driving EMT and metastasis, and to a PPP1R12B complex modulating Grb2/PI3K/Akt signaling, broadening its downstream pathway repertoire across cancer types.","evidence":"PEAK1 KO/OE, Co-IP with PPP1R12B, pharmacologic ERK/JAK2/PI3K-Akt inhibition, and in vivo metastasis models","pmids":["30038287","30472186"],"confidence":"Medium","gaps":["Direct vs indirect engagement of JAK2 and PI3K not established","Single-lab studies in distinct tumor contexts"]},{"year":2020,"claim":"Resolved a defined adhesion-remodeling module in which AXL-phosphorylated NEDD9 recruits CRKII to PEAK1, which complexes with CSK to drive Paxillin phosphorylation and focal-adhesion disassembly, mechanistically linking PEAK1 to invasion downstream of AXL.","evidence":"Phosphoproteomics, Co-IP, proximity labeling, RNAi, and in vivo metastasis assays","pmids":["32681075"],"confidence":"High","gaps":["Direct kinase responsible for Paxillin phosphorylation within the complex not pinned down","Temporal ordering of complex assembly unresolved"]},{"year":2021,"claim":"Extended the PEAK1 interactome to ALK in neuroblastoma and to stromal/transcriptional regulation, showing ALK-activity-dependent interaction, SNAI2-driven PEAK1 expression in MSCs promoting INHBA-mediated lapatinib resistance, and CDC5L-driven PEAK1 transcription activating ERK1/2 and JAK2.","evidence":"BioID/LC-MS with lorlatinib validation; MSC co-culture with PEAK1 KD and INHBA neutralization; ChIP and luciferase reporter assays","pmids":["34273398","34239043","32167655"],"confidence":"Medium","gaps":["Functional consequence of the ALK–PEAK1 interaction not defined","Direct vs indirect transcriptional control by CDC5L and SNAI2 not fully separated"]},{"year":2022,"claim":"Mapped how PEAK1 physically couples to adhesion machinery, showing Tensin3-SH2 binding to pY635 bridges PEAK1 to RGD-binding integrins and pY1188 recruits Shc1, defining phosphosite-specific integrin and EGFR linkages.","evidence":"BioID of β1/β3 integrins, Co-IP, and mutagenesis of Y635, Y1188, and the integrin NPxY motif with migration assays","pmids":["35687021"],"confidence":"High","gaps":["How simultaneous use of distinct phosphosites is coordinated unresolved","Direct structural model of the Tensin3–PEAK1–integrin assembly absent"]},{"year":2024,"claim":"Tested PEAK1 requirement in genetic CRC models, finding it dispensable for Apc/Kras/Pten-driven tumor formation in vivo despite promoting EGF-induced proliferation and spheroid polarization in vitro, refining its in vivo context-dependence.","evidence":"CRISPR PEAK1 knockout in Apc/Kras/Pten CRC mouse models, in vitro proliferation, and 3D spheroid assays","pmids":["39532961"],"confidence":"Medium","gaps":["Why in vitro signaling roles do not translate to in vivo tumor dependence unexplained","Possible compensation by paralogs not addressed"]},{"year":2025,"claim":"Established new mechanistic axes: a CAMK2D/G–PEAK1–PEAK2 feed-forward loop via PLCγ1/Ca2+ in TNBC, and a Src-pY724-dependent PEAK1–ZO-1 interaction that masks ZO-1's LIR to protect tight junctions from autophagy, with PEAK1 loss disrupting intestinal barrier integrity in vivo.","evidence":"AP-MS, Co-IP, domain mapping (aa 714–731), Y724 mutagenesis, CAMK2 inhibitor RA306, autophagy assays, and PEAK1 conditional KO mice with colitis models","pmids":["39984440","40707483"],"confidence":"High","gaps":["Structural basis of PEAK1–PEAK2 association via CAMK2 phosphorylation not determined","How ZO-1 protective and oncogenic functions of PEAK1 are integrated unresolved"]},{"year":null,"claim":"It remains unresolved how PEAK1's many phosphosite-specific interactions, dimerization states, and tissue-specific roles are integrated into a unified regulatory logic, and whether its pseudokinase fold has any catalytic-independent allosteric activity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure capturing regulatory regions and dimer interfaces","No unifying model of how competing partners are selected at distinct phosphosites","RHOV–PEAK1 axis rests on a single preprint without reconstitution"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,4,5,6,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,11,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,14,15]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,7,12,15]}],"complexes":["PEAK1-SgK223 heterodimer","AXL-NEDD9-CRKII-PEAK1-CSK complex","PEAK1-PEAK2 complex"],"partners":["SGK223","GRB2","TNS3","CSK","SHC1","ZO-1","CRKII","CAMK2D"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H792","full_name":"Inactive tyrosine-protein kinase PEAK1","aliases":["Pseudopodium-enriched atypical kinase 1","Sugen kinase 269","Tyrosine-protein kinase SgK269"],"length_aa":1746,"mass_kda":193.1,"function":"Probable catalytically inactive kinase. Scaffolding protein that regulates the cytoskeleton to control cell spreading and migration by modulating focal adhesion dynamics (PubMed:20534451, PubMed:23105102, PubMed:35687021). Acts as a scaffold for mediating EGFR signaling (PubMed:23846654)","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/Q9H792/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEAK1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSK","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PEAK1","total_profiled":1310},"omim":[{"mim_id":"618526","title":"PEAK FAMILY MEMBER 3; PEAK3","url":"https://www.omim.org/entry/618526"},{"mim_id":"617344","title":"PEAK1-RELATED KINASE-ACTIVATING PSEUDOKINASE 1; PRAG1","url":"https://www.omim.org/entry/617344"},{"mim_id":"614248","title":"PEAK FAMILY MEMBER 1; PEAK1","url":"https://www.omim.org/entry/614248"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PEAK1"},"hgnc":{"alias_symbol":["KIAA2002","sgk269"],"prev_symbol":[]},"alphafold":{"accession":"Q9H792","domains":[{"cath_id":"3.30.200.20","chopping":"1316-1406_1456-1467","consensus_level":"medium","plddt":85.214,"start":1316,"end":1467},{"cath_id":"1.10.510.10","chopping":"1469-1531_1548-1669","consensus_level":"medium","plddt":87.8324,"start":1469,"end":1669}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H792","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H792-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H792-F1-predicted_aligned_error_v6.png","plddt_mean":48.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEAK1","jax_strain_url":"https://www.jax.org/strain/search?query=PEAK1"},"sequence":{"accession":"Q9H792","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H792.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H792/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H792"}},"corpus_meta":[{"pmid":"22589274","id":"PMC_22589274","title":"KRas induces a Src/PEAK1/ErbB2 kinase amplification loop that drives metastatic growth and therapy resistance in pancreatic cancer.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22589274","citation_count":96,"is_preprint":false},{"pmid":"25261239","id":"PMC_25261239","title":"A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25261239","citation_count":86,"is_preprint":false},{"pmid":"23378338","id":"PMC_23378338","title":"Involvement of Lyn and the atypical kinase SgK269/PEAK1 in a basal breast cancer signaling pathway.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23378338","citation_count":79,"is_preprint":false},{"pmid":"32681075","id":"PMC_32681075","title":"AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32681075","citation_count":55,"is_preprint":false},{"pmid":"29449544","id":"PMC_29449544","title":"PEAK1, acting as a tumor promoter in colorectal cancer, is regulated by the EGFR/KRas signaling axis and miR-181d.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29449544","citation_count":50,"is_preprint":false},{"pmid":"30472186","id":"PMC_30472186","title":"The PEAK1-PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30472186","citation_count":49,"is_preprint":false},{"pmid":"26267863","id":"PMC_26267863","title":"PEAK1 Acts as a Molecular Switch to Regulate Context-Dependent TGFβ Responses in Breast Cancer.","date":"2015","source":"PloS 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27531744","citation_count":27,"is_preprint":false},{"pmid":"34239043","id":"PMC_34239043","title":"A SNAI2-PEAK1-INHBA stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting subpopulations of tumor cells positive for antiapoptotic and stress signaling markers.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34239043","citation_count":26,"is_preprint":false},{"pmid":"33742335","id":"PMC_33742335","title":"LncRNA NORAD, sponging miR-363-3p, promotes invasion and EMT by upregulating PEAK1 and activating the ERK signaling pathway in NSCLC cells.","date":"2021","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/33742335","citation_count":18,"is_preprint":false},{"pmid":"35687021","id":"PMC_35687021","title":"PEAK1 Y635 phosphorylation regulates cell migration through association with Tensin3 and integrins.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35687021","citation_count":17,"is_preprint":false},{"pmid":"34479583","id":"PMC_34479583","title":"Importance of Circ0009910 in colorectal cancer pathogenesis as a possible regulator of miR-145 and PEAK1.","date":"2021","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34479583","citation_count":15,"is_preprint":false},{"pmid":"25445115","id":"PMC_25445115","title":"Analysis of a cytoskeleton-associated kinase PEAK1 and E-cadherin in gastric cancer.","date":"2014","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/25445115","citation_count":14,"is_preprint":false},{"pmid":"35216916","id":"PMC_35216916","title":"Potential therapeutic effects of hAMSCs secretome on Panc1 pancreatic cancer cells through downregulation of SgK269, E-cadherin, vimentin, and snail expression.","date":"2022","source":"Biologicals : journal of the International Association of Biological Standardization","url":"https://pubmed.ncbi.nlm.nih.gov/35216916","citation_count":13,"is_preprint":false},{"pmid":"29105536","id":"PMC_29105536","title":"The pseudokinases SgK269 and SgK223: A novel oncogenic alliance in human cancer.","date":"2017","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/29105536","citation_count":12,"is_preprint":false},{"pmid":"40707483","id":"PMC_40707483","title":"PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40707483","citation_count":10,"is_preprint":false},{"pmid":"34554318","id":"PMC_34554318","title":"PEAK1 promotes invasion and metastasis and confers drug resistance in breast cancer.","date":"2021","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34554318","citation_count":10,"is_preprint":false},{"pmid":"34273398","id":"PMC_34273398","title":"BioID-Screening Identifies PEAK1 and SHP2 as Components of the ALK Proximitome in Neuroblastoma Cells.","date":"2021","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34273398","citation_count":10,"is_preprint":false},{"pmid":"34365903","id":"PMC_34365903","title":"Pseudopodium enriched atypical kinase 1(PEAK1) promotes invasion and of melanoma cells by activating JAK/STAT3 signals.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34365903","citation_count":8,"is_preprint":false},{"pmid":"36148757","id":"PMC_36148757","title":"Exosome-delivered circSATB2 targets the miR-330-5p/PEAK1 axis to regulate proliferation, migration and invasion of lung cancer cells.","date":"2022","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36148757","citation_count":7,"is_preprint":false},{"pmid":"29392163","id":"PMC_29392163","title":"Ascending the PEAK1 toward targeting TGFβ during cancer progression: Recent advances and future perspectives.","date":"2016","source":"Cancer cell & microenvironment","url":"https://pubmed.ncbi.nlm.nih.gov/29392163","citation_count":6,"is_preprint":false},{"pmid":"39984440","id":"PMC_39984440","title":"Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39984440","citation_count":5,"is_preprint":false},{"pmid":"37095973","id":"PMC_37095973","title":"LncRNA-PEAK1 promotes neuronal apoptosis after intracerebral hemorrhage by miR-466i-5p/caspase 8 axis.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37095973","citation_count":4,"is_preprint":false},{"pmid":"37744286","id":"PMC_37744286","title":"Evaluation of SgK269 expression in colon cancer patients and the effects of hAMSCs secretome on tumor invasion through SgK269/c-Src/p-P130Cas/p-Paxillin/p-ERK1/2 signaling pathway in HT-29 colon cancer cells.","date":"2023","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/37744286","citation_count":4,"is_preprint":false},{"pmid":"40716336","id":"PMC_40716336","title":"Self-calibrated SERS-LFIA biosensor based on AgNF for in-site and rapid detection of protein kinase biomarker PEAK1.","date":"2025","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/40716336","citation_count":4,"is_preprint":false},{"pmid":"38284248","id":"PMC_38284248","title":"Targeting PEAK1 sensitizes anaplastic thyroid carcinoma cells harboring BRAFV600E to Vemurafenib by Bim upregulation.","date":"2024","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38284248","citation_count":3,"is_preprint":false},{"pmid":"40272250","id":"PMC_40272250","title":"Black Phosphorus-Loaded Gelatin Methacryloyl Hydrogels Enhance Angiogenesis via Activation of the PEAK1-MAPK Pathway.","date":"2025","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/40272250","citation_count":2,"is_preprint":false},{"pmid":"39003575","id":"PMC_39003575","title":"MicroRNA-505-3p mediates cell motility of epithelial ovarian cancer via suppressing PEAK1 expression.","date":"2024","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39003575","citation_count":1,"is_preprint":false},{"pmid":"41495812","id":"PMC_41495812","title":"PEAK1 promotes prostate cancer progression and docetaxel resistance by mediating the polarization of tumor-associated macrophages.","date":"2026","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41495812","citation_count":1,"is_preprint":false},{"pmid":"38405732","id":"PMC_38405732","title":"Feed-forward stimulation of CAMK2 by the oncogenic pseudokinase PEAK1 generates a therapeutically \"actionable\" signalling axis in triple negative breast cancer.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38405732","citation_count":1,"is_preprint":false},{"pmid":"39532961","id":"PMC_39532961","title":"Colorectal carcinoma progression is not influenced by the pseudokinase PEAK1.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39532961","citation_count":0,"is_preprint":false},{"pmid":"40326976","id":"PMC_40326976","title":"The expression of circSATB2, PEAK1 in non-small cell lung cancer tissue and their relationships with clinical pathological characteristics, as well as postoperative recurrence and metastasis.","date":"2025","source":"General physiology and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40326976","citation_count":0,"is_preprint":false},{"pmid":"41048551","id":"PMC_41048551","title":"CRISPR/Cas13a-mediated interfacial cleaving of hairpin RNA reporter for PEAK1 nucleic acid sensing.","date":"2025","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/41048551","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.18.649622","title":"TGF/J Regulated Small GTPase RHOV interact with PEAK1 and drive MYC Expression to Promote Cellular Proliferation, Migration and Etoposide resistance","date":"2025-04-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.18.649622","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22097,"output_tokens":4873,"usd":0.069693,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13106,"output_tokens":5083,"usd":0.096302,"stage2_stop_reason":"end_turn"},"total_usd":0.165995,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"X-ray crystal structure of the PEAK1 pseudokinase domain (2.3 Å resolution) revealed a closed nucleotide-binding cleft that may preclude nucleotide binding, and identified N- and C-terminal extensions forming an all α-helical split-helical dimerization (SHED) region that mediates dimerization conserved between PEAK1 and pragmin (SgK223).\",\n      \"method\": \"X-ray crystallography, sequence conservation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.3 Å resolution with structural and sequence-based functional validation in a single rigorous study\",\n      \"pmids\": [\"29212708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PEAK1 localizes to the actin cytoskeleton and focal adhesions in migrating cells; phosphorylation of Tyr-665 (by Src family kinases) is required for normal PEAK1 localization and regulation of focal adhesion assembly and disassembly kinetics; constitutive phosphorylation at Tyr-665 is also disruptive, indicating a requirement for dynamic, spatiotemporally precise regulation.\",\n      \"method\": \"PEAK1 knockdown, phospho-site mutagenesis (Y665F and phosphomimetic), live-cell focal adhesion imaging, Src inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, mutagenesis, live-cell imaging, kinase inhibition), replicated across contexts in one rigorous study\",\n      \"pmids\": [\"23105102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Oncogenic KRas induces a kinase amplification loop involving Src, PEAK1, and ErbB2 in pancreatic cancer cells; blockade of ErbB2 increased Src-dependent PEAK1 expression and PEAK1-dependent Src activation, suggesting PEAK1 mediates ErbB2-inhibitor resistance.\",\n      \"method\": \"In vivo tumor models, RNAi knockdown, pathway epistasis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD experiments with defined signaling epistasis, single lab\",\n      \"pmids\": [\"22589274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The Src family kinase Lyn directly phosphorylates PEAK1 (SgK269) in basal breast cancer cells; Tyr-635 is a major Lyn phosphorylation site on PEAK1 and serves as a Grb2-binding site that promotes Stat3 and Erk activation; mutation Y635F abrogates enhanced acinar size and cellular invasion.\",\n      \"method\": \"Phosphoproteomics (Lyn substrate identification), Co-IP, Y635F mutagenesis, 3D culture invasion assays, RNAi\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphoproteomic identification, mutagenesis, and functional validation with multiple orthogonal assays in one study\",\n      \"pmids\": [\"23378338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PEAK1 (SgK269) undergoes homotypic self-association and heterotypic association with the related pseudokinase SgK223; both associations require the CH (coiled-helix) and PK (pseudokinase) domains of both proteins; SgK269 bridges SgK223 to Grb2 but cannot activate Stat3 or efficiently enhance migration in SgK223 knockout cells, demonstrating that SgK223 is required for full SgK269 signaling output.\",\n      \"method\": \"Mass spectrometry-based interactomics, pulldowns, size-exclusion chromatography, CRISPR/Cas9 SgK223 KO, migration and Stat3 activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods plus genetic KO with defined functional readouts in one study\",\n      \"pmids\": [\"27531744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AXL phosphorylates NEDD9, leading to NEDD9 binding to CRKII, which in turn associates with PEAK1; PEAK1 forms a complex with the tyrosine kinase CSK to mediate phosphorylation of PAXILLIN, thereby driving focal adhesion disassembly, cell migration and invasion downstream of AXL.\",\n      \"method\": \"Phosphoproteomics, Co-IP, proximity labeling, RNAi knockdown, in vivo metastasis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphoproteomic mapping combined with Co-IP complex validation and in vivo functional confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"32681075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PEAK1 interacts indirectly with RGD-binding integrins (α5β1, αVβ3, αVβ5) in focal adhesions through Tensin3; the SH2 domain of Tensin3 binds phosphorylated Tyr-635 on PEAK1 (phosphorylated by Src), and both the integrin β-tail NPxY motif and PEAK1 pY635 are required for this interaction; additionally, phosphorylated Tyr-1188 on PEAK1 recruits Shc1 to focal adhesions, linking PEAK1 to late EGFR/Shc1 signaling.\",\n      \"method\": \"BioID proximity labeling of β1/β3 integrins, Co-IP, mutagenesis (Y635, NPxY), cell migration assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — BioID plus mutagenesis of multiple sites plus Co-IP validation, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"35687021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PEAK1 mediates signaling cross talk between TGFβ receptors and integrin/Src/MAPK pathways; in the context of fibronectin, high PEAK1 expression switches TGFβ signaling from canonical Smad2/3 to non-canonical Src and MAPK pathways, promoting EMT, proliferation and metastasis; PEAK1 is necessary for TGFβ to induce ZEB1-mediated EMT.\",\n      \"method\": \"PEAK1 knockdown/overexpression, Smad2/3 and Src/MAPK pathway reporter assays, fibronectin/ITGB3 manipulation, in vivo metastasis models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined signaling pathway switching and in vivo validation, single lab\",\n      \"pmids\": [\"26267863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PEAK1 is necessary for TGFβ-induced ZEB1 expression and ZEB1-mediated EMT in oncogene-transformed mammary epithelial cells and triple-negative breast cancer cells, specifically in the context of fibronectin/ITGB3 activation.\",\n      \"method\": \"RNAi knockdown, fibronectin/integrin β3 manipulation, ZEB1 Western blot, EMT marker analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular target (ZEB1) in contextual signaling setting, single lab\",\n      \"pmids\": [\"26297948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"eIF5A proteins regulate PDAC cell growth by modulating PEAK1 expression; hypusination of eIF5A (catalyzed by DHPS and DOHH) is required for this regulation, and pharmacologic inhibition of eIF5A hypusination suppresses PEAK1 levels and PDAC cell growth.\",\n      \"method\": \"eIF5A knockdown/overexpression, DHPS/DOHH inhibitors, orthotopic tumor models, Western blot for PEAK1\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacologic perturbation of upstream regulator with PEAK1 as defined downstream effector, single lab\",\n      \"pmids\": [\"25261239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PEAK1 is identified by BioID as a component of the ALK proximitome in neuroblastoma cells; PEAK1 was validated as an ALK interactor in NB cells; interaction was dependent on ALK kinase activity (blocked by lorlatinib).\",\n      \"method\": \"BioID proximity labeling, LC/MS-MS, validation Co-IP/pulldown with ALK TKI lorlatinib\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID discovery plus ALK-activity-dependent interaction validated biochemically, single lab\",\n      \"pmids\": [\"34273398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PEAK1 interacts with ZO-1 via a conserved region (amino acids 714–731), masking the LC3-interacting region on ZO-1 and preventing autophagy-mediated ZO-1 degradation; Src-mediated phosphorylation of PEAK1 at Y724 promotes the PEAK1–ZO-1 interaction; PEAK1 also binds CSK to positively regulate Src activity; loss of PEAK1 in intestinal epithelial cells reduces Src activity and ZO-1 levels, disrupting tight junctions and increasing intestinal permeability in vivo.\",\n      \"method\": \"Co-IP, mutagenesis (Y724), domain mapping (aa 714–731), autophagy assays, PEAK1 conditional KO mice, colitis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, mutagenesis, domain mapping, and in vivo KO with defined mechanistic readouts across multiple orthogonal methods\",\n      \"pmids\": [\"40707483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PEAK1 promotes CAMK2D and CAMK2G activation in TNBC cells via PLCγ1/Ca2+ signaling and direct binding to CAMK2 through a consensus CAMK2 interaction motif in the PEAK1 N-terminus; in turn, CAMK2 phosphorylates PEAK1 to enhance its association with PEAK2, which is critical for PEAK1 oncogenic signaling.\",\n      \"method\": \"Affinity purification-mass spectrometry, Co-IP, CAMK2 inhibitor (RA306), CRISPR PEAK1 ablation, TNBC xenograft/metastasis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AP-MS identification plus Co-IP, pharmacologic and genetic perturbation, in vivo validation — multiple orthogonal methods\",\n      \"pmids\": [\"39984440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In HER2-positive breast cancer, PEAK1 in mesenchymal stem cells (MSCs) mediates secretion of INHBA/activin-A, which promotes lapatinib resistance in co-cultured breast cancer cells; SNAI2 is an upstream transcriptional regulator of PEAK1 in stromal cells.\",\n      \"method\": \"MSC-tumor cell co-culture, PEAK1 knockdown in MSCs, conditioned media experiments, single-cell CycIF, INHBA neutralization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-culture loss-of-function with identified secreted factor (INHBA) as mechanism, single lab\",\n      \"pmids\": [\"34239043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDC5L protein binds directly to the PEAK1 gene promoter to promote PEAK1 transcription in ovarian cancer cells; PEAK1 overexpression in turn activates ERK1/2 and JAK2 signaling pathways.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, Western blot for ERK1/2 and JAK2 phosphorylation\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, single lab with orthogonal reporter assay\",\n      \"pmids\": [\"32167655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEAK1 promotes lung cancer EMT and metastasis by enhancing activation of ERK1/2 and JAK2 signaling pathways; combined inhibition of ERK1/2 (PD98059) and JAK2 (AZD1480) reverses PEAK1-induced EMT, migration and invasion.\",\n      \"method\": \"PEAK1 overexpression/KO, Western blot for p-ERK1/2 and p-JAK2, pharmacologic inhibitors, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/OE plus pharmacologic epistasis with defined pathway readouts, single lab\",\n      \"pmids\": [\"30038287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEAK1 forms a complex with PPP1R12B (protein phosphatase 1 regulatory subunit 12B) in colorectal cancer cells; this axis suppresses activation of the Grb2/PI3K/Akt pathway; PI3K/Akt inhibitors reverse the effects of PEAK1 loss on cell proliferation, migration and invasion.\",\n      \"method\": \"Co-IP, PPP1R12B KD/OE, PI3K/Akt inhibitors, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic and pharmacologic epistasis, single lab\",\n      \"pmids\": [\"30472186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RHOV (an atypical Rho GTPase) directly interacts with PEAK1 as identified by immunoprecipitation coupled with LC-MS; the RHOV-PEAK1 complex is required for MYC upregulation and PI3K/MAPK signaling in NSCLC; PEAK1 depletion abolishes RHOV-driven MYC upregulation; additionally, PEAK1 maintains RHOV expression by inhibiting TGF-β signaling, establishing a negative feedback loop.\",\n      \"method\": \"Co-IP/LC-MS, PEAK1 and RHOV siRNA knockdown, Western blot for MYC/PI3K/MAPK, RNA-seq\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, Co-IP/LC-MS with KD epistasis but no structural or reconstitution validation\",\n      \"pmids\": [\"bio_10.1101_2025.04.18.649622\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PEAK1 ablation in CRC mouse models driven by Apc loss (with or without oncogenic Kras or Pten loss) does not significantly contribute to tumor formation in vivo, although PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization/lumenization in vitro.\",\n      \"method\": \"CRISPR/Cas9 PEAK1 KO, in vivo CRC mouse models (Apc, Kras, Pten), in vitro proliferation assays, 3D spheroid culture\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous in vivo genetic models; negative result for tumor formation but positive result for EGF-proliferation signaling in vitro\",\n      \"pmids\": [\"39532961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEAK1 is a pseudokinase scaffold protein that localizes to focal adhesions and the actin cytoskeleton, where it integrates signals from receptor tyrosine kinases (ErbB2, AXL, ALK, EGFR), Src-family kinases (Lyn, Src), and integrins (via Tensin3) by serving as a phosphorylation-regulated assembly platform; Src phosphorylates PEAK1 at Y635 (promoting Grb2, Tensin3, and integrin binding) and Y724 (promoting ZO-1 binding to protect tight junctions from autophagy), while PEAK1 reciprocally activates Src through CSK binding; PEAK1 dimerizes with itself and heterodimerizes with the related pseudokinase SgK223 through a SHED domain, controlling signal output to Grb2/Stat3/ERK/PI3K-Akt/JAK2 pathways; PEAK1 also activates CAMK2D/G via PLCγ1/Ca²⁺ signaling and direct binding, with CAMK2 phosphorylating PEAK1 to enhance its association with PEAK2, completing a feed-forward oncogenic loop in triple-negative breast cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PEAK1 is a pseudokinase scaffold that localizes to focal adhesions and the actin cytoskeleton, where it acts as a phosphorylation-regulated assembly platform integrating signals from receptor tyrosine kinases, Src-family kinases, and integrins to control cell migration, adhesion dynamics, and epithelial-mesenchymal transition [#1, #6]. Its pseudokinase domain adopts a closed nucleotide-binding cleft and is flanked by N- and C-terminal helical extensions that form a split-helical dimerization (SHED) region, enabling PEAK1 self-association and heterodimerization with the related pseudokinase SgK223; this dimerization is required for full signaling output to Grb2/Stat3 and for efficient migration [#0, #4]. PEAK1 function is gated by Src-family phosphorylation: phosphorylation at Tyr-665 governs proper focal-adhesion localization and the kinetics of adhesion assembly/disassembly, while Lyn/Src phosphorylation of Tyr-635 creates a docking site that recruits Grb2 to drive Stat3 and ERK activation and recruits the Tensin3 SH2 domain to couple PEAK1 to RGD-binding integrins [#1, #3, #6]. Additional phosphosites extend its interactome — pY1188 recruits Shc1 to link PEAK1 to EGFR signaling, and Src-dependent pY724 promotes binding to ZO-1, masking its LC3-interacting region to protect tight junctions from autophagic degradation [#6, #11]. PEAK1 reciprocally activates Src through CSK binding and assembles adhesion-remodeling complexes such as the AXL–NEDD9–CRKII–PEAK1–CSK module that phosphorylates Paxillin to drive focal-adhesion disassembly and invasion [#5, #11]. Through these activities PEAK1 promotes oncogenic signaling and metastasis across multiple tumor contexts, including a CAMK2–PEAK1–PEAK2 feed-forward loop in triple-negative breast cancer and switching of TGFβ signaling toward non-canonical Src/MAPK and ZEB1-driven EMT [#7, #12]. In intestinal epithelium, PEAK1 loss in vivo reduces Src activity and ZO-1 levels, disrupting tight junctions and increasing intestinal permeability [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that PEAK1 is a focal-adhesion and actin-cytoskeleton protein whose function depends on dynamic Src-family phosphorylation, defining it as a spatiotemporally regulated adhesion scaffold rather than a static structural component.\",\n      \"evidence\": \"PEAK1 knockdown, Y665F and phosphomimetic mutagenesis, live-cell focal adhesion imaging, and Src inhibition in migrating cells\",\n      \"pmids\": [\"23105102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not identify the direct partners recruited to pY665\",\n        \"Mechanism linking phosphorylation to adhesion turnover kinetics unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed PEAK1 within an oncogenic KRas-driven Src/ErbB2 amplification loop, linking it to receptor-tyrosine-kinase-inhibitor resistance in pancreatic cancer.\",\n      \"evidence\": \"In vivo tumor models with RNAi knockdown and pathway epistasis between Src, PEAK1, and ErbB2\",\n      \"pmids\": [\"22589274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical interactions among the loop components not mapped\",\n        \"Single-lab in vivo epistasis\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified Tyr-635 as a major Lyn/Src phosphosite that functions as a Grb2-docking site coupling PEAK1 to Stat3 and ERK activation, providing the first defined molecular output of PEAK1 phosphorylation.\",\n      \"evidence\": \"Lyn substrate phosphoproteomics, Co-IP, Y635F mutagenesis, and 3D culture invasion assays\",\n      \"pmids\": [\"23378338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Grb2 recruitment is direct to pY635 versus bridged not fully resolved\",\n        \"Quantitative contribution of Stat3 vs ERK arms not separated\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed PEAK1 expression is controlled by hypusinated eIF5A, positioning PEAK1 as a translationally regulated effector in pancreatic cancer growth.\",\n      \"evidence\": \"eIF5A knockdown/overexpression, DHPS/DOHH inhibitors, and orthotopic tumor models with PEAK1 Western blot\",\n      \"pmids\": [\"25261239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct vs indirect regulation of PEAK1 translation not distinguished\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined PEAK1 as a switch that reroutes TGFβ signaling from canonical Smad2/3 to non-canonical Src/MAPK and ZEB1-driven EMT in a fibronectin/integrin context.\",\n      \"evidence\": \"PEAK1 knockdown/overexpression, pathway reporter assays, fibronectin/ITGB3 manipulation, ZEB1 analysis, and in vivo metastasis models\",\n      \"pmids\": [\"26267863\", \"26297948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of the Smad-to-Src/MAPK switch unresolved\",\n        \"Single-lab findings\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that PEAK1 homo- and heterodimerizes with SgK223 via CH and PK domains, and that SgK223 is required for full PEAK1 signaling output, establishing dimerization as a determinant of scaffold activity.\",\n      \"evidence\": \"Mass spectrometry interactomics, pulldowns, size-exclusion chromatography, CRISPR SgK223 knockout, and migration/Stat3 assays\",\n      \"pmids\": [\"27531744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and architecture of the heterodimer not structurally defined\",\n        \"How dimerization gates downstream signaling mechanistically unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the structural basis for PEAK1 as a pseudokinase, showing a closed nucleotide-binding cleft and a SHED dimerization region conserved with pragmin/SgK223.\",\n      \"evidence\": \"X-ray crystallography of the PEAK1 pseudokinase domain at 2.3 Å with sequence conservation analysis\",\n      \"pmids\": [\"29212708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full-length structure including N-terminal regulatory regions not determined\",\n        \"Whether any nucleotide or small molecule can engage the cleft unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected PEAK1 to ERK1/2 and JAK2 activation driving EMT and metastasis, and to a PPP1R12B complex modulating Grb2/PI3K/Akt signaling, broadening its downstream pathway repertoire across cancer types.\",\n      \"evidence\": \"PEAK1 KO/OE, Co-IP with PPP1R12B, pharmacologic ERK/JAK2/PI3K-Akt inhibition, and in vivo metastasis models\",\n      \"pmids\": [\"30038287\", \"30472186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct vs indirect engagement of JAK2 and PI3K not established\",\n        \"Single-lab studies in distinct tumor contexts\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved a defined adhesion-remodeling module in which AXL-phosphorylated NEDD9 recruits CRKII to PEAK1, which complexes with CSK to drive Paxillin phosphorylation and focal-adhesion disassembly, mechanistically linking PEAK1 to invasion downstream of AXL.\",\n      \"evidence\": \"Phosphoproteomics, Co-IP, proximity labeling, RNAi, and in vivo metastasis assays\",\n      \"pmids\": [\"32681075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct kinase responsible for Paxillin phosphorylation within the complex not pinned down\",\n        \"Temporal ordering of complex assembly unresolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the PEAK1 interactome to ALK in neuroblastoma and to stromal/transcriptional regulation, showing ALK-activity-dependent interaction, SNAI2-driven PEAK1 expression in MSCs promoting INHBA-mediated lapatinib resistance, and CDC5L-driven PEAK1 transcription activating ERK1/2 and JAK2.\",\n      \"evidence\": \"BioID/LC-MS with lorlatinib validation; MSC co-culture with PEAK1 KD and INHBA neutralization; ChIP and luciferase reporter assays\",\n      \"pmids\": [\"34273398\", \"34239043\", \"32167655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the ALK–PEAK1 interaction not defined\",\n        \"Direct vs indirect transcriptional control by CDC5L and SNAI2 not fully separated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped how PEAK1 physically couples to adhesion machinery, showing Tensin3-SH2 binding to pY635 bridges PEAK1 to RGD-binding integrins and pY1188 recruits Shc1, defining phosphosite-specific integrin and EGFR linkages.\",\n      \"evidence\": \"BioID of β1/β3 integrins, Co-IP, and mutagenesis of Y635, Y1188, and the integrin NPxY motif with migration assays\",\n      \"pmids\": [\"35687021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How simultaneous use of distinct phosphosites is coordinated unresolved\",\n        \"Direct structural model of the Tensin3–PEAK1–integrin assembly absent\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tested PEAK1 requirement in genetic CRC models, finding it dispensable for Apc/Kras/Pten-driven tumor formation in vivo despite promoting EGF-induced proliferation and spheroid polarization in vitro, refining its in vivo context-dependence.\",\n      \"evidence\": \"CRISPR PEAK1 knockout in Apc/Kras/Pten CRC mouse models, in vitro proliferation, and 3D spheroid assays\",\n      \"pmids\": [\"39532961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Why in vitro signaling roles do not translate to in vivo tumor dependence unexplained\",\n        \"Possible compensation by paralogs not addressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established new mechanistic axes: a CAMK2D/G–PEAK1–PEAK2 feed-forward loop via PLCγ1/Ca2+ in TNBC, and a Src-pY724-dependent PEAK1–ZO-1 interaction that masks ZO-1's LIR to protect tight junctions from autophagy, with PEAK1 loss disrupting intestinal barrier integrity in vivo.\",\n      \"evidence\": \"AP-MS, Co-IP, domain mapping (aa 714–731), Y724 mutagenesis, CAMK2 inhibitor RA306, autophagy assays, and PEAK1 conditional KO mice with colitis models\",\n      \"pmids\": [\"39984440\", \"40707483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of PEAK1–PEAK2 association via CAMK2 phosphorylation not determined\",\n        \"How ZO-1 protective and oncogenic functions of PEAK1 are integrated unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PEAK1's many phosphosite-specific interactions, dimerization states, and tissue-specific roles are integrated into a unified regulatory logic, and whether its pseudokinase fold has any catalytic-independent allosteric activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No full-length structure capturing regulatory regions and dimer interfaces\",\n        \"No unifying model of how competing partners are selected at distinct phosphosites\",\n        \"RHOV–PEAK1 axis rests on a single preprint without reconstitution\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 4, 5, 6, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 14, 15]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 7, 12, 15]}\n    ],\n    \"complexes\": [\n      \"PEAK1-SgK223 heterodimer\",\n      \"AXL-NEDD9-CRKII-PEAK1-CSK complex\",\n      \"PEAK1-PEAK2 complex\"\n    ],\n    \"partners\": [\n      \"SgK223\",\n      \"Grb2\",\n      \"TNS3\",\n      \"CSK\",\n      \"SHC1\",\n      \"ZO-1\",\n      \"CRKII\",\n      \"CAMK2D\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}