{"gene":"PAK5","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2002,"finding":"PAK5 is a novel target of Rho GTPases Cdc42 and Rac; it promotes filopodia induction and neurite outgrowth in N1E-115 neuroblastoma cells in a kinase activity-dependent manner. Dominant-negative PAK5 inhibited neurite outgrowth, and activated RhoA abolished PAK5-induced neurite formation, placing PAK5 downstream of Cdc42/Rac and antagonistic to Rho in the neurite development pathway. PAK5 also activates the JNK pathway, but dominant-negative JNK did not block neurite outgrowth.","method":"Dominant-negative and constitutively active mutant expression in N1E-115 cells; morphological assays; epistasis with dominant-negative JNK and activated RhoA","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple signaling components, single lab, two orthogonal approaches (dominant-negative and activated mutants)","pmids":["11756552"],"is_preprint":false},{"year":2002,"finding":"PAK5 preferentially binds Cdc42 in a GTP-dependent manner via its CRIB motif, but unlike PAK-I family kinases, its kinase activity does not require Cdc42 binding. Overexpression of PAK5 activates JNK but not p38 or ERK pathways.","method":"GTP-dependent binding assay; CRIB mutant analysis; MAPK pathway activation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and kinase activity assays, CRIB mutagenesis, two orthogonal methods, single lab","pmids":["12032833"],"is_preprint":false},{"year":2003,"finding":"PAK5 is constitutively localized to mitochondria (independent of kinase activity or Cdc42 binding), has constitutively high kinase activity not regulated by Cdc42/Rac, prevents apoptosis induced by camptothecin and C2-ceramide by phosphorylating BAD on Ser-112 in a PKA-independent manner, and prevents BAD localization to mitochondria.","method":"Subcellular fractionation; in vitro kinase assay; site-directed mutagenesis; apoptosis assays with camptothecin and C2-ceramide; BAD phosphorylation analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted kinase assay, subcellular localization by fractionation, mutagenesis, multiple orthogonal methods in single rigorous study","pmids":["12897128"],"is_preprint":false},{"year":2003,"finding":"PAK5 knockout mice develop normally and are fertile, with no apparent nervous system abnormalities, suggesting functional redundancy between PAK5 and other Rho GTPase targets in vivo.","method":"Targeted gene disruption (knockout mice); histological and behavioral analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout, replicated in multiple subsequent studies","pmids":["14517284"],"is_preprint":false},{"year":2005,"finding":"PAK5 directly binds MARK2 via their catalytic domains and suppresses MARK2 kinase activity toward tau protein without requiring phosphorylation. In transfected CHO cells, PAK5 and MARK2 co-localize on endosomes containing AP-1/2. PAK5 keeps microtubules stable by downregulating MARK2 while simultaneously destabilizing F-actin (eliminating stress fibers and focal adhesions) and inducing filopodia.","method":"Co-immunoprecipitation; in vitro kinase assay; deletion/mutagenesis analysis; subcellular fractionation and co-localization in CHO cells; cytoskeletal phenotyping","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding and in vitro kinase inhibition assays with deletion analysis, co-localization, phenotypic readout; multiple orthogonal methods","pmids":["16014608"],"is_preprint":false},{"year":2006,"finding":"PAK5 contains three N-terminal regulatory sequences: a mitochondrial targeting sequence, a nuclear export sequence (NES), and a nuclear localization sequence (NLS). PAK5 shuttles between mitochondria and nucleus; blockade of nuclear export with leptomycin B causes endogenous PAK5 to accumulate in the nucleus. Mitochondrial localization of PAK5 is required for its anti-apoptotic function; a PAK5 mutant unable to localize to mitochondria fails to protect cells from apoptosis. Reduction of endogenous PAK5 in neuroblastoma and neural stem cells increases apoptosis sensitivity.","method":"Deletion mutagenesis of targeting sequences; leptomycin B nuclear export blockade; live-cell imaging and fractionation; apoptosis rescue assays with wild-type vs. localization-defective mutants; endogenous PAK5 knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, pharmacological blockade, knockdown with rescue), functional consequence directly linked to localization","pmids":["16581795"],"is_preprint":false},{"year":2006,"finding":"PAK5 interacts with RhoD and RhoH in addition to Cdc42, and RhoD interaction targets PAK5 to subcellular locations distinct from those driven by Cdc42. The CRIB domain is critical for proper subcellular targeting. Kinase activity is required for PAK5 cycling on and off mitochondria; kinase-inactive PAK5 causes dramatic alterations in mitochondrial morphology.","method":"Deletion analysis; co-immunoprecipitation; subcellular localization by fluorescence microscopy; kinase-inactive mutant expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and imaging-based localization studies, single lab, multiple Rho GTPase interactions tested","pmids":["17064668"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of all active, monophosphorylated group II PAK catalytic domains (PAK4, PAK5, PAK6) reveal catalytic domain plasticity including rearrangements of helix αC forming an additional helical turn and distortion of its C-terminus, interactions between conserved residues linking the glycine-rich loop, αC, and activation segment to anchor αC in an active conformation. A tri-substituted purine inhibitor was co-crystallized with PAK4 and PAK5.","method":"X-ray crystallography (multiple high-resolution structures); inhibitor screening and co-crystallization","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple high-resolution crystal structures of PAK5 catalytic domain, structural comparison across all group II PAKs","pmids":["17292838"],"is_preprint":false},{"year":2008,"finding":"PAK5/PAK6 double-knockout mice are viable and fertile but exhibit locomotor deficits and learning/memory impairment, while PAK5 single-knockout mice show no gross abnormalities. PAK5 and PAK6 together are required for normal locomotion and cognitive function.","method":"Targeted gene disruption (double-knockout mice); behavioral testing (locomotion, learning/memory assays)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockouts with defined behavioral phenotypes, replicated across multiple behavioral paradigms","pmids":["18675265"],"is_preprint":false},{"year":2012,"finding":"Using an analog-sensitive PAK5 mutant to selectively radiolabel substrates in murine brain extract, Pacsin1 and Synaptojanin1 were identified as novel PAK5 substrates. PAK5 (and other group II PAKs) phosphorylated Pacsin1 and Synaptojanin1 in vitro, and PAK5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo, implicating PAK5 in synaptic vesicle endocytosis and recycling.","method":"Analog-sensitive kinase substrate labeling in brain extract; in vitro kinase assay; co-immunoprecipitation (in vitro and in vivo)","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — chemical-genetic substrate identification plus in vitro kinase assay plus co-IP validation in vivo; multiple orthogonal methods","pmids":["22371566"],"is_preprint":false},{"year":2013,"finding":"PAK5 promotes breast cancer cell migration through a PAK5-Egr1-MMP2 signaling pathway; knockdown of PAK5 reduced Egr1 and MMP2 expression and inhibited migration and invasion.","method":"siRNA knockdown; western blot for pathway components; wound healing, migration and invasion assays","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, pathway placement without direct phosphorylation evidence","pmids":["23696025"],"is_preprint":false},{"year":2013,"finding":"PAK5 gain-of-function mutations in lung cancer activate the ERK pathway, and targeted depletion of mutated PAK5 inhibits proliferation and suppresses constitutive ERK pathway activation in lung cancer cells.","method":"Targeted genetic dependency screen; siRNA depletion; ERK pathway activation assays; proliferation assays","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen with pathway validation, single lab, multiple cancer lines tested","pmids":["23836671"],"is_preprint":false},{"year":2015,"finding":"PAK5 phosphorylates GATA1 on Ser161 and Ser187; phosphorylated GATA1 recruits more HDAC3/4 to the E-cadherin promoter, leading to transcriptional repression of E-cadherin and promotion of EMT in breast cancer cells. GATA1 S161A/S187A mutant shows reduced HDAC3/4 recruitment.","method":"Co-immunoprecipitation; phosphorylation assay; HDAC recruitment assay; E-cadherin promoter reporter; site-directed mutagenesis; in vivo metastasis model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay with mutagenesis, Co-IP for complex, single lab","pmids":["25726523"],"is_preprint":false},{"year":2015,"finding":"PAK5 interacts with and phosphorylates E47 transcription factor on Ser39 under HGF stimulation, promoting E47 nuclear accumulation via importin α, enhanced E47 binding to E-cadherin promoter, and EMT/metastasis in colon cancer.","method":"Co-immunoprecipitation; phosphorylation assay; importin α interaction assay; chromatin immunoprecipitation; xenograft metastasis model; site-directed mutagenesis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay with mutagenesis, importin α binding, ChIP; single lab; multiple orthogonal methods","pmids":["26212009"],"is_preprint":false},{"year":2016,"finding":"PAK5 auto-activates through oligomerization mediated by a central domain (residues 109-420) that interferes with AID binding to the catalytic domain, maintaining high constitutive kinase activity. PAK4 is monomeric and inactive, while PAK5 is dimeric; removing oligomerization sequences suppresses PAK5 kinase activity. The PAK5 AID is functionally indistinguishable from PAK4 AID.","method":"Gel filtration (oligomerization); deletion analysis; in vitro kinase assay; cell imaging of puncta formation; AID domain swapping","journal":"Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical reconstitution with deletion analysis and gel filtration, single lab, multiple orthogonal methods","pmids":["27095851"],"is_preprint":false},{"year":2017,"finding":"PAK5 phosphorylates SATB1 on Ser47, initiating EMT cascade and promoting migration and invasion of cervical cancer cells; PAK5 overexpression induces lung metastasis in xenograft models.","method":"Mn2+-Phos-tag SDS-PAGE; western blotting; immunofluorescence; dual luciferase reporter; xenograft metastasis; site-directed mutagenesis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay with Phos-tag, mutagenesis, in vivo xenograft; single lab, multiple orthogonal methods","pmids":["30082769"],"is_preprint":false},{"year":2017,"finding":"PAK5 promotes phosphorylation and nuclear translocation of NF-κB p65 subunit; nuclear p65 binds the Cyclin D1 promoter, increasing Cyclin D1 expression and promoting breast cancer cell cycle progression and proliferation. Co-IP confirmed PAK5-p65 interaction.","method":"Co-immunoprecipitation; phosphorylation assay; nuclear fractionation; Cyclin D1 promoter luciferase reporter; xenograft model; CCK-8 and flow cytometry","journal":"Journal of experimental and clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation assay, reporter assay, in vivo xenograft; single lab, multiple methods","pmids":["29041983"],"is_preprint":false},{"year":2018,"finding":"PAK5 (PAK7) directly binds GSK3β and β-catenin, phosphorylates GSK3β to regulate β-catenin degradation, and activates the Wnt/β-catenin signaling pathway to promote breast cancer proliferation and migration.","method":"Co-immunoprecipitation; co-localization; TOP/FOP luciferase reporter; western blotting; functional proliferation and migration assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assay, binding assays; single lab, multiple methods","pmids":["29805709"],"is_preprint":false},{"year":2018,"finding":"PAK5 promotes EMT and cell migration/invasion in ovarian cancer by activating the PI3K/AKT pathway; PAK5 knockdown reduced phosphorylation of PI3K p85 at Tyr458 and AKT at Ser473.","method":"siRNA knockdown and overexpression; western blot for PI3K/AKT phosphorylation; wound healing and invasion assays","journal":"Analytical cellular pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown/overexpression approach, pathway placement without direct substrate identification","pmids":["30245957"],"is_preprint":false},{"year":2018,"finding":"PAK5 missense mutations in the serine-rich domain (S364L and D421N) drive aberrant melanocyte proliferation by activating ERK through kinase-independent mechanisms and activating PKA through kinase-dependent mechanisms, without affecting single-cell migration or temozolomide resistance.","method":"Stable expression of melanoma-associated PAK5 mutants in immortalized human melanocytes; proliferation assays; ERK and PKA activation assays; kinase-dead mutant analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutant characterization distinguishing kinase-dependent vs. independent mechanisms, single lab, multiple downstream pathways assessed","pmids":["29875996"],"is_preprint":false},{"year":2019,"finding":"PAK5 interacts with and phosphorylates DNPEP (aspartyl aminopeptidase) at Ser119, leading to downregulation of DNPEP and consequent upregulation of USP4; PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway, promoting breast cancer progression.","method":"Co-immunoprecipitation; phosphorylation assay; ubiquitin-proteasome pathway analysis; overexpression and knockdown; in vivo xenograft and metastasis models","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay, co-IP, proteasomal degradation assay; single lab, multiple orthogonal methods","pmids":["31219614"],"is_preprint":false},{"year":2020,"finding":"PAK5 interacts with Cdc42 and Integrin β1 and β3 in colorectal cancer cells, facilitating migration and invasion.","method":"Co-immunoprecipitation; knockdown; migration and invasion assays; in vitro and in vivo models","journal":"Cancer medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP finding, single lab, limited mechanistic follow-up","pmids":["32383357"],"is_preprint":false},{"year":2021,"finding":"PAK5 is a brain mitochondrial kinase whose synthesis and signaling is spatiotemporally activated within axons in response to ischemic stress and axonal injury. PAK5 phosphorylates the mitochondrial anchor syntaphilin (SNPH), releasing the mitochondrial anchor and remobilizing damaged mitochondria to restore axonal energy supply. This axis is activated by upstream AKT signaling.","method":"In vitro neuronal injury and ischemia models; in vivo mouse brain injury models; PAK5 overexpression and knockdown; phosphorylation assay for SNPH; mitochondrial trafficking imaging; genetic rescue experiments","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphorylation assay with defined substrate (SNPH), live mitochondrial imaging, in vitro and in vivo models, AKT epistasis; multiple orthogonal methods","pmids":["34087103"],"is_preprint":false},{"year":2021,"finding":"PAK5 phosphorylates DDX5 on Thr69; this phosphorylation promotes sumoylation of DDX5, stabilizing DDX5. Both phosphorylation and sumoylation of DDX5 enhance formation of a DDX5/Drosha/DGCR8 complex, promoting microRNA-10b processing and maturation, leading to breast cancer cell proliferation and metastasis.","method":"Co-immunoprecipitation; in vitro kinase assay; sumoylation assay; PAK5 knockout (MMTV-PyVT transgenic mice); miRNA processing assays; phospho-specific antibody validation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, direct sumoylation assay, complex formation by Co-IP, in vivo transgenic mouse model validation; multiple orthogonal methods","pmids":["34936874"],"is_preprint":false},{"year":2021,"finding":"PAK5 inhibits apoptosis by phosphorylating AIF at Thr281, inhibiting formation of the AIF/importin α3 complex and thereby preventing AIF nuclear translocation. PAK5 also decreases mitochondrial membrane permeability and maintains membrane potential to inhibit AIF release from mitochondria.","method":"Phosphorylation assay; co-immunoprecipitation (AIF/importin α3); mitochondrial membrane permeability and potential assays; nuclear fractionation; in vitro and in vivo breast cancer models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay with defined site, Co-IP for complex, functional localization consequence; single lab","pmids":["33867848"],"is_preprint":false},{"year":2022,"finding":"14-3-3 interacts with PAK5 in response to phorbol ester-stimulated phosphorylation of Ser99 and EGF-stimulated phosphorylation of Ser288; these phosphorylations regulate PAK5 localization and signaling in melanoma cells.","method":"14-3-3 binding assay; phosphosite mapping; phorbol ester and EGF stimulation; co-immunoprecipitation; cell localization studies","journal":"Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 14-3-3 binding assay with phosphosite identification, stimulus-dependent regulation; single lab","pmids":["35969127"],"is_preprint":false},{"year":2023,"finding":"PAK5 binds to and phosphorylates Slug (SNAI2) at Ser87; phosphorylated Slug transactivates N-cadherin expression, promoting EMT and metastasis in renal cell carcinoma.","method":"Co-immunoprecipitation; phosphorylation assay; western blot; xenograft metastasis model; site-directed mutagenesis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay, Co-IP, mutagenesis, in vivo model; single lab, multiple methods","pmids":["37437827"],"is_preprint":false},{"year":2022,"finding":"PAK5 interacts with transcription factors LMO2 and GATA1 in the nucleus after mitochondria-to-nucleus translocation; without LMO2, PAK5 fails to bind GATA1 and phosphorylate it at Ser161, indicating LMO2 is required as a co-factor for PAK5-mediated GATA1 phosphorylation in hematopoietic cells.","method":"Co-immunoprecipitation; nuclear fractionation; phosphorylation assay; serum-stimulated nuclear translocation assay","journal":"Cellular and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP for complex formation, single lab, limited orthogonal validation in this context","pmids":["36905268"],"is_preprint":false},{"year":2024,"finding":"PAK5 phosphorylates PKM2 at Ser519, enhancing PKM2 protein stability and promoting anaerobic glycolysis in endometriosis. PAK5 inhibition or knockout blocks endometriosis development.","method":"In vitro kinase assay; site-directed mutagenesis; PAK5 knockout mice; pharmacological inhibition (GNE-2861); glycolysis assays; cell proliferation and metastasis assays","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase assay with defined substrate site, genetic and pharmacological inhibition, in vivo mouse model; single lab","pmids":["39331255"],"is_preprint":false},{"year":2025,"finding":"PAK5 phosphorylates METTL14 on Ser399 to enhance m6A modification of lncRNA MALAT1, increasing MALAT1 stability; stabilized MALAT1 inhibits USP8-mediated deubiquitination of nuclear HER2, promoting N-HER2 accumulation and trastuzumab resistance in HER2-positive breast cancer.","method":"Co-immunoprecipitation; m6A modification assay; phosphorylation assay; MALAT1 stability assay; USP8-N-HER2 interaction assay; in vitro and in vivo models","journal":"Cell death and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay, m6A assay, Co-IP for multiple complexes; single lab, multiple orthogonal methods","pmids":["40258843"],"is_preprint":false},{"year":2026,"finding":"PAK5 interacts with and phosphorylates HMGCS2 at Ser138 and Ser311, suppressing intracellular β-hydroxybutyrate synthesis. Ser138 phosphorylation recruits E3 ubiquitin ligase BMI1 to facilitate HMGCS2 degradation; Ser311 phosphorylation reduces HMGCS2 enzymatic activity by inhibiting SIRT3-dependent deacetylation. This PAK5-HMGCS2 pathway promotes breast cancer metastasis.","method":"Co-immunoprecipitation; in vitro kinase assay; site-directed mutagenesis; ubiquitination assay; SIRT3 deacetylation assay; β-HB metabolite measurement; in vitro and in vivo breast cancer models; ketogenic diet rescue","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct kinase assay with two substrate sites, ubiquitination mechanism, enzymatic activity assay, in vivo rescue; multiple orthogonal methods; single lab but comprehensive mechanistic dissection","pmids":["41834498"],"is_preprint":false},{"year":2026,"finding":"PAK5 promotes dynamin-related protein 1 (Drp1) activation, leading to mitochondrial midzone division, reduced Mfn1 expression, and enhanced expression of proliferative proteins (PCNA, Cyclin A, Cyclin D) in pulmonary artery smooth muscle cells, driving vascular remodeling in hypoxic pulmonary hypertension.","method":"In vivo PAK5-silencing mouse model; in vitro hypoxia model; western blot for Drp1, Mfn1, and cell cycle proteins; mitochondrial morphology analysis; hemodynamic measurements","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo silencing with hemodynamic readout, in vitro mechanistic assays, Drp1-Mfn1 pathway validation; single lab","pmids":["41927885"],"is_preprint":false},{"year":2021,"finding":"PAK5 promotes SOX2 phosphorylation in lung squamous cell carcinoma cells, maintaining cancer stem cell-like self-renewal ability; PAK5 absence abolishes SOX2 expression and phosphorylation, reducing oncosphere formation in vitro and tumor growth in vivo.","method":"Co-immunoprecipitation; western blotting; oncosphere-forming assay; xenograft model; PAK5 knockdown and overexpression","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and functional assays but phosphosite not directly mapped; single lab","pmids":["32721391"],"is_preprint":false}],"current_model":"PAK5 is a constitutively active, brain-enriched group II PAK serine/threonine kinase that localizes primarily to mitochondria (via an N-terminal targeting sequence) and shuttles to the nucleus via a regulated NES/NLS system; it inhibits apoptosis by phosphorylating BAD (Ser112) and AIF (Thr281), promotes neurite outgrowth and synaptic vesicle trafficking by phosphorylating Pacsin1 and Synaptojanin1, stabilizes microtubules by suppressing MARK2 kinase activity through direct catalytic-domain binding, remobilizes axonal mitochondria after injury by phosphorylating the anchor protein syntaphilin (downstream of AKT), and drives cancer progression through multiple substrate phosphorylations including E47, GATA1, SATB1, Slug, DDX5, DNPEP, PKM2, HMGCS2, METTL14, NF-κB p65, and GSK3β, with its constitutive high activity maintained by a central oligomerization domain that prevents autoinhibitory AID engagement."},"narrative":{"mechanistic_narrative":"PAK5 (PAK7) is a constitutively active, brain-enriched group II PAK serine/threonine kinase that functions as an effector of Rho-family GTPases in cytoskeletal remodeling, neuronal development, mitochondrial regulation, and apoptotic control, and is co-opted in cancer to drive proliferation and metastasis [PMID:11756552, PMID:12897128]. It binds Cdc42 in a GTP-dependent manner through its CRIB motif, yet unlike group I PAKs its high kinase activity is independent of GTPase binding; this autonomy is maintained by a central oligomerization domain that interferes with autoinhibitory domain engagement of the catalytic domain [PMID:12032833, PMID:27095851]. PAK5 carries N-terminal targeting signals (a mitochondrial targeting sequence, an NES, and an NLS) that direct constitutive mitochondrial localization and regulated shuttling to the nucleus [PMID:16581795]. At the mitochondrion it is anti-apoptotic, phosphorylating BAD on Ser112 to block its mitochondrial localization and phosphorylating AIF on Thr281 to prevent AIF/importin-α3 complex formation and nuclear translocation [PMID:12897128, PMID:33867848]. In neurons, PAK5 promotes filopodia formation and neurite outgrowth downstream of Cdc42/Rac and antagonistic to RhoA, stabilizes microtubules by directly binding and suppressing MARK2 kinase activity toward tau, phosphorylates the synaptic vesicle proteins Pacsin1 and Synaptojanin1 to promote their interaction, and—downstream of AKT—phosphorylates the mitochondrial anchor syntaphilin to remobilize damaged axonal mitochondria after ischemic injury [PMID:11756552, PMID:16014608, PMID:22371566, PMID:34087103]. PAK5/PAK6 double-knockout mice show locomotor and learning/memory deficits, whereas single PAK5 knockouts are grossly normal, indicating functional redundancy among group II PAKs in vivo [PMID:14517284, PMID:18675265]. In cancer, PAK5 phosphorylates a broad set of transcription factors and metabolic and RNA-processing enzymes—including E47 (Ser39), GATA1 (Ser161/Ser187), SATB1 (Ser47), Slug (Ser87), NF-κB p65, DDX5 (Thr69), DNPEP (Ser119), PKM2 (Ser519), METTL14 (Ser399), and HMGCS2—to drive EMT, metastasis, glycolysis, and treatment resistance [PMID:25726523, PMID:26212009, PMID:30082769, PMID:34936874, PMID:39331255, PMID:40258843, PMID:41834498].","teleology":[{"year":2002,"claim":"Established PAK5 as a Rho-GTPase effector controlling neuronal morphology, placing it downstream of Cdc42/Rac and antagonistic to RhoA in neurite development.","evidence":"Dominant-negative and constitutively active mutants in N1E-115 neuroblastoma cells with epistasis against activated RhoA and dominant-negative JNK; GTP-dependent CRIB binding assays","pmids":["11756552","12032833"],"confidence":"Medium","gaps":["Endogenous substrates driving neurite outgrowth not identified","How kinase activity is engaged independent of GTPase binding unresolved at this stage"]},{"year":2003,"claim":"Defined PAK5 as a constitutively active, mitochondrially localized anti-apoptotic kinase, identifying BAD Ser112 as a direct substrate and decoupling activity from Cdc42/Rac.","evidence":"Subcellular fractionation, in vitro kinase assay, site-directed mutagenesis, and apoptosis assays with camptothecin/C2-ceramide","pmids":["12897128"],"confidence":"High","gaps":["Mechanism keeping kinase constitutively active not defined","Other mitochondrial substrates unknown"]},{"year":2003,"claim":"Tested PAK5's in vivo requirement, revealing functional redundancy among Rho-GTPase targets since single-knockout mice are normal.","evidence":"Targeted gene disruption in mice with histological and behavioral analysis","pmids":["14517284"],"confidence":"High","gaps":["Redundant partners not identified in this study","Subtle phenotypes not probed"]},{"year":2005,"claim":"Showed PAK5 stabilizes microtubules through a non-catalytic mechanism by directly binding MARK2 and suppressing its kinase activity toward tau, while reshaping the actin cytoskeleton.","evidence":"Co-IP, in vitro kinase inhibition, deletion mapping, and cytoskeletal phenotyping in CHO cells","pmids":["16014608"],"confidence":"High","gaps":["Structural basis of catalytic-domain interaction not resolved","Physiological relevance in neurons not directly tested"]},{"year":2006,"claim":"Mapped the N-terminal targeting code (MTS/NES/NLS) and linked mitochondrial localization to anti-apoptotic function, establishing regulated mitochondria-to-nucleus shuttling.","evidence":"Deletion mutagenesis, leptomycin B export blockade, fractionation, and knockdown/rescue apoptosis assays; additional Rho GTPase (RhoD/RhoH) interaction analysis","pmids":["16581795","17064668"],"confidence":"High","gaps":["Signals triggering nuclear import not defined","Nuclear substrates not yet identified"]},{"year":2007,"claim":"Provided atomic-resolution structures of the active group II PAK catalytic domain, defining the active αC conformation and enabling inhibitor co-crystallization.","evidence":"X-ray crystallography of PAK4/5/6 catalytic domains with a tri-substituted purine inhibitor","pmids":["17292838"],"confidence":"High","gaps":["Full-length autoregulatory architecture not captured","Oligomerization-based activation not addressed structurally"]},{"year":2008,"claim":"Demonstrated that PAK5 and PAK6 jointly support locomotion and cognition, resolving the single-knockout redundancy as compensation among group II PAKs.","evidence":"PAK5/PAK6 double-knockout mice with behavioral testing for locomotion and learning/memory","pmids":["18675265"],"confidence":"High","gaps":["Cellular/molecular substrates underlying behavioral deficits not identified","Region-specific contributions unresolved"]},{"year":2012,"claim":"Identified Pacsin1 and Synaptojanin1 as brain substrates via unbiased chemical-genetic labeling, linking PAK5 to synaptic vesicle endocytosis.","evidence":"Analog-sensitive kinase substrate labeling in brain extract, in vitro kinase assay, and in vitro/in vivo co-IP","pmids":["22371566"],"confidence":"High","gaps":["Phosphosites on the substrates not pinpointed","In vivo consequence for vesicle recycling not directly measured"]},{"year":2016,"claim":"Explained the molecular basis of PAK5's constitutive activity, showing a central oligomerization domain drives dimerization that blocks autoinhibitory domain engagement.","evidence":"Gel filtration, deletion analysis, in vitro kinase assay, and AID domain swapping comparing PAK4 (monomeric/inactive) and PAK5 (dimeric/active)","pmids":["27095851"],"confidence":"Medium","gaps":["Structure of the oligomerization interface not solved","Whether oligomerization is regulated in cells unknown"]},{"year":2021,"claim":"Established PAK5 as an injury-responsive axonal kinase that remobilizes damaged mitochondria by phosphorylating syntaphilin downstream of AKT.","evidence":"Neuronal injury/ischemia models, in vivo brain injury models, SNPH phosphorylation assay, mitochondrial trafficking imaging, and AKT epistasis","pmids":["34087103"],"confidence":"High","gaps":["SNPH phosphosite not specified here","How injury signals activate PAK5 synthesis spatially not fully resolved"]},{"year":2021,"claim":"Extended the mitochondrial anti-apoptotic program by showing PAK5 phosphorylates AIF (Thr281) to block its importin-α3-dependent nuclear translocation.","evidence":"Phosphorylation assay, AIF/importin-α3 co-IP, mitochondrial membrane potential/permeability assays, and breast cancer models","pmids":["33867848"],"confidence":"Medium","gaps":["Single lab; reciprocal validation of complex disruption limited","Relative contribution versus BAD pathway unquantified"]},{"year":null,"claim":"How PAK5 selects among its large and growing roster of cancer-associated substrates in specific tissue and signaling contexts, and how its mitochondrial/nuclear shuttling is dynamically directed in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate selectivity across tissues","Upstream cues governing nuclear translocation in cancer not defined","Many cancer substrate findings rest on single-lab Co-IP/phosphorylation studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,9,22,23,24,28,30]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,9,23,28,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12,13,15,16,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,5,6,22]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,13,16,27]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,5,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,17,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,13,15,23,28,29,30]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,8,9,22]}],"complexes":[],"partners":["CDC42","MARK2","GATA1","GSK3B","DDX5","DNPEP","YWHAZ","ITGB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQU5","full_name":"Serine/threonine-protein kinase PAK 6","aliases":["PAK-5","p21-activated kinase 6","PAK-6"],"length_aa":681,"mass_kda":74.9,"function":"Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Also inhibits ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. 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Dominant-negative PAK5 inhibited neurite outgrowth, and activated RhoA abolished PAK5-induced neurite formation, placing PAK5 downstream of Cdc42/Rac and antagonistic to Rho in the neurite development pathway. PAK5 also activates the JNK pathway, but dominant-negative JNK did not block neurite outgrowth.\",\n      \"method\": \"Dominant-negative and constitutively active mutant expression in N1E-115 cells; morphological assays; epistasis with dominant-negative JNK and activated RhoA\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple signaling components, single lab, two orthogonal approaches (dominant-negative and activated mutants)\",\n      \"pmids\": [\"11756552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PAK5 preferentially binds Cdc42 in a GTP-dependent manner via its CRIB motif, but unlike PAK-I family kinases, its kinase activity does not require Cdc42 binding. Overexpression of PAK5 activates JNK but not p38 or ERK pathways.\",\n      \"method\": \"GTP-dependent binding assay; CRIB mutant analysis; MAPK pathway activation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and kinase activity assays, CRIB mutagenesis, two orthogonal methods, single lab\",\n      \"pmids\": [\"12032833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PAK5 is constitutively localized to mitochondria (independent of kinase activity or Cdc42 binding), has constitutively high kinase activity not regulated by Cdc42/Rac, prevents apoptosis induced by camptothecin and C2-ceramide by phosphorylating BAD on Ser-112 in a PKA-independent manner, and prevents BAD localization to mitochondria.\",\n      \"method\": \"Subcellular fractionation; in vitro kinase assay; site-directed mutagenesis; apoptosis assays with camptothecin and C2-ceramide; BAD phosphorylation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted kinase assay, subcellular localization by fractionation, mutagenesis, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"12897128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PAK5 knockout mice develop normally and are fertile, with no apparent nervous system abnormalities, suggesting functional redundancy between PAK5 and other Rho GTPase targets in vivo.\",\n      \"method\": \"Targeted gene disruption (knockout mice); histological and behavioral analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout, replicated in multiple subsequent studies\",\n      \"pmids\": [\"14517284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PAK5 directly binds MARK2 via their catalytic domains and suppresses MARK2 kinase activity toward tau protein without requiring phosphorylation. In transfected CHO cells, PAK5 and MARK2 co-localize on endosomes containing AP-1/2. PAK5 keeps microtubules stable by downregulating MARK2 while simultaneously destabilizing F-actin (eliminating stress fibers and focal adhesions) and inducing filopodia.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; deletion/mutagenesis analysis; subcellular fractionation and co-localization in CHO cells; cytoskeletal phenotyping\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding and in vitro kinase inhibition assays with deletion analysis, co-localization, phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"16014608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAK5 contains three N-terminal regulatory sequences: a mitochondrial targeting sequence, a nuclear export sequence (NES), and a nuclear localization sequence (NLS). PAK5 shuttles between mitochondria and nucleus; blockade of nuclear export with leptomycin B causes endogenous PAK5 to accumulate in the nucleus. Mitochondrial localization of PAK5 is required for its anti-apoptotic function; a PAK5 mutant unable to localize to mitochondria fails to protect cells from apoptosis. Reduction of endogenous PAK5 in neuroblastoma and neural stem cells increases apoptosis sensitivity.\",\n      \"method\": \"Deletion mutagenesis of targeting sequences; leptomycin B nuclear export blockade; live-cell imaging and fractionation; apoptosis rescue assays with wild-type vs. localization-defective mutants; endogenous PAK5 knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, pharmacological blockade, knockdown with rescue), functional consequence directly linked to localization\",\n      \"pmids\": [\"16581795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAK5 interacts with RhoD and RhoH in addition to Cdc42, and RhoD interaction targets PAK5 to subcellular locations distinct from those driven by Cdc42. The CRIB domain is critical for proper subcellular targeting. Kinase activity is required for PAK5 cycling on and off mitochondria; kinase-inactive PAK5 causes dramatic alterations in mitochondrial morphology.\",\n      \"method\": \"Deletion analysis; co-immunoprecipitation; subcellular localization by fluorescence microscopy; kinase-inactive mutant expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and imaging-based localization studies, single lab, multiple Rho GTPase interactions tested\",\n      \"pmids\": [\"17064668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of all active, monophosphorylated group II PAK catalytic domains (PAK4, PAK5, PAK6) reveal catalytic domain plasticity including rearrangements of helix αC forming an additional helical turn and distortion of its C-terminus, interactions between conserved residues linking the glycine-rich loop, αC, and activation segment to anchor αC in an active conformation. A tri-substituted purine inhibitor was co-crystallized with PAK4 and PAK5.\",\n      \"method\": \"X-ray crystallography (multiple high-resolution structures); inhibitor screening and co-crystallization\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple high-resolution crystal structures of PAK5 catalytic domain, structural comparison across all group II PAKs\",\n      \"pmids\": [\"17292838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PAK5/PAK6 double-knockout mice are viable and fertile but exhibit locomotor deficits and learning/memory impairment, while PAK5 single-knockout mice show no gross abnormalities. PAK5 and PAK6 together are required for normal locomotion and cognitive function.\",\n      \"method\": \"Targeted gene disruption (double-knockout mice); behavioral testing (locomotion, learning/memory assays)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockouts with defined behavioral phenotypes, replicated across multiple behavioral paradigms\",\n      \"pmids\": [\"18675265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Using an analog-sensitive PAK5 mutant to selectively radiolabel substrates in murine brain extract, Pacsin1 and Synaptojanin1 were identified as novel PAK5 substrates. PAK5 (and other group II PAKs) phosphorylated Pacsin1 and Synaptojanin1 in vitro, and PAK5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo, implicating PAK5 in synaptic vesicle endocytosis and recycling.\",\n      \"method\": \"Analog-sensitive kinase substrate labeling in brain extract; in vitro kinase assay; co-immunoprecipitation (in vitro and in vivo)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — chemical-genetic substrate identification plus in vitro kinase assay plus co-IP validation in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"22371566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAK5 promotes breast cancer cell migration through a PAK5-Egr1-MMP2 signaling pathway; knockdown of PAK5 reduced Egr1 and MMP2 expression and inhibited migration and invasion.\",\n      \"method\": \"siRNA knockdown; western blot for pathway components; wound healing, migration and invasion assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, pathway placement without direct phosphorylation evidence\",\n      \"pmids\": [\"23696025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAK5 gain-of-function mutations in lung cancer activate the ERK pathway, and targeted depletion of mutated PAK5 inhibits proliferation and suppresses constitutive ERK pathway activation in lung cancer cells.\",\n      \"method\": \"Targeted genetic dependency screen; siRNA depletion; ERK pathway activation assays; proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen with pathway validation, single lab, multiple cancer lines tested\",\n      \"pmids\": [\"23836671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAK5 phosphorylates GATA1 on Ser161 and Ser187; phosphorylated GATA1 recruits more HDAC3/4 to the E-cadherin promoter, leading to transcriptional repression of E-cadherin and promotion of EMT in breast cancer cells. GATA1 S161A/S187A mutant shows reduced HDAC3/4 recruitment.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assay; HDAC recruitment assay; E-cadherin promoter reporter; site-directed mutagenesis; in vivo metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay with mutagenesis, Co-IP for complex, single lab\",\n      \"pmids\": [\"25726523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAK5 interacts with and phosphorylates E47 transcription factor on Ser39 under HGF stimulation, promoting E47 nuclear accumulation via importin α, enhanced E47 binding to E-cadherin promoter, and EMT/metastasis in colon cancer.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assay; importin α interaction assay; chromatin immunoprecipitation; xenograft metastasis model; site-directed mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay with mutagenesis, importin α binding, ChIP; single lab; multiple orthogonal methods\",\n      \"pmids\": [\"26212009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PAK5 auto-activates through oligomerization mediated by a central domain (residues 109-420) that interferes with AID binding to the catalytic domain, maintaining high constitutive kinase activity. PAK4 is monomeric and inactive, while PAK5 is dimeric; removing oligomerization sequences suppresses PAK5 kinase activity. The PAK5 AID is functionally indistinguishable from PAK4 AID.\",\n      \"method\": \"Gel filtration (oligomerization); deletion analysis; in vitro kinase assay; cell imaging of puncta formation; AID domain swapping\",\n      \"journal\": \"Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical reconstitution with deletion analysis and gel filtration, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27095851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PAK5 phosphorylates SATB1 on Ser47, initiating EMT cascade and promoting migration and invasion of cervical cancer cells; PAK5 overexpression induces lung metastasis in xenograft models.\",\n      \"method\": \"Mn2+-Phos-tag SDS-PAGE; western blotting; immunofluorescence; dual luciferase reporter; xenograft metastasis; site-directed mutagenesis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay with Phos-tag, mutagenesis, in vivo xenograft; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30082769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PAK5 promotes phosphorylation and nuclear translocation of NF-κB p65 subunit; nuclear p65 binds the Cyclin D1 promoter, increasing Cyclin D1 expression and promoting breast cancer cell cycle progression and proliferation. Co-IP confirmed PAK5-p65 interaction.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assay; nuclear fractionation; Cyclin D1 promoter luciferase reporter; xenograft model; CCK-8 and flow cytometry\",\n      \"journal\": \"Journal of experimental and clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation assay, reporter assay, in vivo xenograft; single lab, multiple methods\",\n      \"pmids\": [\"29041983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAK5 (PAK7) directly binds GSK3β and β-catenin, phosphorylates GSK3β to regulate β-catenin degradation, and activates the Wnt/β-catenin signaling pathway to promote breast cancer proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation; co-localization; TOP/FOP luciferase reporter; western blotting; functional proliferation and migration assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assay, binding assays; single lab, multiple methods\",\n      \"pmids\": [\"29805709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAK5 promotes EMT and cell migration/invasion in ovarian cancer by activating the PI3K/AKT pathway; PAK5 knockdown reduced phosphorylation of PI3K p85 at Tyr458 and AKT at Ser473.\",\n      \"method\": \"siRNA knockdown and overexpression; western blot for PI3K/AKT phosphorylation; wound healing and invasion assays\",\n      \"journal\": \"Analytical cellular pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown/overexpression approach, pathway placement without direct substrate identification\",\n      \"pmids\": [\"30245957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAK5 missense mutations in the serine-rich domain (S364L and D421N) drive aberrant melanocyte proliferation by activating ERK through kinase-independent mechanisms and activating PKA through kinase-dependent mechanisms, without affecting single-cell migration or temozolomide resistance.\",\n      \"method\": \"Stable expression of melanoma-associated PAK5 mutants in immortalized human melanocytes; proliferation assays; ERK and PKA activation assays; kinase-dead mutant analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutant characterization distinguishing kinase-dependent vs. independent mechanisms, single lab, multiple downstream pathways assessed\",\n      \"pmids\": [\"29875996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PAK5 interacts with and phosphorylates DNPEP (aspartyl aminopeptidase) at Ser119, leading to downregulation of DNPEP and consequent upregulation of USP4; PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway, promoting breast cancer progression.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assay; ubiquitin-proteasome pathway analysis; overexpression and knockdown; in vivo xenograft and metastasis models\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay, co-IP, proteasomal degradation assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31219614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PAK5 interacts with Cdc42 and Integrin β1 and β3 in colorectal cancer cells, facilitating migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation; knockdown; migration and invasion assays; in vitro and in vivo models\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP finding, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"32383357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAK5 is a brain mitochondrial kinase whose synthesis and signaling is spatiotemporally activated within axons in response to ischemic stress and axonal injury. PAK5 phosphorylates the mitochondrial anchor syntaphilin (SNPH), releasing the mitochondrial anchor and remobilizing damaged mitochondria to restore axonal energy supply. This axis is activated by upstream AKT signaling.\",\n      \"method\": \"In vitro neuronal injury and ischemia models; in vivo mouse brain injury models; PAK5 overexpression and knockdown; phosphorylation assay for SNPH; mitochondrial trafficking imaging; genetic rescue experiments\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphorylation assay with defined substrate (SNPH), live mitochondrial imaging, in vitro and in vivo models, AKT epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"34087103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAK5 phosphorylates DDX5 on Thr69; this phosphorylation promotes sumoylation of DDX5, stabilizing DDX5. Both phosphorylation and sumoylation of DDX5 enhance formation of a DDX5/Drosha/DGCR8 complex, promoting microRNA-10b processing and maturation, leading to breast cancer cell proliferation and metastasis.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; sumoylation assay; PAK5 knockout (MMTV-PyVT transgenic mice); miRNA processing assays; phospho-specific antibody validation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, direct sumoylation assay, complex formation by Co-IP, in vivo transgenic mouse model validation; multiple orthogonal methods\",\n      \"pmids\": [\"34936874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAK5 inhibits apoptosis by phosphorylating AIF at Thr281, inhibiting formation of the AIF/importin α3 complex and thereby preventing AIF nuclear translocation. PAK5 also decreases mitochondrial membrane permeability and maintains membrane potential to inhibit AIF release from mitochondria.\",\n      \"method\": \"Phosphorylation assay; co-immunoprecipitation (AIF/importin α3); mitochondrial membrane permeability and potential assays; nuclear fractionation; in vitro and in vivo breast cancer models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay with defined site, Co-IP for complex, functional localization consequence; single lab\",\n      \"pmids\": [\"33867848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"14-3-3 interacts with PAK5 in response to phorbol ester-stimulated phosphorylation of Ser99 and EGF-stimulated phosphorylation of Ser288; these phosphorylations regulate PAK5 localization and signaling in melanoma cells.\",\n      \"method\": \"14-3-3 binding assay; phosphosite mapping; phorbol ester and EGF stimulation; co-immunoprecipitation; cell localization studies\",\n      \"journal\": \"Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 14-3-3 binding assay with phosphosite identification, stimulus-dependent regulation; single lab\",\n      \"pmids\": [\"35969127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PAK5 binds to and phosphorylates Slug (SNAI2) at Ser87; phosphorylated Slug transactivates N-cadherin expression, promoting EMT and metastasis in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation; phosphorylation assay; western blot; xenograft metastasis model; site-directed mutagenesis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay, Co-IP, mutagenesis, in vivo model; single lab, multiple methods\",\n      \"pmids\": [\"37437827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PAK5 interacts with transcription factors LMO2 and GATA1 in the nucleus after mitochondria-to-nucleus translocation; without LMO2, PAK5 fails to bind GATA1 and phosphorylate it at Ser161, indicating LMO2 is required as a co-factor for PAK5-mediated GATA1 phosphorylation in hematopoietic cells.\",\n      \"method\": \"Co-immunoprecipitation; nuclear fractionation; phosphorylation assay; serum-stimulated nuclear translocation assay\",\n      \"journal\": \"Cellular and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP for complex formation, single lab, limited orthogonal validation in this context\",\n      \"pmids\": [\"36905268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PAK5 phosphorylates PKM2 at Ser519, enhancing PKM2 protein stability and promoting anaerobic glycolysis in endometriosis. PAK5 inhibition or knockout blocks endometriosis development.\",\n      \"method\": \"In vitro kinase assay; site-directed mutagenesis; PAK5 knockout mice; pharmacological inhibition (GNE-2861); glycolysis assays; cell proliferation and metastasis assays\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase assay with defined substrate site, genetic and pharmacological inhibition, in vivo mouse model; single lab\",\n      \"pmids\": [\"39331255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PAK5 phosphorylates METTL14 on Ser399 to enhance m6A modification of lncRNA MALAT1, increasing MALAT1 stability; stabilized MALAT1 inhibits USP8-mediated deubiquitination of nuclear HER2, promoting N-HER2 accumulation and trastuzumab resistance in HER2-positive breast cancer.\",\n      \"method\": \"Co-immunoprecipitation; m6A modification assay; phosphorylation assay; MALAT1 stability assay; USP8-N-HER2 interaction assay; in vitro and in vivo models\",\n      \"journal\": \"Cell death and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay, m6A assay, Co-IP for multiple complexes; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40258843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PAK5 interacts with and phosphorylates HMGCS2 at Ser138 and Ser311, suppressing intracellular β-hydroxybutyrate synthesis. Ser138 phosphorylation recruits E3 ubiquitin ligase BMI1 to facilitate HMGCS2 degradation; Ser311 phosphorylation reduces HMGCS2 enzymatic activity by inhibiting SIRT3-dependent deacetylation. This PAK5-HMGCS2 pathway promotes breast cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; site-directed mutagenesis; ubiquitination assay; SIRT3 deacetylation assay; β-HB metabolite measurement; in vitro and in vivo breast cancer models; ketogenic diet rescue\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct kinase assay with two substrate sites, ubiquitination mechanism, enzymatic activity assay, in vivo rescue; multiple orthogonal methods; single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"41834498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PAK5 promotes dynamin-related protein 1 (Drp1) activation, leading to mitochondrial midzone division, reduced Mfn1 expression, and enhanced expression of proliferative proteins (PCNA, Cyclin A, Cyclin D) in pulmonary artery smooth muscle cells, driving vascular remodeling in hypoxic pulmonary hypertension.\",\n      \"method\": \"In vivo PAK5-silencing mouse model; in vitro hypoxia model; western blot for Drp1, Mfn1, and cell cycle proteins; mitochondrial morphology analysis; hemodynamic measurements\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo silencing with hemodynamic readout, in vitro mechanistic assays, Drp1-Mfn1 pathway validation; single lab\",\n      \"pmids\": [\"41927885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAK5 promotes SOX2 phosphorylation in lung squamous cell carcinoma cells, maintaining cancer stem cell-like self-renewal ability; PAK5 absence abolishes SOX2 expression and phosphorylation, reducing oncosphere formation in vitro and tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation; western blotting; oncosphere-forming assay; xenograft model; PAK5 knockdown and overexpression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and functional assays but phosphosite not directly mapped; single lab\",\n      \"pmids\": [\"32721391\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PAK5 is a constitutively active, brain-enriched group II PAK serine/threonine kinase that localizes primarily to mitochondria (via an N-terminal targeting sequence) and shuttles to the nucleus via a regulated NES/NLS system; it inhibits apoptosis by phosphorylating BAD (Ser112) and AIF (Thr281), promotes neurite outgrowth and synaptic vesicle trafficking by phosphorylating Pacsin1 and Synaptojanin1, stabilizes microtubules by suppressing MARK2 kinase activity through direct catalytic-domain binding, remobilizes axonal mitochondria after injury by phosphorylating the anchor protein syntaphilin (downstream of AKT), and drives cancer progression through multiple substrate phosphorylations including E47, GATA1, SATB1, Slug, DDX5, DNPEP, PKM2, HMGCS2, METTL14, NF-κB p65, and GSK3β, with its constitutive high activity maintained by a central oligomerization domain that prevents autoinhibitory AID engagement.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PAK5 (PAK7) is a constitutively active, brain-enriched group II PAK serine/threonine kinase that functions as an effector of Rho-family GTPases in cytoskeletal remodeling, neuronal development, mitochondrial regulation, and apoptotic control, and is co-opted in cancer to drive proliferation and metastasis [#0, #2]. It binds Cdc42 in a GTP-dependent manner through its CRIB motif, yet unlike group I PAKs its high kinase activity is independent of GTPase binding; this autonomy is maintained by a central oligomerization domain that interferes with autoinhibitory domain engagement of the catalytic domain [#1, #14]. PAK5 carries N-terminal targeting signals (a mitochondrial targeting sequence, an NES, and an NLS) that direct constitutive mitochondrial localization and regulated shuttling to the nucleus [#5]. At the mitochondrion it is anti-apoptotic, phosphorylating BAD on Ser112 to block its mitochondrial localization and phosphorylating AIF on Thr281 to prevent AIF/importin-α3 complex formation and nuclear translocation [#2, #24]. In neurons, PAK5 promotes filopodia formation and neurite outgrowth downstream of Cdc42/Rac and antagonistic to RhoA, stabilizes microtubules by directly binding and suppressing MARK2 kinase activity toward tau, phosphorylates the synaptic vesicle proteins Pacsin1 and Synaptojanin1 to promote their interaction, and—downstream of AKT—phosphorylates the mitochondrial anchor syntaphilin to remobilize damaged axonal mitochondria after ischemic injury [#0, #4, #9, #22]. PAK5/PAK6 double-knockout mice show locomotor and learning/memory deficits, whereas single PAK5 knockouts are grossly normal, indicating functional redundancy among group II PAKs in vivo [#3, #8]. In cancer, PAK5 phosphorylates a broad set of transcription factors and metabolic and RNA-processing enzymes—including E47 (Ser39), GATA1 (Ser161/Ser187), SATB1 (Ser47), Slug (Ser87), NF-κB p65, DDX5 (Thr69), DNPEP (Ser119), PKM2 (Ser519), METTL14 (Ser399), and HMGCS2—to drive EMT, metastasis, glycolysis, and treatment resistance [#12, #13, #15, #23, #28, #29, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established PAK5 as a Rho-GTPase effector controlling neuronal morphology, placing it downstream of Cdc42/Rac and antagonistic to RhoA in neurite development.\",\n      \"evidence\": \"Dominant-negative and constitutively active mutants in N1E-115 neuroblastoma cells with epistasis against activated RhoA and dominant-negative JNK; GTP-dependent CRIB binding assays\",\n      \"pmids\": [\"11756552\", \"12032833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous substrates driving neurite outgrowth not identified\", \"How kinase activity is engaged independent of GTPase binding unresolved at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined PAK5 as a constitutively active, mitochondrially localized anti-apoptotic kinase, identifying BAD Ser112 as a direct substrate and decoupling activity from Cdc42/Rac.\",\n      \"evidence\": \"Subcellular fractionation, in vitro kinase assay, site-directed mutagenesis, and apoptosis assays with camptothecin/C2-ceramide\",\n      \"pmids\": [\"12897128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism keeping kinase constitutively active not defined\", \"Other mitochondrial substrates unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Tested PAK5's in vivo requirement, revealing functional redundancy among Rho-GTPase targets since single-knockout mice are normal.\",\n      \"evidence\": \"Targeted gene disruption in mice with histological and behavioral analysis\",\n      \"pmids\": [\"14517284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundant partners not identified in this study\", \"Subtle phenotypes not probed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed PAK5 stabilizes microtubules through a non-catalytic mechanism by directly binding MARK2 and suppressing its kinase activity toward tau, while reshaping the actin cytoskeleton.\",\n      \"evidence\": \"Co-IP, in vitro kinase inhibition, deletion mapping, and cytoskeletal phenotyping in CHO cells\",\n      \"pmids\": [\"16014608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of catalytic-domain interaction not resolved\", \"Physiological relevance in neurons not directly tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped the N-terminal targeting code (MTS/NES/NLS) and linked mitochondrial localization to anti-apoptotic function, establishing regulated mitochondria-to-nucleus shuttling.\",\n      \"evidence\": \"Deletion mutagenesis, leptomycin B export blockade, fractionation, and knockdown/rescue apoptosis assays; additional Rho GTPase (RhoD/RhoH) interaction analysis\",\n      \"pmids\": [\"16581795\", \"17064668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering nuclear import not defined\", \"Nuclear substrates not yet identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided atomic-resolution structures of the active group II PAK catalytic domain, defining the active αC conformation and enabling inhibitor co-crystallization.\",\n      \"evidence\": \"X-ray crystallography of PAK4/5/6 catalytic domains with a tri-substituted purine inhibitor\",\n      \"pmids\": [\"17292838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length autoregulatory architecture not captured\", \"Oligomerization-based activation not addressed structurally\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that PAK5 and PAK6 jointly support locomotion and cognition, resolving the single-knockout redundancy as compensation among group II PAKs.\",\n      \"evidence\": \"PAK5/PAK6 double-knockout mice with behavioral testing for locomotion and learning/memory\",\n      \"pmids\": [\"18675265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular/molecular substrates underlying behavioral deficits not identified\", \"Region-specific contributions unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Pacsin1 and Synaptojanin1 as brain substrates via unbiased chemical-genetic labeling, linking PAK5 to synaptic vesicle endocytosis.\",\n      \"evidence\": \"Analog-sensitive kinase substrate labeling in brain extract, in vitro kinase assay, and in vitro/in vivo co-IP\",\n      \"pmids\": [\"22371566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites on the substrates not pinpointed\", \"In vivo consequence for vesicle recycling not directly measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Explained the molecular basis of PAK5's constitutive activity, showing a central oligomerization domain drives dimerization that blocks autoinhibitory domain engagement.\",\n      \"evidence\": \"Gel filtration, deletion analysis, in vitro kinase assay, and AID domain swapping comparing PAK4 (monomeric/inactive) and PAK5 (dimeric/active)\",\n      \"pmids\": [\"27095851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structure of the oligomerization interface not solved\", \"Whether oligomerization is regulated in cells unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established PAK5 as an injury-responsive axonal kinase that remobilizes damaged mitochondria by phosphorylating syntaphilin downstream of AKT.\",\n      \"evidence\": \"Neuronal injury/ischemia models, in vivo brain injury models, SNPH phosphorylation assay, mitochondrial trafficking imaging, and AKT epistasis\",\n      \"pmids\": [\"34087103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SNPH phosphosite not specified here\", \"How injury signals activate PAK5 synthesis spatially not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the mitochondrial anti-apoptotic program by showing PAK5 phosphorylates AIF (Thr281) to block its importin-α3-dependent nuclear translocation.\",\n      \"evidence\": \"Phosphorylation assay, AIF/importin-α3 co-IP, mitochondrial membrane potential/permeability assays, and breast cancer models\",\n      \"pmids\": [\"33867848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation of complex disruption limited\", \"Relative contribution versus BAD pathway unquantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PAK5 selects among its large and growing roster of cancer-associated substrates in specific tissue and signaling contexts, and how its mitochondrial/nuclear shuttling is dynamically directed in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for substrate selectivity across tissues\", \"Upstream cues governing nuclear translocation in cancer not defined\", \"Many cancer substrate findings rest on single-lab Co-IP/phosphorylation studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 9, 22, 23, 24, 28, 30]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 9, 23, 28, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [12, 13, 15, 16, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 5, 6, 22]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 13, 16, 27]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 5, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 17, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 13, 15, 23, 28, 29, 30]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 8, 9, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CDC42\", \"MARK2\", \"GATA1\", \"GSK3B\", \"DDX5\", \"DNPEP\", \"YWHAZ\", \"ITGB1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}