{"gene":"PAK6","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2001,"finding":"PAK6 physically interacts with the androgen receptor (AR) in a domain-specific and ligand-dependent manner; PAK6 co-translocates into the nucleus with AR in response to androgen; PAK6 represses AR-mediated transcription in transient transfection assays.","method":"Yeast two-hybrid, in vitro binding, immunofluorescence co-localization, transient transfection reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo interaction confirmed, co-localization, functional reporter assay; independently replicated by Lee et al. 2002 (PMID:11773441)","pmids":["11278661"],"is_preprint":false},{"year":2002,"finding":"PAK6 binds strongly to GTP-bound Cdc42 and weakly to GTP-Rac via its CRIB domain; PAK6 kinase activity is not stimulated by Cdc42 or Rac but can be stimulated by AR binding; PAK6 also binds ERα with binding enhanced by 4-hydroxytamoxifen; PAK6 inhibits both AR and ERα transcriptional activity; epitope-tagged PAK6 is primarily cytoplasmic.","method":"Mammalian one-hybrid assay, in vitro binding, GTPase binding assays, transient transfection reporter assay, immunofluorescence localization","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assays, kinase activity, reporter assays, localization); independently corroborates PMID:11278661","pmids":["11773441"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of active, monophosphorylated PAK6 catalytic domain reveal group II PAK structural plasticity including rearrangements of helix αC forming an additional helical turn at αC N-terminus and a distortion of its C-terminus, forming interactions that link the glycine-rich loop, αC, and the activation segment to anchor αC in an active conformation.","method":"X-ray crystallography (multiple high-resolution structures of PAK4, PAK5, PAK6 catalytic domains; inhibitor co-crystal structures)","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures with structural comparison across all group II PAK catalytic domains","pmids":["17292838"],"is_preprint":false},{"year":2008,"finding":"Pak5/Pak6 double-knockout mice are viable and fertile but exhibit locomotor deficits and learning and memory impairments, establishing that PAK6 together with PAK5 is required for normal locomotion and cognitive function in vivo.","method":"Gene knockout (mouse), behavioral assays (locomotion, learning and memory)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined behavioral phenotypes, replicated in follow-up study (PMID:23593460)","pmids":["18675265"],"is_preprint":false},{"year":2008,"finding":"PAK6 co-immunoprecipitates with IQGAP1 and protein phosphatase 1B (PP1B) in prostate cancer cells, identifying these as PAK6 interacting proteins.","method":"Immunopurification of 3xFlag-tagged PAK6 followed by LC/MS/MS, confirmed by co-immunoprecipitation","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with MS identification confirmed by reciprocal co-IP, single lab","pmids":["18642328"],"is_preprint":false},{"year":2010,"finding":"PAK6 inhibition reduces phosphorylation of BAD at Ser112, leading to increased BAD binding to Bcl-2 and Bcl-XL, cytochrome c release, caspase activation, and apoptosis; PAK6 knockdown also increases radiosensitivity of prostate cancer cells.","method":"shRNA stable knockdown, clonogenic survival assay, apoptosis assay (flow cytometry), Western blot (BAD phosphorylation, Bcl-2 binding, cleaved caspase-3)","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined molecular pathway (BAD phosphorylation → apoptosis), single lab with multiple readouts","pmids":["20054820"],"is_preprint":false},{"year":2012,"finding":"PAK6 phosphorylates AR at Ser-578, promoting AR association with E3 ligase Mdm2 and AR ubiquitin-mediated degradation; PAK6 also phosphorylates Mdm2 at Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation; PAK6 co-localizes with AR in the cytoplasm of normal prostate epithelium.","method":"In vitro kinase assay, immunofluorescence co-localization, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with specific phosphosite identification, mutagenesis validation, co-IP, and in vivo confirmation; multiple orthogonal methods in single lab","pmids":["23132866"],"is_preprint":false},{"year":2012,"finding":"PAK6 is a novel effector of the atypical Rho GTPase Chp/RhoV; interaction depends on the activation state of Chp and involves the effector domain of Chp and the CRIB motif of PAK6; Chp does not activate PAK6 (no change in S560 phosphorylation); in NCI-H1299 cells, Chp co-localizes with PAK6 on vesicular structures in an activation state-dependent manner.","method":"Yeast two-hybrid, co-immunoprecipitation, point mutagenesis of effector domain and CRIB motif, immunofluorescence co-localization","journal":"Biochemistry (Biokhimiia)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP with mutagenesis, single lab","pmids":["22339630"],"is_preprint":false},{"year":2013,"finding":"PAK6 localizes to cell-cell junctions and directly interacts with IQGAP1 via its kinase domain; PAK6 forms a complex with E-cadherin and IQGAP1 downstream of HGF signaling; β-catenin is a novel PAK6 substrate at cell-cell junctions; PAK6/IQGAP1 complex drives epithelial colony escape and cell-cell dissociation.","method":"Co-immunoprecipitation, immunofluorescence localization, kinase domain binding assay, co-expression overexpression/depletion assays, cell colony escape assay","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct interaction (co-IP of kinase domain), substrate identification, functional rescue, single lab with multiple orthogonal methods","pmids":["24352566"],"is_preprint":false},{"year":2013,"finding":"PAK6 has a peptide substrate specificity similar to PAK4 and PAK5; PAK6 is autoinhibited by an N-terminal pseudosubstrate peptide; a melanoma-associated P52L mutation in the pseudosubstrate reduces autoinhibition and increases phosphorylation of PACSIN1 (Syndapin I) in cells; co-crystal structures of PAK6 catalytic domain with PF-3758309 (1.4 Å) and sunitinib (1.95 Å) determined.","method":"Peptide library substrate profiling, in vitro kinase assay, pseudosubstrate peptide inhibition assay, site-directed mutagenesis (P52L), cellular phosphorylation assay, X-ray crystallography","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures at high resolution, in vitro kinase assay with mutagenesis, substrate identification; multiple orthogonal methods in single lab","pmids":["24204982"],"is_preprint":false},{"year":2013,"finding":"PAK6 kinase activation is stimulated by direct AR interaction in response to androgen; siRNA knockdown of AR reduces androgen-stimulated PAK6 kinase activation; a non-AR-interacting PAK6 mutant shows dampened kinase activation and fails to promote androgen-stimulated cell motility and invasion.","method":"In vitro kinase assay, siRNA knockdown, cell motility and invasion assay, mutant PAK6 expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase activity measured with genetic perturbation (AR siRNA and PAK6 mutant), single lab with multiple methods","pmids":["24130878"],"is_preprint":false},{"year":2015,"finding":"PAK6 targeting to cell-cell adhesions requires both its CRIB domain and an adjacent polybasic region in the N-terminus; Cdc42 knockdown inhibits PAK6 localization to cell-cell adhesions; PAK6-driven epithelial colony escape requires kinase activity and is abolished by mutations disrupting cell-cell adhesion targeting.","method":"Deletion/point mutagenesis, siRNA knockdown of Cdc42, immunofluorescence localization, colony escape assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function analysis with multiple domain mutants and genetic knockdown, single lab","pmids":["26598554"],"is_preprint":false},{"year":2015,"finding":"PAK6 phosphorylates LIMK1 at Thr-508, activating it; activated LIMK1 phosphorylates cofilin, promoting stress fiber and actin filament formation required for cell motility and invasion; PAK6 and LIMK1 co-localize in the cytoplasm.","method":"Co-immunoprecipitation, immunofluorescence co-localization, Western blot (phospho-LIMK1, phospho-cofilin), in vivo orthotopic mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, phosphorylation site identified, co-localization, in vivo model; single lab, moderate method rigor","pmids":["25714010"],"is_preprint":false},{"year":2017,"finding":"PAK6 phosphorylates 14-3-3γ at Ser59; this phosphorylation dissociates 14-3-3γ from client proteins including LRRK2, causing LRRK2 dephosphorylation at Ser935; constitutively active PAK6 rescues G2019S LRRK2-associated neurite shortening through 14-3-3γ phosphorylation.","method":"Co-immunoprecipitation (PAK6 interactome), in vitro kinase assay (phosphorylation of 14-3-3γ at Ser59), co-IP (14-3-3γ/LRRK2 dissociation), immunofluorescence (neurite length assay), constitutively active PAK6 rescue experiment","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — kinase assay with specific phosphosite identification, functional consequence (LRRK2 regulation), neuronal rescue experiment, multiple orthogonal methods","pmids":["29311810"],"is_preprint":false},{"year":2017,"finding":"RhoD recruits PAK6 to the plasma membrane to antagonize RhoC signaling during cell contraction and blebbing; vaccinia virus protein F11 inhibits RhoD signaling, preventing RhoD from activating PAK6, thereby releasing suppression of RhoC-ROCK-mediated cell contraction.","method":"Genetic epistasis (RhoD, PAK6, RhoC knockdown/overexpression), immunofluorescence localization, cell contraction and blebbing assays","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined pathway placement (RhoD→PAK6⊣RhoC-ROCK), single lab with multiple genetic perturbations","pmids":["28486133"],"is_preprint":false},{"year":2018,"finding":"DNMT1 represses PAK6 transcription by interacting with EZH2 (PRC2 core enzyme) to mediate repressive H3K27 trimethylation at PAK6 gene regulatory regions; inhibition of EZH2 elevates PAK6 expression and increases morphological complexity in cortical interneurons, rescued by PAK6 siRNA knockdown.","method":"ChIP (H3K4me3, H3K27me3 at PAK6 locus), EZH2 inhibition, DNMT1 knockdown, siRNA-mediated PAK6 knockdown, morphological analysis","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct histone modification at PAK6 locus, genetic epistasis with rescue, single lab","pmids":["29912614"],"is_preprint":false},{"year":2020,"finding":"PAK6 is mainly located in the mitochondrial inner membrane; PAK6 promotes SIRT4 ubiquitin-mediated proteolysis; SIRT4 deacetylates ANT2 at K105 to promote ANT2 ubiquitination degradation; PAK6 directly phosphorylates ANT2 at T107 to inhibit apoptosis of prostate cancer cells; the PAK6-SIRT4-ANT2 complex regulates mitochondrial apoptosis.","method":"Immunofluorescence, immunoelectron microscopy (subcellular localization), co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K105, T107), flow cytometry (apoptosis), xenograft model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including subcellular localization, co-IP, ubiquitination assay, mutagenesis of specific phospho/acetylation sites, and in vivo validation; single lab","pmids":["32194820"],"is_preprint":false},{"year":2020,"finding":"Pharmacological inhibition of PAK6 perturbs the RAS/MAPK pathway and mitochondrial activity in CML drug-resistant cells, sensitizing them to TKI therapy.","method":"PAK6 pharmacological inhibition, pathway analysis (RAS/MAPK), mitochondrial activity assay, xenotransplantation model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — PAK6 inhibitor with pathway readouts in cancer cells; single lab, limited mechanistic dissection","pmids":["32270193"],"is_preprint":false},{"year":2022,"finding":"PAK6 moves into the nucleus to promote ATR activation, which activates CHK1 and recruits RAD51 from cytoplasm to DNA damage sites to enable homologous recombination repair; ATR inhibitor (AZD6738) blocks PAK6-mediated HR repair, reversing oxaliplatin resistance.","method":"PAK6 knockdown/overexpression, ATR inhibitor treatment, HR repair assay (RAD51 foci), Western blot (ATR/CHK1 activation), nuclear fractionation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear translocation with functional consequence (HR repair), pathway epistasis with ATR inhibitor, single lab","pmids":["35902562"],"is_preprint":false},{"year":2022,"finding":"PAK6 interacts with GSK3β (confirmed by co-IP and fluorescence co-localization) and activates the Wnt/β-catenin signaling pathway, leading to GSK3β phosphorylation, increased Cyclin D1, and decreased β-catenin phosphorylation and E-cadherin.","method":"Co-immunoprecipitation, fluorescence co-localization, shRNA knockdown and overexpression, Western blot (Wnt/β-catenin pathway components)","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with co-localization and functional pathway analysis, single lab; limited mechanistic depth","pmids":["32782556"],"is_preprint":false},{"year":2022,"finding":"PAK6 phosphorylates the PP2A regulatory subunit PPP2R2C at Ser381; this phosphorylation alters PPP2R2C binding to LRRK2 and changes PPP2R2C subcellular localization in a phosphorylation-dependent manner; however, LRRK2 dephosphorylation by PAK6 is unaffected by PPP2R2C S381 phosphorylation, indicating the 14-3-3γ phosphorylation mechanism is dominant.","method":"PhosTag gel electrophoresis with purified proteins (in vitro kinase assay), co-immunoprecipitation, subcellular localization imaging, site-directed mutagenesis (S381A phosphodead)","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay with purified proteins, mutagenesis, co-IP, localization; single lab","pmids":["35016853"],"is_preprint":false},{"year":2023,"finding":"PAK6 phosphorylates the PP2A regulatory subunit PPP2R2C at S381 (confirmed with purified proteins); S381 phosphorylation does not affect PP2A holoenzyme formation but a S381A phosphodead mutant shows impaired binding to LRRK2; PAK6 kinase activity changes PPP2R2C subcellular localization in a S381-dependent manner.","method":"In vitro kinase assay (PhosTag gel, purified proteins), co-immunoprecipitation, subcellular localization, site-directed mutagenesis","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — reconstituted kinase assay with purified proteins, mutagenesis, co-IP; single lab","pmids":["38169846"],"is_preprint":false},{"year":2024,"finding":"PAK6 localizes at the centrosome and cilium; PAK6 positively regulates ciliogenesis in tumor cells, neurons, and astrocytes; constitutively active PAK6 rescues ciliogenesis and centrosomal cohesion defects caused by LRRK2 G2019S but not R1441C mutation; PD mutations in LRRK2 affecting Roc-COR structure (including R1441C) substantially decrease PAK6 affinity for LRRK2 (measured by microscale thermophoresis and AlphaFold2 modeling).","method":"Protein-protein interaction arrays, immunofluorescence (endogenous PAK6 at centrosome/cilium), ciliogenesis assay (multiple cell types), constitutively active PAK6 rescue, microscale thermophoresis (binding affinity), AlphaFold2 computational modeling","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple cell types, direct localization with functional consequence (ciliogenesis), binding affinity measured by MST, mutation-specific rescue; multiple orthogonal methods","pmids":["39419978"],"is_preprint":false},{"year":2024,"finding":"PAK6 acts downstream of IQGAP3 to promote RhoA-dependent actomyosin contractility, cell migration, and invadopodia formation in triple-negative breast cancer cells; PAK6 depletion phenocopies IQGAP3 depletion and PAK6 overexpression rescues IQGAP3 depletion phenotype.","method":"Co-immunoprecipitation (IQGAP3-PAK6 interaction), siRNA knockdown, overexpression rescue, RhoA activity assay, cell migration assay, invadopodia assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, genetic epistasis (rescue experiment), RhoA activity measured, single lab","pmids":["38763182"],"is_preprint":false},{"year":2025,"finding":"PAK6 phosphorylates MDM2, and PAK6 inhibition in TKI-resistant CML cells induces G2-M cell cycle arrest and cellular senescence through a PAK6-MDM2-p21 axis.","method":"Lentiviral PAK6 knockdown, pharmacological PAK6 inhibition, cell cycle analysis, senescence assays, Western blot (MDM2, p21)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic and pharmacological perturbation with pathway readouts (MDM2-p21), single lab, limited direct kinase assay evidence in abstract","pmids":["40650306"],"is_preprint":false},{"year":2025,"finding":"PAK6 phosphorylates MAPK14 at Ser56, promoting proliferation, migration, and invasion of cervical cancer cells; METTL3-mediated m6A modification of PAK6 mRNA stabilizes it through the m6A reader IGF2BP1, increasing PAK6 protein levels.","method":"In vitro and cellular kinase assay (PAK6 phosphorylates MAPK14 at Ser56), gain/loss-of-function studies, m6A methylation assay, m6A reader pulldown, in vivo xenograft","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific phosphorylation site identified with gain/loss-of-function, m6A mechanism identified with reader protein; single lab","pmids":["40194572"],"is_preprint":false},{"year":2025,"finding":"NeuO probe undergoes phosphorylation by PAK6 kinase, resulting in structural changes that cause high fluorescence and intracellular retention in neurons (fluorogenic activation).","method":"In vitro kinase assay (PAK6 phosphorylates NeuO probe), fluorescence measurement, neuronal selectivity assay","journal":"Angewandte Chemie","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — in vitro kinase assay identifying PAK6 as the kinase for NeuO phosphorylation; single study, novel substrate","pmids":["40734467"],"is_preprint":false},{"year":2025,"finding":"HNRNPC lactylation at K176 strengthens binding to poly-U motifs in PAK6 pre-mRNA, facilitating expression of an oncogenic PAK6 isoform (PAK6S) through alternative splicing in pancreatic cancer.","method":"Lactylation proteomics, RNA immunoprecipitation (HNRNPC binding to PAK6 pre-mRNA), alternative splicing analysis, gain/loss-of-function studies","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA immunoprecipitation identifies direct binding to PAK6 pre-mRNA, splicing isoform functionally characterized; single lab","pmids":["41435694"],"is_preprint":false},{"year":2025,"finding":"PUM1 binds PAK6 mRNA and stabilizes it, contributing to ferroptosis resistance in lung adenocarcinoma cells; PAK6 silencing elevates Fe2+ and MDA levels and enhances Erastin-induced ferroptosis.","method":"RNA immunoprecipitation (PUM1-PAK6 mRNA binding), luciferase assay, siRNA knockdown, ferroptosis markers (Fe2+, MDA), in vivo xenograft","journal":"Pathology, research and practice","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA-IP with functional ferroptosis readout, single lab, limited mechanistic detail in abstract","pmids":["40694989"],"is_preprint":false}],"current_model":"PAK6 is a group II serine/threonine kinase that functions as an effector for Rho-family GTPases (Cdc42, Rac, RhoD, Chp/RhoV) and directly interacts with steroid hormone receptors (AR, ERα) to regulate their transcriptional activity; it phosphorylates diverse substrates including AR (Ser578), Mdm2 (Thr158/Ser186), LIMK1 (Thr508), ANT2 (T107), β-catenin, 14-3-3γ (Ser59), PPP2R2C (Ser381), MAPK14 (Ser56), and BAD (Ser112), thereby controlling AR homeostasis/degradation, cytoskeletal dynamics (via LIMK1-cofilin and IQGAP1-RhoA axes), mitochondrial apoptosis (PAK6-SIRT4-ANT2 complex), LRRK2 regulation (via 14-3-3γ phosphorylation causing LRRK2 dephosphorylation), ciliogenesis, DNA damage response (ATR-CHK1-RAD51 homologous recombination), and Wnt/β-catenin signaling; PAK6 localization is regulated by Cdc42 (targeting to cell-cell junctions via CRIB domain) and by PKA/PKB-mediated phosphorylation of Ser133 (causing 14-3-3 docking that prevents junction localization), and PAK6 is autoinhibited by an N-terminal pseudosubstrate sequence."},"narrative":{"mechanistic_narrative":"PAK6 is a group II p21-activated serine/threonine kinase that couples Rho-family GTPase and steroid hormone receptor signaling to cytoskeletal dynamics, apoptosis, and gene expression [PMID:11773441, PMID:17292838]. It binds GTP-loaded Cdc42 strongly and Rac weakly through its CRIB motif and is an effector of the atypical GTPases Chp/RhoV and RhoD, yet these GTPases do not stimulate its catalytic activity; instead PAK6 kinase activation is driven by direct, ligand-dependent binding to the androgen receptor [PMID:11773441, PMID:22339630, PMID:28486133, PMID:24130878]. The catalytic domain adopts a group II PAK active conformation through rearrangement of helix αC, and the kinase is held in check by an N-terminal pseudosubstrate sequence whose disruption (melanoma-associated P52L) relieves autoinhibition [PMID:17292838, PMID:24204982]. Through AR, PAK6 acts as a transcriptional corepressor and co-translocates to the nucleus with hormone, and it controls AR homeostasis by phosphorylating AR at Ser578 and Mdm2 at Thr158/Ser186 to promote AR ubiquitin-mediated degradation [PMID:11278661, PMID:23132866]. PAK6 governs cell motility and cell-cell adhesion via multiple substrates: it phosphorylates LIMK1 (Thr508) to drive the cofilin/actin axis, phosphorylates β-catenin at cell-cell junctions in an IQGAP1- and E-cadherin-containing complex, and acts downstream of IQGAP3 to promote RhoA-dependent contractility and invadopodia [PMID:25714010, PMID:24352566, PMID:38763182]. Its targeting to cell-cell adhesions requires the CRIB motif plus an adjacent polybasic region and depends on Cdc42 [PMID:26598554]. In mitochondria, PAK6 phosphorylates ANT2 (Thr107) and destabilizes SIRT4 within a PAK6-SIRT4-ANT2 complex to suppress apoptosis, and it phosphorylates BAD at Ser112 to restrain the intrinsic death pathway [PMID:32194820, PMID:20054820]. A neuronal axis links PAK6 to LRRK2: PAK6 phosphorylates 14-3-3γ at Ser59 to dissociate it from LRRK2, driving LRRK2 dephosphorylation, and localizes to the centrosome and cilium where it positively regulates ciliogenesis, with constitutively active PAK6 rescuing LRRK2 G2019S-associated defects [PMID:29311810, PMID:39419978]. PAK6 also promotes ATR-CHK1-RAD51 homologous recombination repair, Wnt/β-catenin signaling via GSK3β, and MAPK14 (Ser56) phosphorylation in cancer cells [PMID:35902562, PMID:32782556, PMID:40194572]. In vivo, Pak5/Pak6 double-knockout mice are viable but show locomotor and learning/memory deficits [PMID:18675265].","teleology":[{"year":2001,"claim":"Established PAK6's first physiological partner by showing it binds the androgen receptor and represses its transcriptional output, defining PAK6 as a hormone receptor coregulator rather than a generic GTPase effector.","evidence":"Yeast two-hybrid, in vitro binding, co-localization, and reporter assays in mammalian cells","pmids":["11278661"],"confidence":"High","gaps":["Did not identify the kinase substrate underlying repression","Mechanism of co-translocation not defined"]},{"year":2002,"claim":"Resolved the puzzle of how PAK6 is regulated by showing GTPases bind but do not activate it, while AR/ERα binding does, distinguishing PAK6 from canonical GTPase-activated PAKs.","evidence":"One-hybrid, GTPase binding assays, kinase activity, reporter assays, localization","pmids":["11773441"],"confidence":"High","gaps":["Did not explain the structural basis of GTPase-independent activation","ERα substrate not identified"]},{"year":2007,"claim":"Defined the structural basis of the group II PAK active state, showing helix αC rearrangements that anchor the active conformation.","evidence":"High-resolution X-ray crystallography of group II PAK catalytic domains","pmids":["17292838"],"confidence":"High","gaps":["Full-length regulatory architecture not captured","No GTPase or AR co-structure"]},{"year":2008,"claim":"Connected PAK6 to organism-level locomotor and cognitive function through genetics, and identified IQGAP1/PP1B as physical partners pointing toward cytoskeletal and adhesion roles.","evidence":"Pak5/Pak6 double-knockout mouse behavior; immunopurification-LC/MS/MS with reciprocal co-IP","pmids":["18675265","18642328"],"confidence":"High","gaps":["Redundancy with PAK5 obscures PAK6-specific contribution","Behavioral phenotype not linked to a molecular substrate"]},{"year":2010,"claim":"Showed PAK6 is pro-survival by phosphorylating BAD at Ser112 to block intrinsic apoptosis, establishing a therapeutically relevant radiosensitization node.","evidence":"shRNA knockdown, clonogenic and apoptosis assays, phospho-BAD/Bcl-2 Western blots in prostate cancer cells","pmids":["20054820"],"confidence":"Medium","gaps":["Direct kinase assay on BAD not shown","Single cell-type context"]},{"year":2012,"claim":"Defined the AR homeostasis mechanism: PAK6 phosphorylates AR (Ser578) and Mdm2 (Thr158/Ser186) to drive AR ubiquitin-mediated degradation, and established Chp/RhoV as a vesicular effector partner.","evidence":"In vitro kinase, mutagenesis, co-IP, ubiquitination, xenograft; yeast two-hybrid and co-IP for Chp","pmids":["23132866","22339630"],"confidence":"High","gaps":["Functional output of Chp-PAK6 vesicular co-localization unresolved","How AR-bound PAK6 selects Mdm2 vs other substrates not defined"]},{"year":2013,"claim":"Established PAK6 substrate specificity, pseudosubstrate autoinhibition, and an oncogenic activating mutation, while defining AR-stimulated kinase activation as a driver of motility and β-catenin as a junctional substrate within an IQGAP1/E-cadherin complex.","evidence":"Peptide profiling, kinase assays, P52L mutagenesis, co-crystal structures; co-IP, junction localization, colony escape assays; AR siRNA and PAK6 mutant motility assays","pmids":["24204982","24352566","24130878"],"confidence":"High","gaps":["Physiological relevance of PACSIN1 phosphorylation untested in vivo","Direct β-catenin phosphosite not mapped"]},{"year":2015,"claim":"Mapped the cytoskeletal effector arm by showing PAK6 phosphorylates LIMK1 (Thr508) to engage cofilin and actin dynamics, and defined the CRIB-plus-polybasic, Cdc42-dependent targeting to cell-cell adhesions required for kinase-dependent colony escape.","evidence":"Co-IP, phospho-LIMK1/cofilin blots, orthotopic mouse model; domain mutagenesis and Cdc42 knockdown with colony escape assay","pmids":["25714010","26598554"],"confidence":"Medium","gaps":["Direct LIMK1 kinase assay limited","How Cdc42 promotes localization without activating kinase unresolved"]},{"year":2017,"claim":"Linked PAK6 to Parkinson's-relevant LRRK2 biology by showing 14-3-3γ Ser59 phosphorylation dissociates LRRK2 and drives its dephosphorylation, with rescue of G2019S neurite defects; RhoD was placed upstream as a plasma-membrane recruiter antagonizing RhoC-ROCK.","evidence":"Co-IP interactome, in vitro kinase assay, neurite rescue; genetic epistasis with RhoD/RhoC and viral F11","pmids":["29311810","28486133"],"confidence":"High","gaps":["Endogenous PAK6 activation cue at the membrane not defined","Whether 14-3-3γ phosphorylation occurs in disease tissue untested"]},{"year":2018,"claim":"Showed PAK6 is itself epigenetically controlled, repressed by a DNMT1-EZH2/PRC2 H3K27me3 mechanism that limits cortical interneuron morphological complexity.","evidence":"ChIP at the PAK6 locus, EZH2 inhibition, DNMT1 and PAK6 knockdown with morphological rescue","pmids":["29912614"],"confidence":"Medium","gaps":["Direct DNMT1 recruitment to the PAK6 locus not shown","Downstream PAK6 substrates in interneurons unidentified"]},{"year":2020,"claim":"Defined a mitochondrial pro-survival module: PAK6 localizes to the inner membrane, phosphorylates ANT2 (Thr107), and destabilizes SIRT4 to suppress apoptosis, with pharmacological PAK6 inhibition shown to sensitize drug-resistant cancer cells via RAS/MAPK and mitochondrial effects.","evidence":"Immuno-EM localization, co-IP, ubiquitination, K105/T107 mutagenesis, apoptosis, xenograft; PAK6 inhibitor with pathway and mitochondrial readouts in CML","pmids":["32194820","32270193"],"confidence":"High","gaps":["How a kinase reaches the inner membrane mechanistically unclear","RAS/MAPK linkage in CML not mechanistically dissected"]},{"year":2022,"claim":"Expanded PAK6 into nuclear DNA repair, Wnt signaling, and PP2A regulation: it promotes ATR-CHK1-RAD51 homologous recombination, activates Wnt/β-catenin via GSK3β, and phosphorylates PPP2R2C (Ser381) to modulate its LRRK2 binding while leaving the dominant 14-3-3γ LRRK2 mechanism intact.","evidence":"Nuclear fractionation, RAD51 foci, ATR inhibitor epistasis; co-IP and Wnt pathway blots; PhosTag in vitro kinase with purified PPP2R2C and S381A mutant","pmids":["35902562","32782556","35016853"],"confidence":"Medium","gaps":["Direct nuclear substrate driving ATR activation not identified","Whether GSK3β is a direct PAK6 substrate not shown"]},{"year":2024,"claim":"Established PAK6 at the centrosome/cilium as a positive regulator of ciliogenesis and refined the LRRK2 interface, showing PD mutations in the Roc-COR region reduce PAK6-LRRK2 affinity and that active PAK6 rescues G2019S but not R1441C defects.","evidence":"Endogenous localization, ciliogenesis assays across cell types, active-PAK6 rescue, microscale thermophoresis and AlphaFold2 modeling; reconstituted PPP2R2C kinase assay","pmids":["39419978","38169846"],"confidence":"High","gaps":["Ciliary substrate of PAK6 not identified","Mechanism distinguishing G2019S vs R1441C rescue at the molecular level incomplete"]},{"year":2025,"claim":"Detailed post-transcriptional and cell-cycle control of PAK6 oncogenic function across cancers: METTL3/IGF2BP1 m6A, HNRNPC-lactylation-driven oncogenic isoform splicing, and PUM1-mediated mRNA stabilization upregulate PAK6, while PAK6 phosphorylates MAPK14 (Ser56) and acts through MDM2-p21 and ferroptosis pathways.","evidence":"Kinase assays (MAPK14 Ser56, NeuO probe), m6A/RIP/lactylation proteomics, splicing analysis, PAK6 knockdown/inhibition with senescence and ferroptosis readouts, xenografts","pmids":["40194572","41435694","40650306","40694989","40734467"],"confidence":"Medium","gaps":["Whether MDM2-p21 effects require direct MDM2 phosphorylation not fully shown","PUM1-ferroptosis link rests on a single low-confidence study","Isoform-specific activities not biochemically separated"]},{"year":null,"claim":"How a single GTPase-binding kinase that is not activated by its GTPases integrates AR, LRRK2, mitochondrial, ciliary, and DNA-repair signaling into context-specific outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model of how upstream cues select among PAK6 substrate sets","Endogenous activation mechanism in neurons vs epithelia undefined","No full-length structure showing pseudosubstrate-to-active transition"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,8,12,13,16,20,21,25,26]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[6,9,12,16,20,25]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,6,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,11,14]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[16]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[22]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,14,19,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,16]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,16]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[22]}],"complexes":["PAK6-SIRT4-ANT2 complex","PAK6-IQGAP1-E-cadherin complex"],"partners":["AR","IQGAP1","LRRK2","CDC42","MDM2","LIMK1","GSK3B","SIRT4"],"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. May protect cells from apoptosis through phosphorylation of BAD","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NQU5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PAK6","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PAK6","total_profiled":1310},"omim":[{"mim_id":"608110","title":"p21 PROTEIN-ACTIVATED KINASE 6; PAK6","url":"https://www.omim.org/entry/608110"},{"mim_id":"608038","title":"p21 PROTEIN-ACTIVATED KINASE 5; PAK5","url":"https://www.omim.org/entry/608038"},{"mim_id":"605451","title":"p21 PROTEIN-ACTIVATED KINASE 4; PAK4","url":"https://www.omim.org/entry/605451"},{"mim_id":"605022","title":"p21 PROTEIN-ACTIVATED KINASE 2; PAK2","url":"https://www.omim.org/entry/605022"},{"mim_id":"602590","title":"p21 PROTEIN-ACTIVATED KINASE 1; PAK1","url":"https://www.omim.org/entry/602590"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":31.0},{"tissue":"esophagus","ntpm":24.5},{"tissue":"skin 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transfection reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo interaction confirmed, co-localization, functional reporter assay; independently replicated by Lee et al. 2002 (PMID:11773441)\",\n      \"pmids\": [\"11278661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PAK6 binds strongly to GTP-bound Cdc42 and weakly to GTP-Rac via its CRIB domain; PAK6 kinase activity is not stimulated by Cdc42 or Rac but can be stimulated by AR binding; PAK6 also binds ERα with binding enhanced by 4-hydroxytamoxifen; PAK6 inhibits both AR and ERα transcriptional activity; epitope-tagged PAK6 is primarily cytoplasmic.\",\n      \"method\": \"Mammalian one-hybrid assay, in vitro binding, GTPase binding assays, transient transfection reporter assay, immunofluorescence localization\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assays, kinase activity, reporter assays, localization); independently corroborates PMID:11278661\",\n      \"pmids\": [\"11773441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of active, monophosphorylated PAK6 catalytic domain reveal group II PAK structural plasticity including rearrangements of helix αC forming an additional helical turn at αC N-terminus and a distortion of its C-terminus, forming interactions that link the glycine-rich loop, αC, and the activation segment to anchor αC in an active conformation.\",\n      \"method\": \"X-ray crystallography (multiple high-resolution structures of PAK4, PAK5, PAK6 catalytic domains; inhibitor co-crystal structures)\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures with structural comparison across all group II PAK catalytic domains\",\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 and memory impairments, establishing that PAK6 together with PAK5 is required for normal locomotion and cognitive function in vivo.\",\n      \"method\": \"Gene knockout (mouse), behavioral assays (locomotion, learning and memory)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined behavioral phenotypes, replicated in follow-up study (PMID:23593460)\",\n      \"pmids\": [\"18675265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PAK6 co-immunoprecipitates with IQGAP1 and protein phosphatase 1B (PP1B) in prostate cancer cells, identifying these as PAK6 interacting proteins.\",\n      \"method\": \"Immunopurification of 3xFlag-tagged PAK6 followed by LC/MS/MS, confirmed by co-immunoprecipitation\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with MS identification confirmed by reciprocal co-IP, single lab\",\n      \"pmids\": [\"18642328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PAK6 inhibition reduces phosphorylation of BAD at Ser112, leading to increased BAD binding to Bcl-2 and Bcl-XL, cytochrome c release, caspase activation, and apoptosis; PAK6 knockdown also increases radiosensitivity of prostate cancer cells.\",\n      \"method\": \"shRNA stable knockdown, clonogenic survival assay, apoptosis assay (flow cytometry), Western blot (BAD phosphorylation, Bcl-2 binding, cleaved caspase-3)\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined molecular pathway (BAD phosphorylation → apoptosis), single lab with multiple readouts\",\n      \"pmids\": [\"20054820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PAK6 phosphorylates AR at Ser-578, promoting AR association with E3 ligase Mdm2 and AR ubiquitin-mediated degradation; PAK6 also phosphorylates Mdm2 at Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation; PAK6 co-localizes with AR in the cytoplasm of normal prostate epithelium.\",\n      \"method\": \"In vitro kinase assay, immunofluorescence co-localization, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with specific phosphosite identification, mutagenesis validation, co-IP, and in vivo confirmation; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"23132866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PAK6 is a novel effector of the atypical Rho GTPase Chp/RhoV; interaction depends on the activation state of Chp and involves the effector domain of Chp and the CRIB motif of PAK6; Chp does not activate PAK6 (no change in S560 phosphorylation); in NCI-H1299 cells, Chp co-localizes with PAK6 on vesicular structures in an activation state-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, point mutagenesis of effector domain and CRIB motif, immunofluorescence co-localization\",\n      \"journal\": \"Biochemistry (Biokhimiia)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP with mutagenesis, single lab\",\n      \"pmids\": [\"22339630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAK6 localizes to cell-cell junctions and directly interacts with IQGAP1 via its kinase domain; PAK6 forms a complex with E-cadherin and IQGAP1 downstream of HGF signaling; β-catenin is a novel PAK6 substrate at cell-cell junctions; PAK6/IQGAP1 complex drives epithelial colony escape and cell-cell dissociation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, kinase domain binding assay, co-expression overexpression/depletion assays, cell colony escape assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct interaction (co-IP of kinase domain), substrate identification, functional rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24352566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAK6 has a peptide substrate specificity similar to PAK4 and PAK5; PAK6 is autoinhibited by an N-terminal pseudosubstrate peptide; a melanoma-associated P52L mutation in the pseudosubstrate reduces autoinhibition and increases phosphorylation of PACSIN1 (Syndapin I) in cells; co-crystal structures of PAK6 catalytic domain with PF-3758309 (1.4 Å) and sunitinib (1.95 Å) determined.\",\n      \"method\": \"Peptide library substrate profiling, in vitro kinase assay, pseudosubstrate peptide inhibition assay, site-directed mutagenesis (P52L), cellular phosphorylation assay, X-ray crystallography\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures at high resolution, in vitro kinase assay with mutagenesis, substrate identification; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"24204982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAK6 kinase activation is stimulated by direct AR interaction in response to androgen; siRNA knockdown of AR reduces androgen-stimulated PAK6 kinase activation; a non-AR-interacting PAK6 mutant shows dampened kinase activation and fails to promote androgen-stimulated cell motility and invasion.\",\n      \"method\": \"In vitro kinase assay, siRNA knockdown, cell motility and invasion assay, mutant PAK6 expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase activity measured with genetic perturbation (AR siRNA and PAK6 mutant), single lab with multiple methods\",\n      \"pmids\": [\"24130878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAK6 targeting to cell-cell adhesions requires both its CRIB domain and an adjacent polybasic region in the N-terminus; Cdc42 knockdown inhibits PAK6 localization to cell-cell adhesions; PAK6-driven epithelial colony escape requires kinase activity and is abolished by mutations disrupting cell-cell adhesion targeting.\",\n      \"method\": \"Deletion/point mutagenesis, siRNA knockdown of Cdc42, immunofluorescence localization, colony escape assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function analysis with multiple domain mutants and genetic knockdown, single lab\",\n      \"pmids\": [\"26598554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAK6 phosphorylates LIMK1 at Thr-508, activating it; activated LIMK1 phosphorylates cofilin, promoting stress fiber and actin filament formation required for cell motility and invasion; PAK6 and LIMK1 co-localize in the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, Western blot (phospho-LIMK1, phospho-cofilin), in vivo orthotopic mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, phosphorylation site identified, co-localization, in vivo model; single lab, moderate method rigor\",\n      \"pmids\": [\"25714010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PAK6 phosphorylates 14-3-3γ at Ser59; this phosphorylation dissociates 14-3-3γ from client proteins including LRRK2, causing LRRK2 dephosphorylation at Ser935; constitutively active PAK6 rescues G2019S LRRK2-associated neurite shortening through 14-3-3γ phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation (PAK6 interactome), in vitro kinase assay (phosphorylation of 14-3-3γ at Ser59), co-IP (14-3-3γ/LRRK2 dissociation), immunofluorescence (neurite length assay), constitutively active PAK6 rescue experiment\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay with specific phosphosite identification, functional consequence (LRRK2 regulation), neuronal rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"29311810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RhoD recruits PAK6 to the plasma membrane to antagonize RhoC signaling during cell contraction and blebbing; vaccinia virus protein F11 inhibits RhoD signaling, preventing RhoD from activating PAK6, thereby releasing suppression of RhoC-ROCK-mediated cell contraction.\",\n      \"method\": \"Genetic epistasis (RhoD, PAK6, RhoC knockdown/overexpression), immunofluorescence localization, cell contraction and blebbing assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined pathway placement (RhoD→PAK6⊣RhoC-ROCK), single lab with multiple genetic perturbations\",\n      \"pmids\": [\"28486133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNMT1 represses PAK6 transcription by interacting with EZH2 (PRC2 core enzyme) to mediate repressive H3K27 trimethylation at PAK6 gene regulatory regions; inhibition of EZH2 elevates PAK6 expression and increases morphological complexity in cortical interneurons, rescued by PAK6 siRNA knockdown.\",\n      \"method\": \"ChIP (H3K4me3, H3K27me3 at PAK6 locus), EZH2 inhibition, DNMT1 knockdown, siRNA-mediated PAK6 knockdown, morphological analysis\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct histone modification at PAK6 locus, genetic epistasis with rescue, single lab\",\n      \"pmids\": [\"29912614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PAK6 is mainly located in the mitochondrial inner membrane; PAK6 promotes SIRT4 ubiquitin-mediated proteolysis; SIRT4 deacetylates ANT2 at K105 to promote ANT2 ubiquitination degradation; PAK6 directly phosphorylates ANT2 at T107 to inhibit apoptosis of prostate cancer cells; the PAK6-SIRT4-ANT2 complex regulates mitochondrial apoptosis.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy (subcellular localization), co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K105, T107), flow cytometry (apoptosis), xenograft model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including subcellular localization, co-IP, ubiquitination assay, mutagenesis of specific phospho/acetylation sites, and in vivo validation; single lab\",\n      \"pmids\": [\"32194820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pharmacological inhibition of PAK6 perturbs the RAS/MAPK pathway and mitochondrial activity in CML drug-resistant cells, sensitizing them to TKI therapy.\",\n      \"method\": \"PAK6 pharmacological inhibition, pathway analysis (RAS/MAPK), mitochondrial activity assay, xenotransplantation model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — PAK6 inhibitor with pathway readouts in cancer cells; single lab, limited mechanistic dissection\",\n      \"pmids\": [\"32270193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PAK6 moves into the nucleus to promote ATR activation, which activates CHK1 and recruits RAD51 from cytoplasm to DNA damage sites to enable homologous recombination repair; ATR inhibitor (AZD6738) blocks PAK6-mediated HR repair, reversing oxaliplatin resistance.\",\n      \"method\": \"PAK6 knockdown/overexpression, ATR inhibitor treatment, HR repair assay (RAD51 foci), Western blot (ATR/CHK1 activation), nuclear fractionation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear translocation with functional consequence (HR repair), pathway epistasis with ATR inhibitor, single lab\",\n      \"pmids\": [\"35902562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PAK6 interacts with GSK3β (confirmed by co-IP and fluorescence co-localization) and activates the Wnt/β-catenin signaling pathway, leading to GSK3β phosphorylation, increased Cyclin D1, and decreased β-catenin phosphorylation and E-cadherin.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence co-localization, shRNA knockdown and overexpression, Western blot (Wnt/β-catenin pathway components)\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with co-localization and functional pathway analysis, single lab; limited mechanistic depth\",\n      \"pmids\": [\"32782556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PAK6 phosphorylates the PP2A regulatory subunit PPP2R2C at Ser381; this phosphorylation alters PPP2R2C binding to LRRK2 and changes PPP2R2C subcellular localization in a phosphorylation-dependent manner; however, LRRK2 dephosphorylation by PAK6 is unaffected by PPP2R2C S381 phosphorylation, indicating the 14-3-3γ phosphorylation mechanism is dominant.\",\n      \"method\": \"PhosTag gel electrophoresis with purified proteins (in vitro kinase assay), co-immunoprecipitation, subcellular localization imaging, site-directed mutagenesis (S381A phosphodead)\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay with purified proteins, mutagenesis, co-IP, localization; single lab\",\n      \"pmids\": [\"35016853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PAK6 phosphorylates the PP2A regulatory subunit PPP2R2C at S381 (confirmed with purified proteins); S381 phosphorylation does not affect PP2A holoenzyme formation but a S381A phosphodead mutant shows impaired binding to LRRK2; PAK6 kinase activity changes PPP2R2C subcellular localization in a S381-dependent manner.\",\n      \"method\": \"In vitro kinase assay (PhosTag gel, purified proteins), co-immunoprecipitation, subcellular localization, site-directed mutagenesis\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstituted kinase assay with purified proteins, mutagenesis, co-IP; single lab\",\n      \"pmids\": [\"38169846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PAK6 localizes at the centrosome and cilium; PAK6 positively regulates ciliogenesis in tumor cells, neurons, and astrocytes; constitutively active PAK6 rescues ciliogenesis and centrosomal cohesion defects caused by LRRK2 G2019S but not R1441C mutation; PD mutations in LRRK2 affecting Roc-COR structure (including R1441C) substantially decrease PAK6 affinity for LRRK2 (measured by microscale thermophoresis and AlphaFold2 modeling).\",\n      \"method\": \"Protein-protein interaction arrays, immunofluorescence (endogenous PAK6 at centrosome/cilium), ciliogenesis assay (multiple cell types), constitutively active PAK6 rescue, microscale thermophoresis (binding affinity), AlphaFold2 computational modeling\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types, direct localization with functional consequence (ciliogenesis), binding affinity measured by MST, mutation-specific rescue; multiple orthogonal methods\",\n      \"pmids\": [\"39419978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PAK6 acts downstream of IQGAP3 to promote RhoA-dependent actomyosin contractility, cell migration, and invadopodia formation in triple-negative breast cancer cells; PAK6 depletion phenocopies IQGAP3 depletion and PAK6 overexpression rescues IQGAP3 depletion phenotype.\",\n      \"method\": \"Co-immunoprecipitation (IQGAP3-PAK6 interaction), siRNA knockdown, overexpression rescue, RhoA activity assay, cell migration assay, invadopodia assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, genetic epistasis (rescue experiment), RhoA activity measured, single lab\",\n      \"pmids\": [\"38763182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PAK6 phosphorylates MDM2, and PAK6 inhibition in TKI-resistant CML cells induces G2-M cell cycle arrest and cellular senescence through a PAK6-MDM2-p21 axis.\",\n      \"method\": \"Lentiviral PAK6 knockdown, pharmacological PAK6 inhibition, cell cycle analysis, senescence assays, Western blot (MDM2, p21)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic and pharmacological perturbation with pathway readouts (MDM2-p21), single lab, limited direct kinase assay evidence in abstract\",\n      \"pmids\": [\"40650306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PAK6 phosphorylates MAPK14 at Ser56, promoting proliferation, migration, and invasion of cervical cancer cells; METTL3-mediated m6A modification of PAK6 mRNA stabilizes it through the m6A reader IGF2BP1, increasing PAK6 protein levels.\",\n      \"method\": \"In vitro and cellular kinase assay (PAK6 phosphorylates MAPK14 at Ser56), gain/loss-of-function studies, m6A methylation assay, m6A reader pulldown, in vivo xenograft\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific phosphorylation site identified with gain/loss-of-function, m6A mechanism identified with reader protein; single lab\",\n      \"pmids\": [\"40194572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NeuO probe undergoes phosphorylation by PAK6 kinase, resulting in structural changes that cause high fluorescence and intracellular retention in neurons (fluorogenic activation).\",\n      \"method\": \"In vitro kinase assay (PAK6 phosphorylates NeuO probe), fluorescence measurement, neuronal selectivity assay\",\n      \"journal\": \"Angewandte Chemie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — in vitro kinase assay identifying PAK6 as the kinase for NeuO phosphorylation; single study, novel substrate\",\n      \"pmids\": [\"40734467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPC lactylation at K176 strengthens binding to poly-U motifs in PAK6 pre-mRNA, facilitating expression of an oncogenic PAK6 isoform (PAK6S) through alternative splicing in pancreatic cancer.\",\n      \"method\": \"Lactylation proteomics, RNA immunoprecipitation (HNRNPC binding to PAK6 pre-mRNA), alternative splicing analysis, gain/loss-of-function studies\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA immunoprecipitation identifies direct binding to PAK6 pre-mRNA, splicing isoform functionally characterized; single lab\",\n      \"pmids\": [\"41435694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PUM1 binds PAK6 mRNA and stabilizes it, contributing to ferroptosis resistance in lung adenocarcinoma cells; PAK6 silencing elevates Fe2+ and MDA levels and enhances Erastin-induced ferroptosis.\",\n      \"method\": \"RNA immunoprecipitation (PUM1-PAK6 mRNA binding), luciferase assay, siRNA knockdown, ferroptosis markers (Fe2+, MDA), in vivo xenograft\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA-IP with functional ferroptosis readout, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"40694989\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PAK6 is a group II serine/threonine kinase that functions as an effector for Rho-family GTPases (Cdc42, Rac, RhoD, Chp/RhoV) and directly interacts with steroid hormone receptors (AR, ERα) to regulate their transcriptional activity; it phosphorylates diverse substrates including AR (Ser578), Mdm2 (Thr158/Ser186), LIMK1 (Thr508), ANT2 (T107), β-catenin, 14-3-3γ (Ser59), PPP2R2C (Ser381), MAPK14 (Ser56), and BAD (Ser112), thereby controlling AR homeostasis/degradation, cytoskeletal dynamics (via LIMK1-cofilin and IQGAP1-RhoA axes), mitochondrial apoptosis (PAK6-SIRT4-ANT2 complex), LRRK2 regulation (via 14-3-3γ phosphorylation causing LRRK2 dephosphorylation), ciliogenesis, DNA damage response (ATR-CHK1-RAD51 homologous recombination), and Wnt/β-catenin signaling; PAK6 localization is regulated by Cdc42 (targeting to cell-cell junctions via CRIB domain) and by PKA/PKB-mediated phosphorylation of Ser133 (causing 14-3-3 docking that prevents junction localization), and PAK6 is autoinhibited by an N-terminal pseudosubstrate sequence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PAK6 is a group II p21-activated serine/threonine kinase that couples Rho-family GTPase and steroid hormone receptor signaling to cytoskeletal dynamics, apoptosis, and gene expression [#1, #2]. It binds GTP-loaded Cdc42 strongly and Rac weakly through its CRIB motif and is an effector of the atypical GTPases Chp/RhoV and RhoD, yet these GTPases do not stimulate its catalytic activity; instead PAK6 kinase activation is driven by direct, ligand-dependent binding to the androgen receptor [#1, #7, #14, #10]. The catalytic domain adopts a group II PAK active conformation through rearrangement of helix \\u03b1C, and the kinase is held in check by an N-terminal pseudosubstrate sequence whose disruption (melanoma-associated P52L) relieves autoinhibition [#2, #9]. Through AR, PAK6 acts as a transcriptional corepressor and co-translocates to the nucleus with hormone, and it controls AR homeostasis by phosphorylating AR at Ser578 and Mdm2 at Thr158/Ser186 to promote AR ubiquitin-mediated degradation [#0, #6]. PAK6 governs cell motility and cell-cell adhesion via multiple substrates: it phosphorylates LIMK1 (Thr508) to drive the cofilin/actin axis, phosphorylates \\u03b2-catenin at cell-cell junctions in an IQGAP1- and E-cadherin-containing complex, and acts downstream of IQGAP3 to promote RhoA-dependent contractility and invadopodia [#12, #8, #23]. Its targeting to cell-cell adhesions requires the CRIB motif plus an adjacent polybasic region and depends on Cdc42 [#11]. In mitochondria, PAK6 phosphorylates ANT2 (Thr107) and destabilizes SIRT4 within a PAK6-SIRT4-ANT2 complex to suppress apoptosis, and it phosphorylates BAD at Ser112 to restrain the intrinsic death pathway [#16, #5]. A neuronal axis links PAK6 to LRRK2: PAK6 phosphorylates 14-3-3\\u03b3 at Ser59 to dissociate it from LRRK2, driving LRRK2 dephosphorylation, and localizes to the centrosome and cilium where it positively regulates ciliogenesis, with constitutively active PAK6 rescuing LRRK2 G2019S-associated defects [#13, #22]. PAK6 also promotes ATR-CHK1-RAD51 homologous recombination repair, Wnt/\\u03b2-catenin signaling via GSK3\\u03b2, and MAPK14 (Ser56) phosphorylation in cancer cells [#18, #19, #25]. In vivo, Pak5/Pak6 double-knockout mice are viable but show locomotor and learning/memory deficits [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established PAK6's first physiological partner by showing it binds the androgen receptor and represses its transcriptional output, defining PAK6 as a hormone receptor coregulator rather than a generic GTPase effector.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-localization, and reporter assays in mammalian cells\",\n      \"pmids\": [\"11278661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the kinase substrate underlying repression\", \"Mechanism of co-translocation not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the puzzle of how PAK6 is regulated by showing GTPases bind but do not activate it, while AR/ER\\u03b1 binding does, distinguishing PAK6 from canonical GTPase-activated PAKs.\",\n      \"evidence\": \"One-hybrid, GTPase binding assays, kinase activity, reporter assays, localization\",\n      \"pmids\": [\"11773441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain the structural basis of GTPase-independent activation\", \"ER\\u03b1 substrate not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the structural basis of the group II PAK active state, showing helix \\u03b1C rearrangements that anchor the active conformation.\",\n      \"evidence\": \"High-resolution X-ray crystallography of group II PAK catalytic domains\",\n      \"pmids\": [\"17292838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length regulatory architecture not captured\", \"No GTPase or AR co-structure\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected PAK6 to organism-level locomotor and cognitive function through genetics, and identified IQGAP1/PP1B as physical partners pointing toward cytoskeletal and adhesion roles.\",\n      \"evidence\": \"Pak5/Pak6 double-knockout mouse behavior; immunopurification-LC/MS/MS with reciprocal co-IP\",\n      \"pmids\": [\"18675265\", \"18642328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with PAK5 obscures PAK6-specific contribution\", \"Behavioral phenotype not linked to a molecular substrate\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed PAK6 is pro-survival by phosphorylating BAD at Ser112 to block intrinsic apoptosis, establishing a therapeutically relevant radiosensitization node.\",\n      \"evidence\": \"shRNA knockdown, clonogenic and apoptosis assays, phospho-BAD/Bcl-2 Western blots in prostate cancer cells\",\n      \"pmids\": [\"20054820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase assay on BAD not shown\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the AR homeostasis mechanism: PAK6 phosphorylates AR (Ser578) and Mdm2 (Thr158/Ser186) to drive AR ubiquitin-mediated degradation, and established Chp/RhoV as a vesicular effector partner.\",\n      \"evidence\": \"In vitro kinase, mutagenesis, co-IP, ubiquitination, xenograft; yeast two-hybrid and co-IP for Chp\",\n      \"pmids\": [\"23132866\", \"22339630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of Chp-PAK6 vesicular co-localization unresolved\", \"How AR-bound PAK6 selects Mdm2 vs other substrates not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established PAK6 substrate specificity, pseudosubstrate autoinhibition, and an oncogenic activating mutation, while defining AR-stimulated kinase activation as a driver of motility and \\u03b2-catenin as a junctional substrate within an IQGAP1/E-cadherin complex.\",\n      \"evidence\": \"Peptide profiling, kinase assays, P52L mutagenesis, co-crystal structures; co-IP, junction localization, colony escape assays; AR siRNA and PAK6 mutant motility assays\",\n      \"pmids\": [\"24204982\", \"24352566\", \"24130878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of PACSIN1 phosphorylation untested in vivo\", \"Direct \\u03b2-catenin phosphosite not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the cytoskeletal effector arm by showing PAK6 phosphorylates LIMK1 (Thr508) to engage cofilin and actin dynamics, and defined the CRIB-plus-polybasic, Cdc42-dependent targeting to cell-cell adhesions required for kinase-dependent colony escape.\",\n      \"evidence\": \"Co-IP, phospho-LIMK1/cofilin blots, orthotopic mouse model; domain mutagenesis and Cdc42 knockdown with colony escape assay\",\n      \"pmids\": [\"25714010\", \"26598554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LIMK1 kinase assay limited\", \"How Cdc42 promotes localization without activating kinase unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked PAK6 to Parkinson's-relevant LRRK2 biology by showing 14-3-3\\u03b3 Ser59 phosphorylation dissociates LRRK2 and drives its dephosphorylation, with rescue of G2019S neurite defects; RhoD was placed upstream as a plasma-membrane recruiter antagonizing RhoC-ROCK.\",\n      \"evidence\": \"Co-IP interactome, in vitro kinase assay, neurite rescue; genetic epistasis with RhoD/RhoC and viral F11\",\n      \"pmids\": [\"29311810\", \"28486133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous PAK6 activation cue at the membrane not defined\", \"Whether 14-3-3\\u03b3 phosphorylation occurs in disease tissue untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PAK6 is itself epigenetically controlled, repressed by a DNMT1-EZH2/PRC2 H3K27me3 mechanism that limits cortical interneuron morphological complexity.\",\n      \"evidence\": \"ChIP at the PAK6 locus, EZH2 inhibition, DNMT1 and PAK6 knockdown with morphological rescue\",\n      \"pmids\": [\"29912614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNMT1 recruitment to the PAK6 locus not shown\", \"Downstream PAK6 substrates in interneurons unidentified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a mitochondrial pro-survival module: PAK6 localizes to the inner membrane, phosphorylates ANT2 (Thr107), and destabilizes SIRT4 to suppress apoptosis, with pharmacological PAK6 inhibition shown to sensitize drug-resistant cancer cells via RAS/MAPK and mitochondrial effects.\",\n      \"evidence\": \"Immuno-EM localization, co-IP, ubiquitination, K105/T107 mutagenesis, apoptosis, xenograft; PAK6 inhibitor with pathway and mitochondrial readouts in CML\",\n      \"pmids\": [\"32194820\", \"32270193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a kinase reaches the inner membrane mechanistically unclear\", \"RAS/MAPK linkage in CML not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded PAK6 into nuclear DNA repair, Wnt signaling, and PP2A regulation: it promotes ATR-CHK1-RAD51 homologous recombination, activates Wnt/\\u03b2-catenin via GSK3\\u03b2, and phosphorylates PPP2R2C (Ser381) to modulate its LRRK2 binding while leaving the dominant 14-3-3\\u03b3 LRRK2 mechanism intact.\",\n      \"evidence\": \"Nuclear fractionation, RAD51 foci, ATR inhibitor epistasis; co-IP and Wnt pathway blots; PhosTag in vitro kinase with purified PPP2R2C and S381A mutant\",\n      \"pmids\": [\"35902562\", \"32782556\", \"35016853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct nuclear substrate driving ATR activation not identified\", \"Whether GSK3\\u03b2 is a direct PAK6 substrate not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established PAK6 at the centrosome/cilium as a positive regulator of ciliogenesis and refined the LRRK2 interface, showing PD mutations in the Roc-COR region reduce PAK6-LRRK2 affinity and that active PAK6 rescues G2019S but not R1441C defects.\",\n      \"evidence\": \"Endogenous localization, ciliogenesis assays across cell types, active-PAK6 rescue, microscale thermophoresis and AlphaFold2 modeling; reconstituted PPP2R2C kinase assay\",\n      \"pmids\": [\"39419978\", \"38169846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ciliary substrate of PAK6 not identified\", \"Mechanism distinguishing G2019S vs R1441C rescue at the molecular level incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detailed post-transcriptional and cell-cycle control of PAK6 oncogenic function across cancers: METTL3/IGF2BP1 m6A, HNRNPC-lactylation-driven oncogenic isoform splicing, and PUM1-mediated mRNA stabilization upregulate PAK6, while PAK6 phosphorylates MAPK14 (Ser56) and acts through MDM2-p21 and ferroptosis pathways.\",\n      \"evidence\": \"Kinase assays (MAPK14 Ser56, NeuO probe), m6A/RIP/lactylation proteomics, splicing analysis, PAK6 knockdown/inhibition with senescence and ferroptosis readouts, xenografts\",\n      \"pmids\": [\"40194572\", \"41435694\", \"40650306\", \"40694989\", \"40734467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MDM2-p21 effects require direct MDM2 phosphorylation not fully shown\", \"PUM1-ferroptosis link rests on a single low-confidence study\", \"Isoform-specific activities not biochemically separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single GTPase-binding kinase that is not activated by its GTPases integrates AR, LRRK2, mitochondrial, ciliary, and DNA-repair signaling into context-specific outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model of how upstream cues select among PAK6 substrate sets\", \"Endogenous activation mechanism in neurons vs epithelia undefined\", \"No full-length structure showing pseudosubstrate-to-active transition\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 8, 12, 13, 16, 20, 21, 25, 26]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [6, 9, 12, 16, 20, 25]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 11, 14]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 14, 19, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 16]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [\n      \"PAK6-SIRT4-ANT2 complex\",\n      \"PAK6-IQGAP1-E-cadherin complex\"\n    ],\n    \"partners\": [\n      \"AR\",\n      \"IQGAP1\",\n      \"LRRK2\",\n      \"Cdc42\",\n      \"MDM2\",\n      \"LIMK1\",\n      \"GSK3B\",\n      \"SIRT4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}