Affinage

PAK3

Serine/threonine-protein kinase PAK 3 · UniProt O75914

Audit flag: ungrounded claim
Length
559 aa
Mass
62.3 kDa
Annotated
2026-06-10
72 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAK3 is a group I p21-activated serine/threonine kinase that links Rho-family GTPase signalling to actin cytoskeletal remodelling, neuronal connectivity, and synaptic plasticity (PMID:9731525, PMID:25109462). Its effector domain binds GTP-loaded Cdc42, and binding propagates side-chain dynamics that rigidify the nucleotide pocket while loosening the guanine ring, coupling GTPase engagement to kinase activation (PMID:25109462); a brain-specific splice variant (PAK3b) inserts 15 residues into the autoinhibitory domain to render the kinase constitutively active and GTPase-independent (PMID:12464619). PAK3 is also activated through Gi/Go-coupled receptor signalling in a PI3K-independent manner (PMID:11025445) and by upstream scaffolds/GEFs including ARHGEF6/αPIX and GIT1, which feed into hippocampal spine morphogenesis and synaptic signalling (PMID:17105769, PMID:27457813, PMID:31843706). In neurons, PAK3 is required for dendritic spine maturation and synapse formation, is recruited into spines by activity to stabilize new connections, and supports late-phase LTP and CREB-dependent plasticity (PMID:15574732, PMID:16014725, PMID:22238087); it functions in part by heterodimerizing with PAK1, which trans-inhibits PAK3a but not PAK3b, and by associating with adaptor and scaffold proteins (Nck2/Grb4, paxillin) (PMID:11096073, PMID:21949127, PMID:22815483). PAK3 phosphorylates defined substrates to execute these roles, including the AMPA receptor subunit GluA1 at Ser863 downstream of EphB2–Cdc42 to control receptor trafficking (PMID:26013460) and signalling through a PAK3–LIMK1–cofilin axis governing the F/G-actin ratio (PMID:38131292). Loss-of-function mutations that abolish kinase activity cause X-linked intellectual disability by impairing spine formation, synaptic plasticity, and adult hippocampal neurogenesis, with severity modulated by gain of dominant-negative or aberrant scaffold-binding properties (PMID:9731525, PMID:24556213, PMID:31843706, PMID:31943058, PMID:41223971). Beyond the nervous system, PAK3 controls actin organization and cell migration in multiple contexts and acts as a transcriptionally regulated node in cancer and cardiac disease: it phosphorylates cardiac troponin I at Ser151 to raise myofilament Ca2+ sensitivity (PMID:20540949), hyperactivates mTORC1 to suppress autophagy and drive SREBP1c-dependent lipotoxic cardiac remodelling (PMID:37324527, PMID:39137120), and phosphorylates SLC3A2 at Ser175 to block STUB1-mediated ubiquitination and confer ferroptosis and chemotherapy resistance (PMID:41786277).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1998 Medium

    Established PAK3 as a neuronal Rho-GTPase effector kinase whose disruption causes human disease, defining the gene's clinical and signalling significance.

    Evidence Nonsense mutation in an X-linked mental retardation pedigree with PAK3 immunolocalization in postmitotic cortical and hippocampal neurons

    PMID:9731525

    Open questions at the time
    • Kinase disruption inferred from truncation rather than directly assayed
    • No substrates identified in this study
  2. 1997 Medium

    Tested whether PAK3 couples to MAP kinase cascades, distinguishing direct from indirect activation.

    Evidence In vitro kinase assay (no direct MEKK1 phosphorylation) plus in vivo co-expression activation in COS cells

    PMID:9065412

    Open questions at the time
    • Mechanism of indirect MEKK1 activation undefined
    • Physiological relevance not established
  3. 1998 Medium

    Proposed PAK3 as a Raf-1 S338 kinase placing it at the Rac/Cdc42–Ras-Raf-MAPK intersection, a claim later contested.

    Evidence In vitro and in vivo phospho-specific analysis of Raf-1 S338; subsequently challenged by pharmacological/genetic dissection showing PAK3-independent S338 phosphorylation

    PMID:11259591 PMID:9823899

    Open questions at the time
    • Physiological contribution of PAK3 to Raf-1 S338 phosphorylation contradicted
    • Cellular context dependence unresolved
  4. 2000 Medium

    Defined PAK3 scaffold partners and upstream receptor inputs, situating PAK3 within focal-adhesion and GPCR signalling.

    Evidence Co-IP and in vitro kinase assays with paxillin alpha/beta; thrombin/PAR1 activation of PAK3 dissected with pertussis toxin and PI3K inhibitors

    PMID:11025445 PMID:11096073

    Open questions at the time
    • Functional consequence of paxillin phosphorylation not defined
    • Single-lab observations
  5. 2000 Low

    Linked a GTPase-binding-domain missense mutation (R67C) to nonsyndromic intellectual disability, implicating GTPase coupling in disease.

    Evidence Sequencing in an MRX pedigree; functional effect inferred from domain conservation

    PMID:10946356

    Open questions at the time
    • No biochemical assay of GTPase binding performed in this study
    • Functional effect remained inferred
  6. 2002 High

    Revealed splice-isoform control of PAK3 activation, showing a brain-specific variant escapes both autoinhibition and GTPase dependence.

    Evidence Cloning of PAK3b; comparative in vitro kinase and GTPase-binding assays with autoinhibitory-domain analysis

    PMID:12464619

    Open questions at the time
    • In vivo functional role of PAK3b vs PAK3a not resolved
    • Tissue distribution of isoforms incompletely mapped
  7. 2003 Medium

    Connected PAK3 to APP-dependent neuronal death, implicating Go signalling upstream of PAK3 in a neurodegeneration context.

    Evidence Dominant-negative and APP-binding-domain deletion constructs, pertussis toxin and Go rescue in primary neurons

    PMID:12890786

    Open questions at the time
    • Direct PAK3-APP binding interface not mapped biochemically
    • Relevance to sporadic Alzheimer disease unaddressed
  8. 2004 High

    Established PAK3 as essential for dendritic spine maturation, synapse formation, AMPA receptor expression, and LTP, defining its core neuronal function.

    Evidence Antisense/siRNA and dominant-negative PAK3 in hippocampal slices with ultrastructure, electrophysiology, and AMPAR immunostaining

    PMID:15574732

    Open questions at the time
    • Substrates mediating spine effects not identified in this study
    • Mechanism linking kinase activity to spine shape unresolved
  9. 2005 High

    Showed PAK3 loss disrupts late-phase LTP and learning with reduced active CREB, connecting PAK3 to transcription-dependent plasticity.

    Evidence PAK3 knockout mice with hippocampal LTP, behavior, and phospho-CREB immunoblotting

    PMID:16014725

    Open questions at the time
    • Mechanistic link from PAK3 to CREB phosphorylation undefined
    • Compensation by PAK1 not assessed here
  10. 2006 Medium

    Placed PAK3 epistatically downstream of the GEF ARHGEF6 in spine morphogenesis.

    Evidence siRNA of ARHGEF6 and PAK3 in hippocampal slices with constitutively active PAK3 rescue and PSD95 co-localization

    PMID:17105769

    Open questions at the time
    • Direct GEF-to-GTPase-to-PAK3 step not biochemically reconstituted
    • Single lab
  11. 2008 Medium

    Distinguished PAK3 from PAK1 in spine morphogenesis while showing functional redundancy that permits compensation.

    Evidence siRNA knockdown and constitutively active rescue of PAK1/PAK3 in hippocampal slices

    PMID:18481281

    Open questions at the time
    • Molecular basis of isoform-specific roles undefined
    • Endogenous compensation in vivo not measured
  12. 2010 High

    Identified cardiac troponin I Ser151 as a PAK3 substrate, extending PAK3 function to myofilament Ca2+ regulation.

    Evidence Reconstituted thin-filament FRET and stopped-flow kinetics with cTnI(S151E) phospho-mimetic

    PMID:20540949

    Open questions at the time
    • In vivo cardiac role of cTnI S151 phosphorylation by PAK3 not established here
    • Endogenous PAK3 activity in cardiomyocytes not measured
  13. 2011 Medium

    Defined a kinase-independent PAK3-Nck2/Grb4 interaction that regulates synaptic transmission, distinguishing scaffold from catalytic functions.

    Evidence Brain Co-IP, interfering peptide in cortical slices, P12A mutant, and mEPSC/evoked transmission electrophysiology

    PMID:21949127

    Open questions at the time
    • Downstream effectors of the Nck2 complex undefined
    • Single lab
  14. 2012 High

    Established PAK1–PAK3 heterodimerization with trans-inhibition and showed disease mutations impair dimerization, linking complex assembly to function.

    Evidence Brain Co-IP, PSD co-purification, subcellular fractionation, and in vitro trans-regulation kinase assays

    PMID:22815483

    Open questions at the time
    • Stoichiometry and regulation of heterodimers in vivo unresolved
    • How PAK3b escapes trans-inhibition mechanistically partial
  15. 2012 Medium

    Showed activity-dependent recruitment of PAK3 into spines stabilizes new connections, framing PAK3 as a regulator of plasticity-driven remodelling.

    Evidence Time-lapse imaging of spine dynamics and PAK3 translocation with mutant expression in hippocampal slices

    PMID:22238087

    Open questions at the time
    • Recruitment signal/anchor not identified
    • Single lab
  16. 2013 Medium

    Extended PAK3 function to cell-cycle exit/differentiation and to transcriptionally regulated migration and transformation.

    Evidence Pak3 knockout pancreas analysis (Ngn3/Ccnd1); siRNA migration assays and PAK3 promoter luciferase/ChIP for AP-1 (cJun)

    PMID:23818969 PMID:24163148

    Open questions at the time
    • Direct PAK3 substrates in these contexts not defined
    • Tissue-specific generality untested
  17. 2014 High

    Resolved the structural basis of Cdc42-coupled PAK3 activation and demonstrated that some XLID mutations act through dominant-negative, kinase-independent mechanisms.

    Evidence NMR relaxation analysis of PBD46·Cdc42Hs; in vitro kinase, stability, and MAPK assays plus zebrafish modeling of K389N

    PMID:24556213 PMID:25109462

    Open questions at the time
    • Full-length PAK3-Cdc42 dynamics not solved
    • Dominant-negative mechanism for MAPK perturbation incomplete
  18. 2015 High

    Identified GluA1 Ser863 as a PAK3 substrate in an EphB2-Cdc42-PAK3 cascade controlling AMPAR trafficking, and confirmed conserved migration roles via the Drosophila ortholog.

    Evidence In vitro kinase assay, siRNA and pharmacological PAK inhibition in cortical neurons; Drosophila border-cell RNAi, imaging, and genetic interactions

    PMID:26013460 PMID:26395489

    Open questions at the time
    • In vivo significance of GluA1 S863 phosphorylation in plasticity not fully established
    • Cross-species conservation of substrate specificity untested
  19. 2016 Medium

    Placed GIT1 upstream of PAK3 with disease-associated alleles failing to activate it, and revealed a cell-type-specific role in oligodendrocyte differentiation.

    Evidence Cell-based PAK3 activation/MAPK assays with GIT1 allelic series and neuronal validation; Pak3 KO OPC differentiation analysis

    PMID:27457813 PMID:27940202

    Open questions at the time
    • Mechanism of GIT1-mediated PAK3 activation not biochemically defined
    • Substrate of PAK3 in OPC differentiation unknown
  20. 2019 High

    Explained genotype–phenotype severity in PAK3 ID by linking kinase loss to aberrant protein stabilization, increased αPIX binding, and adhesion/migration defects.

    Evidence In vitro kinase, stability, αPIX Co-IP, and cell spreading/migration assays comparing G424R, K389N, and A365E

    PMID:31843706

    Open questions at the time
    • In vivo cell-migration consequences in cortex not directly tested here
    • How A365E spares cellular phenotype mechanistically unclear
  21. 2020 Medium

    Linked the R67C disease variant to impaired adult hippocampal neurogenesis and memory in a knock-in model, connecting PAK3 dysfunction to neurogenic deficits.

    Evidence R67C knock-in mice with behavior, BrdU/DCX neurogenesis, c-Fos recruitment, and KCC2b analysis

    PMID:31943058

    Open questions at the time
    • Molecular pathway from R67C to neuronal survival undefined
    • KCC2b regulation mechanism unresolved
  22. 2021 Medium

    Established PAK3 as a transcriptionally repressed metastatic driver through a Smad4-miRNA-PAK3-JNK-Jun axis.

    Evidence Conditional Kras/p53/Smad4 mouse model with miR-495/miR-543 3'UTR luciferase assays and pathway analysis

    PMID:34381046

    Open questions at the time
    • Direct PAK3 substrates driving metastasis not identified
    • Generality across tumor types untested
  23. 2023 Medium

    Connected PAK3 to mTORC1-mediated autophagy suppression in pathological cardiac remodelling, and to actin-turnover control of cognition after irradiation.

    Evidence Cardiac-specific PAK3 overexpression with mTORC1/autophagy flux assays and autophagic rescue; irradiation model with miR-206-3p antagomiR restoring PAK3-LIMK1-cofilin signalling

    PMID:37324527 PMID:38131292

    Open questions at the time
    • Direct PAK3 substrate in mTORC1 activation not identified
    • Single-lab cardiac and CNS models
  24. 2024 Medium

    Expanded PAK3 metabolic and developmental roles: lipotoxic SREBP1c signalling in heart, cortical interneuron migration switching, and transcriptional repression by Tgif1 in osteoblasts.

    Evidence Cardiac overexpression/knockdown with mTOR-S6K1-SREBP1c analysis; CA/kinase-dead PAK3 in cortical interneurons with imaging; Tgif1 KO osteoblasts with PAK3 rescue

    PMID:38454080 PMID:38661167 PMID:39137120

    Open questions at the time
    • Direct substrate linking PAK3 to mTOR/S6K1 unknown
    • Tissue-specific upstream regulators incompletely defined
  25. 2025 Medium

    Refined the R67C disease mechanism, showing enhanced PIX interaction, altered focal adhesions, and reduced synaptic efficacy with preserved synapse structure.

    Evidence Biochemical PIX interaction assays, COS7 focal-adhesion imaging, and R67C knock-in mouse electrophysiology/behavior

    PMID:41223971

    Open questions at the time
    • How enhanced PIX binding causes functional deficits unresolved
    • Structural-only-normal synapses with functional deficit mechanism unclear
  26. 2026 Medium

    Identified SLC3A2 Ser175 as a PAK3 substrate that blocks STUB1 ubiquitination to confer ferroptosis and gemcitabine resistance, defining a tumor stroma-driven PAK3 pathway.

    Evidence Transcriptomics, PAK3 kinase assay on SLC3A2, STUB1 ubiquitination assays, and FGF1/PAX6 CAF co-culture analysis

    PMID:41786277

    Open questions at the time
    • In vivo therapeutic relevance not established
    • Single-lab biochemical mechanism

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PAK3 substrate selection and scaffold versus catalytic functions are coordinated across its diverse contexts (synaptic plasticity, cardiac remodelling, migration, cancer), and what unifies its mTORC1-activating and cytoskeletal roles mechanistically.
  • No structural model of full-length PAK3 in complex with substrates
  • Direct substrate driving mTORC1 hyperactivation unidentified
  • In vivo substrate specificity across tissues unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-9612973 Autophagy 1
Partners
APPARHGEF6CDC42GIT1NCK2PAK1PXNRAC1
Complex memberships
PAK1-PAK3 heterodimerpost-synaptic density

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PAK3 is a serine-threonine kinase that functions as a downstream effector linking Rho GTPases (Rac/Cdc42) to cytoskeletal reorganization and nuclear signalling; a nonsense mutation causing premature termination disrupts kinase function and causes X-linked mental retardation (MRX30). Point mutation identification in human pedigree; immunofluorescence showing PAK3 highly expressed in postmitotic neurons of developing/postnatal cerebral cortex and hippocampus Nature genetics Medium 9731525
1998 PAK3 phosphorylates Raf-1 on serine 338 both in vitro and in vivo, positively regulating Raf-1 activity; this places PAK3 at the intersection of Rac/Cdc42 signalling and the Ras-Raf-MAPK pathway. In vitro kinase assay with recombinant PAK3 and Raf-1; in vivo phosphorylation confirmed in cells; phospho-specific analysis Nature Medium 9823899
2001 PAK3-mediated phosphorylation of Raf-1 S338 occurs in the cytosol and does not stimulate Raf-1 kinase activity; growth factor-stimulated Raf-1 S338 phosphorylation is independent of PI3-K and PAK3, arguing against PAK3 being a physiological mediator of S338 phosphorylation in growth factor-stimulated cells. Phospho-specific antibody to S338; PI3-K inhibitors (LY294002, wortmannin); constitutively active Cdc42 and activating PAK3 mutants; Raf-1 kinase activity assay Molecular and cellular biology Medium 11259591
1997 PAK3 can activate MEKK1 in vivo, but this is indirect; PAK3 does not directly phosphorylate MEKK1 in vitro. In vitro kinase assay (no direct phosphorylation detected); in vivo co-expression activation assay in COS cells; site-directed mutagenesis of MEKK1 threonines The Journal of biological chemistry Medium 9065412
2000 PAK3 directly binds paxillin alpha and beta isoforms (but not gamma); paxillin alpha associates with both kinase-inactive and Cdc42-activated PAK3 without affecting kinase activation state; paxillin alpha competes with Nck and betaPIX for PAK3 binding; PAK3 phosphorylates paxillin alpha on serine. Co-immunoprecipitation; direct binding assays with focal adhesion proteins; in vitro kinase assay showing PAK3 phosphorylates paxillin alpha The Journal of biological chemistry Medium 11096073
2000 Missense mutation R67C in the conserved polybasic domain (AA 66-68) of PAK3, predicted to affect GTPase binding and stimulation of PAK activity, causes X-linked nonsyndromic mental retardation (MRX47). DGGE and direct sequencing in MRX pedigree; mutation location in GTPase-binding domain inferred from conservation American journal of medical genetics Low 10946356
2002 A brain-specific PAK3 splice variant, PAK3b, contains a 15-amino acid insert within the autoinhibitory domain that renders the kinase constitutively active by preventing autoinhibition; PAK3b cannot bind Rac or Cdc42 GTPases, distinguishing its regulation from PAK3a. Cloning of alternatively spliced isoform; in vitro kinase assay comparing PAK3a and PAK3b; GTPase binding assays; autoinhibitory domain functional analysis The Journal of biological chemistry High 12464619
2003 PAK3 physically interacts with the amyloid precursor protein (APP) and mediates FAD mutant APP-induced neuronal apoptosis and DNA synthesis; dominant-negative PAK3 inhibits these effects, and deletion of the PAK3 APP-binding domain abolishes the protective effect; FAD APP-induced signalling also requires G-protein Go upstream of PAK3. Dominant-negative PAK3 expression in primary neurons; APP-binding domain deletion constructs; pertussis toxin inhibition; Go rescue experiments; apoptosis and DNA synthesis assays The Journal of neuroscience Medium 12890786
2004 PAK3 is required for normal dendritic spine morphogenesis and synapse formation in hippocampus; antisense/siRNA suppression or dominant-negative PAK3 (MRX30 mutation) causes elongated spines/filopodia, reduced mature synapses lacking PSDs, reduced AMPA receptor expression, and defective LTP. Antisense and siRNA knockdown; dominant-negative PAK3 expression in hippocampal organotypic slice cultures; ultrastructural analysis; electrophysiology (LTP, spontaneous activity); AMPA receptor immunostaining The Journal of neuroscience High 15574732
2005 PAK3 knockout mice exhibit deficient hippocampal late-phase LTP and impaired learning/memory; a dramatic reduction in active CREB (phospho-CREB) in knockout mice implicates PAK3-Rho signalling in regulating CREB-dependent synaptic plasticity. PAK3 knockout mouse; hippocampal LTP electrophysiology; behavioral learning/memory tests; phospho-CREB immunoblotting The Journal of neuroscience High 16014725
2006 ARHGEF6 (a Rac1/Cdc42 GEF) acts upstream of PAK3 in hippocampal spine morphogenesis; ARHGEF6 knockdown phenocopies PAK3 knockdown (elongated spines), and this is rescued by constitutively active PAK3 but not wild-type PAK3, placing PAK3 downstream of ARHGEF6 in this pathway. siRNA knockdown of ARHGEF6 and PAK3 in hippocampal slice cultures; rescue with constitutively active PAK3; co-localization with PSD95 Journal of cell science Medium 17105769
2008 PAK3 loss-of-function and gain-of-function experiments show PAK3 and PAK1 have distinct roles in spine morphogenesis: PAK3 knockdown increases thin elongated immature spines, while PAK1 knockdown has no effect; constitutively active PAK1 can rescue the PAK3 knockdown phenotype, indicating functional overlap allowing compensation. siRNA knockdown of PAK3 and PAK1; constitutively active PAK1 and PAK3 expression; hippocampal slice cultures; spine morphology analysis Hippocampus Medium 18481281
2010 PAK3 phosphorylates cardiac troponin I (cTnI) at Ser151; pseudo-phosphorylation (S151E) increases myofilament Ca2+ sensitivity by shortening intersite distances between cTnC and cTnI and reducing Ca2+ dissociation-induced kinetic rates in reconstituted thin filaments. Reconstituted thin filament FRET (steady-state and time-resolved); stopped-flow kinetics; pseudo-phosphorylation mutant cTnI(S151E) Journal of molecular biology High 20540949
2011 PAK3 preferentially interacts with Nck2/Grb4 adaptor (over Nck1) in brain and transfected cells; this interaction is independent of PAK3 kinase activity; disrupting the PAK3-Nck2 interaction with an interfering peptide increases evoked synaptic transmission; P12A mutation in PAK3 reduces Nck2 binding and eliminates PAK3's ability to decrease miniature excitatory current amplitude. Co-immunoprecipitation from brain extracts; interfering peptide in acute cortical slices; electrophysiology (evoked transmission, mEPSCs); P12A PAK3 mutant expression in hippocampal cultures The Journal of biological chemistry Medium 21949127
2012 PAK3 forms heterodimers with PAK1 in brain; PAK1 inhibits PAK3a activity in trans (but not PAK3b splice variant); two intellectual disability mutations impair PAK3 dimerization with PAK1; PAK1 and PAK3 co-localize in dendritic spines and co-purify with post-synaptic densities. Co-immunoprecipitation from brain lysates; co-purification with PSDs; in vitro kinase assay (trans-regulation); subcellular fractionation; confocal co-localization The Journal of biological chemistry High 22815483
2012 PAK3 is specifically recruited by synaptic activity from dendrites into spines; inhibition of PAK3 increases formation of unstable new spines (activity-dependent, clustered) and impairs plasticity-mediated spine stabilization, demonstrating a role in activity-mediated synaptic connectivity remodeling. Time-lapse imaging of spine dynamics in hippocampal slice cultures; PAK3 mutant expression; activity manipulation; fluorescence tracking of PAK3 translocation The Journal of neuroscience Medium 22238087
2013 PAK3 acts downstream of Neurogenin3 to promote cell cycle exit and differentiation of beta-cells in the embryonic pancreas; PAK3 deficiency increases proliferation of Ngn3+ progenitors concomitantly with upregulation of Ccnd1, suggesting PAK3 represses Ccnd1 to promote cycle exit. Pak3 knockout mouse; pancreas development analysis; Ngn3+ progenitor proliferation assays; Ccnd1 expression analysis; glucose tolerance testing in adults Diabetes Medium 24163148
2013 PAK3 is required for actin organization and cell migration associated with AP-1 (cJun)-mediated cellular transformation; AP-1 directly binds a Jun binding site in the PAK3 promoter to regulate PAK3 transcription. siRNA knockdown of PAK3; PAK3 promoter luciferase assay with site-directed mutagenesis; cell migration assays; actin staining PloS one Medium 23818969
2014 The PAK3 K389N mutation abolishes kinase activity (like other XLID mutations) but additionally confers dominant-negative function; the mutant protein escapes physiologic degradation and perturbs MAPK signalling through a kinase-independent mechanism, causing brain and craniofacial structural defects in zebrafish. In vitro kinase assay; zebrafish in vivo model; biochemical stability assays; MAPK signalling analysis Human molecular genetics Medium 24556213
2014 The PAK3 effector domain (PBD46) binds Cdc42Hs; upon binding, side-chain dynamics propagate away from the binding interface causing rigidification near the nucleotide-binding pocket (slowing GTP hydrolysis) and increased flexibility around the guanine ring (facilitating nucleotide exchange). NMR 15N backbone and 13C methyl relaxation measurements; order parameter analysis on activated GMPPCP·Cdc42Hs Journal of molecular biology High 25109462
2015 PAK3 phosphorylates GluA1 AMPAR subunit at Ser863 in vitro; PAK3 loss and pharmacological PAK inhibition disrupt activity-dependent S863 phosphorylation in cortical neurons; EphB2-Cdc42-PAK3 signalling cascade controls GluA1 surface trafficking. In vitro kinase assay (PAK3 phosphorylates S863); PAK3 siRNA knockdown; pharmacological PAK inhibition; EphB2/Zizimin1 signalling pathway analysis in cortical neurons Proceedings of the National Academy of Sciences of the United States of America High 26013460
2015 In Drosophila border cells, Pak3 functions downstream of guidance receptor signalling through Rac GTPase to regulate F-actin distribution, protrusion stability/directionality, and apical-basal polarity during collective migration; Pak3 genetically interacts with Scribble and regulates JNK signalling. Pak3 RNAi in border cells; time-lapse imaging; genetic interaction with Scribble and Jra (JNK pathway); F-actin staining; polarity marker localization Development (Cambridge, England) Medium 26395489
2016 GIT1 activates PAK3 in cells; SCZ-associated GIT1 variants (R283W, S601N) fail to activate PAK3 and MAPK signalling; GIT1-R283W also fails to stimulate PAK phosphorylation in hippocampal neurons, placing GIT1 upstream of PAK3 in a synaptic signalling pathway. Cell-based co-expression assays for PAK3 activation; MAPK activity assays; hippocampal neuron culture PAK phosphorylation assay; allelic series functional analysis Molecular psychiatry Medium 27457813
2016 PAK3 is highly expressed in oligodendrocyte precursor cells (OPCs); Pak3 knockout impairs OPC differentiation into mature oligodendrocytes in the developing corpus callosum in a cell-autonomous manner, without affecting OPC proliferation or migration. Pak3 KO mouse; OPC culture in vitro; differentiation assays; white matter analysis; cell-autonomous rescue experiments Neurobiology of disease Medium 27940202
2019 PAK3 mutations G424R and K389N (associated with severe ID and corpus callosum agenesis) abolish kinase activity, stabilize the protein, increase interaction with αPIX/ARHGEF6, disturb adhesion point dynamics and cell spreading, and severely impair cell migration; the milder A365E variant also abolishes kinase activity but does not affect these cellular processes, explaining differential severity. In vitro kinase assays; protein stability assays; co-immunoprecipitation with αPIX; cell spreading/adhesion dynamics assays; migration assays; comparison of three PAK3 mutations Neurobiology of disease High 31843706
2020 PAK3-R67C knock-in mice show impaired long-term spatial memory and pattern separation, and exhibit accelerated death of adult-born hippocampal neurons during the 18-28 day critical period; young newborn neurons fail to be recruited during memory tasks, show decreased KCC2b chloride co-transporter, and altered dendritic development. R67C knock-in mouse model; behavioral testing (spatial memory, pattern separation); adult hippocampal neurogenesis BrdU/DCX analysis; post-recall c-Fos activation; KCC2b immunostaining Human molecular genetics Medium 31943058
2021 PAK3 mediates metastatic signal transduction via the PAK3-JNK-Jun pathway downstream of Smad4; Smad4 loss-of-function upregulates PAK3 by reducing Smad4-dependent transcription of miR-495 and miR-543, which directly target the PAK3 3'UTR. Conditional KrasG12D/p53/Smad4 knockout mouse model; PAK3-JNK-Jun pathway analysis; miRNA-PAK3 3'UTR luciferase assays; miRNA overexpression/inhibition Nature communications Medium 34381046
2023 PAK3 suppresses autophagy through hyper-activation of mTORC1; cardiac-specific PAK3 overexpression causes pathological remodelling, hypertrophy, fibrosis, and apoptosis; PAK3-provoked cardiac dysfunction is mitigated by autophagic inducers. Cardiac-specific PAK3 overexpression in mice; isoprenaline stimulation; mTORC1 activity assays; autophagy flux assays in cardiomyocytes; pharmacological autophagic induction rescue iScience Medium 37324527
2024 PAK3 promotes nuclear expression of SREBP1c through activation of mTOR and S6K1 in cardiomyocytes, resulting in abnormal lipid gene expression, lipid accumulation, and oxidative stress; PAK3 knockdown attenuates fatty acid-induced lipotoxicity in cardiomyocytes; S6K1 or SREBP1c inhibition alleviates PAK3-triggered lipid overload. Cardiac-specific PAK3 overexpression mice; PAK3 knockdown in rat and human cardiomyocytes; mTOR/S6K1/SREBP1c pathway analysis; lipid accumulation assays; pharmacological inhibitors Diabetes Medium 39137120
2024 PAK3 kinase activity promotes tangential-to-radial migration switch of cortical interneurons by shortening leading processes and inducing polarity changes; constitutively active PAK3 impairs processive tangential migration and causes accumulation in deep cortical layers; kinase-dead PAK3 promotes branched leading processes and maintains processive tangential migration. Constitutively active and kinase-dead PAK3 expression in embryonic cortical interneurons; pharmacological PAK3 inhibition; time-lapse imaging; process dynamics quantification Molecular psychiatry Medium 38454080
2024 Tgif1 acts as a transcriptional repressor of PAK3 in osteoblasts; Tgif1 deficiency increases PAK3 expression, impairing osteoblast spreading, adhesion to collagen type I, and migration; these cytoskeletal defects are PAK3-dependent. Tgif1 knockout osteoblasts; PAK3 expression analysis; PAK3 knockdown rescue; cell spreading/adhesion/migration assays; chromatin analysis of PAK3 promoter eLife Medium 38661167
2000 PAK3 is activated by thrombin signalling through PAR1 and G-protein-coupled receptor systems in a pertussis toxin-sensitive (Gi/Go-dependent) but PI3-K-independent manner; constitutively active PAK3 does not activate JNK, showing that thrombin-stimulated JNK activation occurs independently of PAK3. HA-tagged PAK3 kinase assay in transfected CCL39 cells; pertussis toxin and LY294002 inhibition; constitutively active PAK3 inducible expression; JNK activity assay Journal of cellular physiology Medium 11025445
2025 PAK3-R67C variant enhances interactions with PAK-interacting exchange factors (PIX) in vitro; expression of PAK3-R67C in COS7 cells alters focal adhesion distribution; Pak3-R67C knock-in mice exhibit reduced hippocampal synaptic efficacy and defects in LTP despite unaltered synapse structure. Biochemical interaction assays; focal adhesion imaging in COS7 cells; Pak3-R67C knock-in mouse electrophysiology; behavioral analysis Neurobiology of disease Medium 41223971
2023 Cranial irradiation downregulates PAK3 via upregulation of miR-206-3p targeting PAK3, disrupting the PAK3-LIMK1-cofilin actin turnover signalling pathway and the F/G-actin ratio; inhibition of miR-206-3p with antagomiR restores PAK3 signalling and cognitive function in irradiated mice. Cranial irradiation mouse model; PAK3-LIMK1-cofilin pathway analysis; antagomiR-206-3p intranasal administration; F/G-actin ratio measurement; behavioral testing eLife Medium 38131292
2026 PAK3 phosphorylates SLC3A2 at Serine 175 in gemcitabine-resistant pancreatic cancer cells, enhancing SLC3A2 protein stability by preventing its recognition and ubiquitination by E3 ligase STUB1, thereby promoting ferroptosis resistance and gemcitabine resistance; PAK3 transcription is driven by FGF1-induced PAX6 from cancer-associated fibroblasts. Transcriptomic sequencing of resistant cells; PAK3 kinase assay on SLC3A2; ubiquitination assays with STUB1; PAX6 transcription analysis; CAF co-culture model Cancer letters Medium 41786277

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 PAK3 mutation in nonsyndromic X-linked mental retardation. Nature genetics 384 9731525
1998 The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 375 9823899
2005 Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. The Journal of neuroscience : the official journal of the Society for Neuroscience 155 16014725
2004 The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 146 15574732
2000 Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. American journal of medical genetics 106 10946356
2003 DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. The Journal of neuroscience : the official journal of the Society for Neuroscience 105 12890786
2001 S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3. Molecular and cellular biology 65 11259591
2015 Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation. Proceedings of the National Academy of Sciences of the United States of America 61 26460013
2006 Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Journal of cell science 60 17105769
1997 Identification of two essential phosphorylated threonine residues in the catalytic domain of Mekk1. Indirect activation by Pak3 and protein kinase C. The Journal of biological chemistry 58 9065412
2003 X-linked mild non-syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3. American journal of medical genetics. Part A 56 12884430
2000 Interaction of paxillin with p21-activated Kinase (PAK). Association of paxillin alpha with the kinase-inactive and the Cdc42-activated forms of PAK3. The Journal of biological chemistry 55 11096073
2021 Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation. Nature communications 50 34381046
2010 Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3. Proceedings of the National Academy of Sciences of the United States of America 48 20616055
2013 Pak3 promotes cell cycle exit and differentiation of β-cells in the embryonic pancreas and is necessary to maintain glucose homeostasis in adult mice. Diabetes 45 24163148
2007 PAK3 related mental disability: further characterization of the phenotype. American journal of medical genetics. Part A 45 17853471
2012 Alteration of synaptic network dynamics by the intellectual disability protein PAK3. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 22238087
2014 A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype. Human molecular genetics 35 24556213
2008 A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features. European journal of human genetics : EJHG 34 18523455
2020 Decreased microRNA-125b-5p disrupts follicle steroidogenesis through targeting PAK3/ERK1/2 signalling in mouse preantral follicles. Metabolism: clinical and experimental 31 32304754
2016 Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity. Molecular psychiatry 30 27457813
2002 A new constitutively active brain PAK3 isoform displays modified specificities toward Rac and Cdc42 GTPases. The Journal of biological chemistry 29 12464619
1996 Regional localisation of two non-specific X-linked mental retardation genes (MRX30 and MRX31). American journal of medical genetics 29 8826460
2016 The intellectual disability protein PAK3 regulates oligodendrocyte precursor cell differentiation. Neurobiology of disease 28 27940202
2011 p21-Activated kinase 3 (PAK3) protein regulates synaptic transmission through its interaction with the Nck2/Grb4 protein adaptor. The Journal of biological chemistry 28 21949127
2015 Pak3 regulates apical-basal polarity in migrating border cells during Drosophila oogenesis. Development (Cambridge, England) 27 26395489
2020 Circ_0000190 suppresses gastric cancer progression potentially via inhibiting miR-1252/PAK3 pathway. Cancer cell international 22 32742198
2012 The p21-activated kinase PAK3 forms heterodimers with PAK1 in brain implementing trans-regulation of PAK3 activity. The Journal of biological chemistry 22 22815483
2012 Requirement for Pak3 in Rac1-induced organization of actin and myosin during Drosophila larval wound healing. FEBS letters 21 22449966
2008 Distinct, but compensatory roles of PAK1 and PAK3 in spine morphogenesis. Hippocampus 21 18481281
2018 Improvement of Self-Injury With Dopamine and Serotonin Replacement Therapy in a Patient With a Hemizygous PAK3 Mutation: A New Therapeutic Strategy for Neuropsychiatric Features of an Intellectual Disability Syndrome. Journal of child neurology 20 29246092
2009 Pak3 inhibits local actin filament formation to regulate global cell polarity. HFSP journal 20 19639041
2019 PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration. Neurobiology of disease 19 31843706
2017 A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins. European journal of medical genetics 19 28126652
2022 PAK3 promotes the metastasis of hepatocellular carcinoma by regulating EMT process. Journal of Cancer 18 34976179
2020 LncRNA TTN-AS1/miR-134-5p/PAK3 axis regulates the radiosensitivity of human large intestine cancer cells through the P21 pathway and AKT/GSK-3β/β-catenin pathway. Cell biology international 18 32749739
2013 Dlx1 transcription factor regulates dendritic growth and postsynaptic differentiation through inhibition of neuropilin-2 and PAK3 expression. The European journal of neuroscience 17 24236816
1992 A new member of the adenylate kinase family in yeast: PAK3 is highly homologous to mammalian AK3 and is targeted to mitochondria. Molecular & general genetics : MGG 17 1620094
2022 Oncogenic potential of PIK3CD in glioblastoma is exerted through cytoskeletal proteins PAK3 and PLEK2. Laboratory investigation; a journal of technical methods and pathology 15 35851857
2021 PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth. Cellular oncology (Dordrecht, Netherlands) 15 34550532
2020 LncRNA PVT1 Acts as a Tumor Promoter in Thyroid Cancer and Promotes Tumor Progression by Mediating miR-423-5p-PAK3. Cancer management and research 15 33408513
2013 p21-activated kinase 3 (PAK3) is an AP-1 regulated gene contributing to actin organisation and migration of transformed fibroblasts. PloS one 15 23818969
2020 The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis. Human molecular genetics 13 31943058
1999 Cloning, central nervous system expression and chromosomal mapping of the mouse PAK-1 and PAK-3 genes. Gene 13 10352232
1998 A YAC contig in Xq22.3-q23, from DXS287 to DXS8088, spanning the brain-specific genes doublecortin (DCX) and PAK3. Genomics 12 9782089
2022 Over-expression of miR-193a-3p regulates the apoptosis of colorectal cancer cells by targeting PAK3. American journal of translational research 11 35273739
2020 Novel PAK3 gene missense variant associated with two Chinese siblings with intellectual disability: a case report. BMC medical genetics 11 32050918
2019 A novel PAK3 pathogenic variant identified in two siblings from a Japanese family with X-linked intellectual disability: case report and review of the literature. Cold Spring Harbor molecular case studies 11 31444167
2010 Accelerated evolution of PAK3- and PIM1-like kinase gene families in the zebra finch, Taeniopygia guttata. Molecular biology and evolution 11 20237222
2008 Sequence analysis of P21-activated kinase 3 (PAK3) in chronic schizophrenia with cognitive impairment. Schizophrenia research 10 18805672
2014 Dynamic and thermodynamic response of the Ras protein Cdc42Hs upon association with the effector domain of PAK3. Journal of molecular biology 9 25109462
2010 Structural and kinetic effects of PAK3 phosphorylation mimic of cTnI(S151E) on the cTnC-cTnI interaction in the cardiac thin filament. Journal of molecular biology 9 20540949
2024 PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy. Diabetes 8 39137120
2020 Integration of hepatitis B virus DNA into p21-activated kinase 3 (PAK3) gene in HepG2.2.15 cells. Virus genes 7 31897927
2024 PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity. Molecular psychiatry 6 38454080
2015 Lethality of PAK3 and SGK2 shRNAs to human papillomavirus positive cervical cancer cells is independent of PAK3 and SGK2 knockdown. PloS one 6 25615606
2023 Restored autophagy is protective against PAK3-induced cardiac dysfunction. iScience 5 37324527
2021 Clinical and Molecular Aspects of the Neurodevelopmental Disorder Associated with PAK3 Perturbation. Journal of molecular neuroscience : MN 5 34227036
2021 Disruption of PAK3 Signaling in Social Interaction Induced cFos Positive Cells Impairs Social Recognition Memory. Cells 5 34831234
2023 PAK3 downregulation induces cognitive impairment following cranial irradiation. eLife 4 38131292
2021 Protein-Activated Kinase 3 (PAK3)-Related Intellectual Disability Associated with Combined Immunodeficiency: A Case Report. The American journal of case reports 4 34014906
2004 bPAK-interacting exchange factor may regulate actin cytoskeleton through interaction with actin. Experimental & molecular medicine 4 15665591
2000 Independent activation of endogenous p21-activated protein kinase-3 (PAK3) and JNK by thrombin in CCL39 fibroblasts. Journal of cellular physiology 4 11025445
2025 PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism. Epilepsia open 3 39806575
2024 Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling. eLife 1 38661167
2020 Suppression of spastin Mutant Phenotypes by Pak3 Loss Implicates a Role for Reactive Glia in AD-HSP. Frontiers in neuroscience 1 33013303
2026 Artificial Intelligence Driven Virtual Screening and Molecular Docking Approaches Identified LIFR, BTG2, EPHX2, and PAK3 as Targets and BI-2536, AP-24534, and AZ-628 as Repurposed Drugs for PDAC. IEEE transactions on computational biology and bioinformatics 0 41605175
2026 Cancer-associated fibroblasts drive gemcitabine resistance in pancreatic cancer by promoting ferroptosis resistance via the PAX6/PAK3/SLC3A2 axis. Cancer letters 0 41786277
2025 Folliculosebaceous Poromas With PAK2 and PAK3 Rearrangements: A Report of Two Cases and Review of the Literature. The Journal of dermatology 0 41084995
2025 Second occurrence of the PAK3-R67C variation and multiscale analysis of the corresponding knock-in mice reveal novel phenotypic features and functional synaptic defects. Neurobiology of disease 0 41223971
2023 [Analysis of a child with X-linked intellectual disability due to a maternal de novo splicing variant of the PAK3 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 37368392
2007 [Research progress on nonsyndromic X-linked mental retardation related gene PAK3]. Yi chuan = Hereditas 0 17548318

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