Affinage

PKN1

Serine/threonine-protein kinase N1 · UniProt Q16512

Round 2 corrected
Length
942 aa
Mass
103.9 kDa
Annotated
2026-04-28
130 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PKN1 is a Rho/Rac-activated AGC-family serine/threonine kinase that transduces small GTPase signals into cytoskeletal remodeling, cell cycle control, transcriptional regulation, and stress-protective responses. Its N-terminal HR1a domain binds GTP-RhoA while HR1b binds both Rac1 and RhoA, relieving an internal autoinhibitory segment (residues 455–511) to activate a C-terminal catalytic domain that phosphorylates intermediate filament proteins (neurofilament L, vimentin, GFAP) to inhibit their polymerization, tau at the PKN1-specific site Ser320 to disrupt microtubules, Cdc25C to delay mitotic entry, CPI-17 to promote myosin phosphatase inhibition, RPH3A to drive polarized RAB21-dependent vesicle trafficking in neutrophils, and EGFR at Thr654 (PMID:8571127, PMID:8621664, PMID:11104762, PMID:11134534, PMID:17301291, PMID:28636945, PMID:21749319). PKN1 also functions as a gatekeeper kinase that recruits PKCβI to androgen receptor target promoters, enabling H3T6 phosphorylation that protects H3K4 methylation marks from LSD1 demethylation, and it represses NF-κB and Wnt/β-catenin signaling (PMID:20228790, PMID:16611232, PMID:24114839). Under stress, PKN1 translocates to the nucleus and, in the heart, protects against ischemia/reperfusion injury by phosphorylating αB-crystallin and stimulating proteasome activity through a Src–RhoA–PDK1 activation cascade (PMID:8816775, PMID:20595653, PMID:21037231).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Identification of PKN1 as the first serine/threonine kinase directly activated by a Rho-family GTPase established a new effector arm downstream of RhoA signaling, answering how Rho could regulate serine/threonine phosphorylation.

    Evidence Co-immunoprecipitation, in vitro kinase assays, and C3 exoenzyme inhibition in COS-7 and Swiss 3T3 cells

    PMID:8571127 PMID:8647255

    Open questions at the time
    • Mechanism of kinase activation by RhoA binding not yet resolved
    • Physiological substrates unknown at this stage
  2. 1996 High

    Discovery that PKN1 phosphorylates MARCKS at PKC sites and undergoes stress-induced nuclear translocation placed PKN1 at the intersection of PKC-like signaling and nuclear stress responses, expanding its functional scope beyond a simple Rho effector.

    Evidence In vitro kinase assays with phosphopeptide mapping (MARCKS); immunofluorescence and subcellular fractionation under heat shock, arsenite, and serum starvation

    PMID:8557118 PMID:8816775

    Open questions at the time
    • Nuclear targets of translocated PKN1 not identified
    • Whether nuclear translocation is kinase-activity-dependent was unknown
  3. 1997 High

    Demonstration that PKN1 phosphorylates intermediate filament proteins (neurofilament subunits, vimentin, GFAP) and inhibits their polymerization in vitro established a direct role for PKN1 in cytoskeletal remodeling, answering how Rho signaling controls intermediate filament dynamics.

    Evidence In vitro kinase and filament assembly assays with purified neurofilaments, vimentin, and GFAP; yeast two-hybrid and GST pulldown mapping

    PMID:8621664 PMID:9175763

    Open questions at the time
    • In vivo relevance of intermediate filament phosphorylation by PKN1 not demonstrated
    • Specific phosphorylation sites on vimentin/GFAP not fully mapped
  4. 1998 High

    Structural dissection of the HR1 repeats showed that HR1a and HR1b independently bind RhoA with different nucleotide-state preferences, and that caspase-3 cleaves PKN1 to generate a constitutively active fragment during apoptosis, resolving two key regulatory mechanisms: GTPase-selective activation and irreversible proteolytic activation.

    Evidence In vitro binding with truncation mutants and nucleotide-loaded GTPases; in vitro caspase-3 cleavage with site-directed mutagenesis in apoptotic cells

    PMID:9446575 PMID:9751706

    Open questions at the time
    • Whether caspase-generated fragment has distinct substrates in vivo unknown
    • Crystal structure of HR1a–RhoA complex not yet available
  5. 1999 High

    Identification of a pseudosubstrate autoinhibitory domain (residues 455–511) relieved by arachidonic acid, and key autophosphorylation sites including activation-loop Thr774, defined the intramolecular regulation of PKN1 kinase activity, answering how the enzyme stays inactive in the absence of upstream signals.

    Evidence In vitro kinase assays with deletion/point mutants expressed in insect cells, competitive inhibition kinetics

    PMID:10467162

    Open questions at the time
    • Whether arachidonic acid activates PKN1 physiologically in cells was not resolved
    • Full interplay between GTPase binding and autoinhibition release not structurally defined
  6. 1999 High

    Discovery that PKN1 is scaffolded at the centrosome and Golgi via CG-NAP/AKAP450 alongside PKA, PP2A, and PP1 revealed a spatially organized signaling platform, answering how PKN1 is positioned near specific substrates in dividing cells.

    Evidence Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization

    PMID:10358086

    Open questions at the time
    • Functional consequence of centrosomal PKN1 not directly tested
    • Whether CG-NAP scaffolding is regulated by Rho-GTP unknown
  7. 1999 High

    Drosophila Pkn loss-of-function mutants showed defective dorsal closure (epidermal cell shape changes) in a Rho1-dependent but Rac-JNK-independent pathway, providing the first in vivo genetic evidence that PKN family kinases act specifically in Rho-driven morphogenesis.

    Evidence Genetic loss-of-function and epistasis analysis in Drosophila embryos combined with in vitro kinase assays

    PMID:10323867

    Open questions at the time
    • Mammalian in vivo requirement for PKN1 in morphogenesis not established at this stage
    • Substrates of Drosophila Pkn during dorsal closure unknown
  8. 2000 High

    PKN1 was shown to phosphorylate tau at the novel PKN1-specific site Ser320 (disrupting microtubules) and to stimulate ANF gene transcription via SRE in cardiomyocytes, broadening PKN1's substrate repertoire to include microtubule-associated proteins and revealing a role in cardiac gene regulation.

    Evidence In vitro kinase assays with phospho-specific antibodies and cell-based tubulin polymerization assays (tau); luciferase reporter assays with dominant-active/negative Rho in neonatal cardiomyocytes (ANF)

    PMID:10843871 PMID:11104762

    Open questions at the time
    • Whether PKN1-mediated tau phosphorylation contributes to tauopathy in vivo unknown
    • Transcriptional targets beyond ANF in cardiomyocytes not identified
  9. 2001 High

    Direct phosphorylation of Cdc25C by PKN1, which delayed Cdc2 dephosphorylation and mitotic entry in Xenopus extracts and embryos, answered how a Rho effector kinase could regulate cell cycle progression.

    Evidence Xenopus microinjection, cycling egg extract assays, in vitro kinase assay with kinase-dead control

    PMID:11134534

    Open questions at the time
    • Cdc25C phosphorylation site by PKN1 not identified
    • Whether this mitotic delay function operates in mammalian somatic cells untested
  10. 2004 High

    Discovery of a Ser377-phosphorylation-dependent plasma membrane pool of PKN1 that is required for both RhoA-dependent androgen receptor transactivation and neurite retraction resolved the question of how spatial compartmentalization controls PKN1 function.

    Evidence Membrane fractionation, S377A mutagenesis, AR reporter and neurite retraction assays

    PMID:15375078

    Open questions at the time
    • Kinase responsible for Ser377 phosphorylation not identified
    • Whether membrane-integrated PKN1 has distinct substrates unknown
  11. 2006 High

    PKN1 was identified as a negative regulator of NF-κB signaling, exploited by the Salmonella effector SspH1 to suppress host immunity, answering how Rho-dependent kinase activity intersects with innate immune transcription.

    Evidence Yeast two-hybrid, co-immunoprecipitation, NF-κB reporter with PKN1 overexpression and siRNA depletion

    PMID:16611232

    Open questions at the time
    • Direct phosphorylation target linking PKN1 to NF-κB inhibition not identified
    • In vivo relevance to Salmonella infection in animals untested
  12. 2007 High

    NMR structure of the HR1b–Rac1 complex revealed a novel recognition mechanism involving Rac1's polybasic C-terminal region, resolving the structural basis for PKN1's dual GTPase specificity and answering how a single kinase integrates Rho and Rac inputs.

    Evidence NMR solution structure with mutational validation of binding interface

    PMID:18006505

    Open questions at the time
    • How simultaneous Rho and Rac binding is coordinated on full-length PKN1 is unresolved
    • No full-length PKN1 structure available
  13. 2007 Medium

    PKN1 phosphorylation of CPI-17 in pregnant human myometrium linked Rho–PKN1 signaling to calcium sensitization and smooth muscle contraction, while PKN1 regulation of tight junction sealing in mammary epithelium revealed tissue-specific roles in epithelial barrier function.

    Evidence Immunohistochemistry and phosphorylation assays on human myometrial tissue; transgenic mouse mammary model with dominant-negative and constitutively active PKN1

    PMID:17301291 PMID:17591691

    Open questions at the time
    • CPI-17 phosphorylation site specificity by PKN1 not mapped
    • Myometrial data are correlative with preterm labor rather than causal
    • Tight junction mechanism downstream of PKN1 not molecularly resolved
  14. 2010 High

    PKN1 was established as a cardioprotective kinase during ischemia/reperfusion via phosphorylation of αB-crystallin and stimulation of proteasome activity, activated through a Src→RhoA→PKN1 cascade under osmotic and ischemic stress, answering how Rho signaling promotes cardiomyocyte survival.

    Evidence Cardiac-specific transgenic mice with constitutively active/dominant-negative PKN1 in I/R models; siRNA and overexpression with ERK readout in hypotonic stress

    PMID:20595653 PMID:21037231

    Open questions at the time
    • αB-crystallin phosphorylation site(s) by PKN1 not identified
    • Whether PKN1 and PKN2 have redundant roles in cardiac protection unknown
  15. 2010 High

    PKN1 was shown to act as a gatekeeper kinase that recruits PKCβI to androgen receptor target promoters, enabling H3T6 phosphorylation that prevents LSD1-mediated H3K4 demethylation, establishing PKN1 as a chromatin-level regulator of hormone-dependent transcription.

    Evidence ChIP, RNAi, in vitro histone phosphorylation, prostate cancer xenograft model

    PMID:20228790

    Open questions at the time
    • Whether PKN1 directly phosphorylates a chromatin substrate at AR promoters or acts solely as a scaffold is unclear
    • Generalizability to other nuclear receptor targets untested
  16. 2011 High

    Systematic substrate specificity profiling defined the PKN1 consensus motif (requiring Arg at −3) and validated EGFR Thr654 as a direct PKN1 substrate, broadening the kinase's substrate landscape to include receptor tyrosine kinases.

    Evidence Oriented peptide library, protein array, in vitro and in vivo phosphorylation of EGFR Thr654

    PMID:21749319

    Open questions at the time
    • Functional consequence of EGFR Thr654 phosphorylation by PKN1 not determined
    • Many of the 22 novel array-identified substrates remain unvalidated in cells
  17. 2017 High

    Discovery that PKN1 phosphorylates RPH3A to enhance its binding to GTP-RAB21, driving polarized vesicle trafficking, integrin activation, and neutrophil adhesion, answered how PKN1 controls immune cell polarity and provided the first in vivo loss-of-function phenotype for mammalian PKN1 (reduced renal ischemia-reperfusion injury in myeloid-specific knockouts).

    Evidence In vitro kinase assay, co-immunoprecipitation, neutrophil polarization/adhesion assays, conditional PKN1 knockout mice, renal I/R model

    PMID:28636945

    Open questions at the time
    • Whether RPH3A phosphorylation by PKN1 operates in non-myeloid contexts unknown
    • Specific phosphorylation site(s) on RPH3A not reported
  18. 2023 Medium

    In GNAQ-mutant uveal melanoma, PKN/PRK was placed in a non-canonical Gαq–RhoA signaling arm that converges with ROCK to control FAK, identifying PKN as a therapeutic vulnerability synergizing with FAK inhibition.

    Evidence Chemogenetic drug screen, kinase inhibitor profiling, preclinical mouse metastasis models

    PMID:37858338

    Open questions at the time
    • PKN isoform specificity (PKN1 vs PKN2/3) in uveal melanoma not resolved
    • Direct PKN substrates mediating FAK regulation not identified
    • Darovasertib inhibits both PKC and PKN, confounding isoform-specific conclusions

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structure of PKN1 showing how HR1-mediated GTPase binding, autoinhibitory domain relief, and activation-loop phosphorylation are coordinated remains unavailable, and tissue-specific non-redundant functions relative to PKN2 and PKN3 are incompletely mapped despite single-knockout viability data.
  • No full-length PKN1 crystal or cryo-EM structure
  • Tissue-specific conditional knockout phenotypes for PKN1 beyond myeloid cells are lacking
  • Nuclear substrates mediating PKN1's transcriptional effects are mostly unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 13 GO:0016740 transferase activity 8 GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005794 Golgi apparatus 1 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1640170 Cell Cycle 1 R-HSA-397014 Muscle contraction 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ACTN1AKAP9FZD7MAPTRAC1RHOARPH3ASPAG9
Complex memberships
CG-NAP/AKAP450 scaffold complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 PKN (PKN1) was identified as a direct binding partner and downstream effector of RhoA. GTP-bound RhoA physically interacted with and activated PKN in vitro and in COS-7 cells, and PKN was phosphorylated in Swiss 3T3 cells stimulated with lysophosphatidic acid in a Rho-dependent manner, establishing PKN as the first serine/threonine kinase target of Rho GTPase. Co-immunoprecipitation, in vitro kinase assay, botulinum C3 exoenzyme inhibition in cells Science High 8571127
1996 The amino-terminal region of PKN1 (residues 33–111, particularly residues 74–113) is sufficient for RhoA binding, and this interaction inhibits the GTPase activity of RhoA, suggesting a reciprocal regulatory mechanism that sustains GTP-bound active RhoA. Yeast two-hybrid, in vitro binding assay with synthetic peptide competition FEBS letters High 8647255
1996 PKN1 phosphorylates MARCKS at the same PKC sites (serine 152, 156, and 163) in cell extracts and in vitro, identifying MARCKS as a shared substrate for PKN1 and PKC signaling pathways. In vitro kinase assay with cell extracts, phosphopeptide mapping FEBS letters High 8557118
1996 PKN1 undergoes stress-induced nuclear translocation: under heat shock (42°C), sodium arsenite, or serum starvation, PKN1 redistributes from the cytoplasm to the nucleus in NIH 3T3, BALB/c 3T3, and Rat-1 cells, and returns to the cytoplasm after recovery, indicating PKN1 may relay stress signals to the nucleus. Immunofluorescence confocal microscopy, biochemical subcellular fractionation and immunoblotting Proceedings of the National Academy of Sciences of the United States of America High 8816775
1997 PKN1 interacts with alpha-actinin via its N-terminal region (outside the RhoA-binding domain), binding specifically to the third spectrin-like repeats of both skeletal and non-muscle alpha-actinin. The interaction with non-muscle alpha-actinin's EF-hand motifs is Ca2+-sensitive, and phosphatidylinositol 4,5-bisphosphate stimulates binding of full-length alpha-actinin to PKN1, linking PKN1 to the cytoskeletal network. Yeast two-hybrid, in vitro binding with truncation mutants, co-immunoprecipitation from COS7 cells The Journal of biological chemistry High 9030526
1997 PKN1 associates with and phosphorylates the head-rod domain of neurofilament L, M, and H subunits. PKN1 binding was mapped to the amino-terminal regulatory region of PKN1 and the head-rod domain of neurofilaments. Phosphorylation of neurofilament L by PKN1 inhibited its polymerization in vitro. Yeast two-hybrid, GST pulldown, in vitro kinase assay with purified neurofilaments, polymerization assay The Journal of biological chemistry High 8621664
1997 PKN1 phosphorylates vimentin and GFAP in the head domain, and this phosphorylation nearly completely inhibits filament formation of both intermediate filament proteins in vitro. The interaction was mapped by yeast two-hybrid and in vitro binding assay to the regulatory domain of PKN1. Yeast two-hybrid, in vitro binding assay, in vitro kinase assay, filament assembly assay Biochemical and biophysical research communications High 9175763
1998 PRK1/PKN1 contains two HR1 repeats (HR1a and HR1b) that both bind RhoA independently; HR1a binds exclusively to GTP-RhoA, while HR1b binds both GTP- and GDP-RhoA, indicating two independent contact sites on RhoA. The related HR1 motif in PRK2 also confers RhoA binding, and a C. elegans HR1a sequence similarly binds RhoA. In vitro binding assays with truncation mutants, Rho/Rac chimeras, nucleotide-loaded RhoA variants The Journal of biological chemistry High 9446575
1998 PKN1 is cleaved by caspase-3 at specific aspartate residues during apoptosis (Fas ligation, staurosporin, etoposide treatment), generating a constitutively active kinase fragment. The major cleavage occurs between the N-terminal regulatory and C-terminal catalytic domains. Site-directed mutagenesis of the aspartate cleavage sites prevented fragment generation. In vitro caspase-3 cleavage assay, site-directed mutagenesis, immunoblotting of apoptotic cells with caspase inhibitor Proceedings of the National Academy of Sciences of the United States of America High 9751706
1999 Drosophila Pkn (ortholog of mammalian PKN1) binds specifically to GTP-activated Rho1 and Rac1 through distinct binding sites, and binding to either GTPase increases kinase activity. Loss-of-function pkn mutants show defects specifically in epidermal cell shape changes during dorsal closure, acting in a Rho1-dependent pathway independent of the Rac-JNK transcriptional cascade. Genetic loss-of-function mutant analysis, in vitro binding and kinase assays, epistasis in Drosophila embryogenesis Genes & development High 10323867
1999 PKN1 contains an autoinhibitory domain within residues 455–511 that inhibits kinase activity in a substrate-competitive manner (Ki = 0.6 µM) and is selectively relieved by arachidonic acid (IC50 raised ~100-fold). Autophosphorylation at Thr64, Ser374, and Thr531 in the regulatory region and Thr774 in the activation loop are required for full PKN1 kinase activity. In vitro kinase assay with deletion/point mutants expressed in insect cells, competitive inhibition analysis Journal of biochemistry High 10467162
1999 CG-NAP (later known as AKAP450/AKAP9) was identified as a PKN1-interacting scaffolding protein that co-localizes with PKN1 at the centrosome and Golgi apparatus. CG-NAP also binds PKA regulatory subunit RIIα, PP2A catalytic subunit, and PP1, establishing it as a multi-enzyme scaffold at these organelles. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence microscopy The Journal of biological chemistry High 10358086
2000 PKN1 phosphorylates tau at microtubule-binding domain sites Ser258, Ser320, and Ser352; Ser320 is a PKN1-specific site not phosphorylated by any PKC subtype. PKN1 activation disrupts microtubule arrays both in vitro and in vivo, and dephosphorylation at Ser320 is regulated by calcineurin (PP2B). In vitro kinase assay, site-directed mutagenesis, phosphorylation-specific antibody (HIA3), cell-based tubulin polymerization assay The Journal of biological chemistry High 11104762
2000 PKN1 (as a Rho effector) stimulates ANF gene transcription via a serum response element (SRE) in cardiomyocytes. Constitutively active PKN1 robustly activated a luciferase reporter driven by the ANF promoter SRE, and this effect required dominant-active Rho; dominant-negative Rho blocked both phenylephrine-induced and PKN1-stimulated ANF expression. Luciferase reporter assay in neonatal rat ventricular myocytes, dominant-negative/constitutively active mutant expression American journal of physiology. Heart and circulatory physiology Medium 10843871
2001 PKN1 inhibits Cdc25C phosphatase activity by direct phosphorylation, thereby delaying mitotic timing. Active PKN1 microinjected into Xenopus embryos caused cleavage arrest; in cycling egg extracts, active PKN1 delayed Tyr15 dephosphorylation of Cdc2 and Cdc2/cyclin B activation. The kinase-negative form had no effect. Xenopus microinjection, cell-free cycling extract assay, in vitro kinase assay of Cdc25C by PKN1 Proceedings of the National Academy of Sciences of the United States of America High 11134534
2003 PKN1 is one of three mammalian isoforms (PKNα/PAK-1/PRK-1, PKNβ, and PRK2/PAK-2/PKNγ) of a serine/threonine kinase family with a catalytic domain homologous to PKC and a unique regulatory region containing antiparallel coiled-coil (ACC/HR1) domains. PKN1 is the first identified serine/threonine kinase activated by a small GTPase (Rho) and also activated by fatty acids such as arachidonic acid in vitro. Review synthesizing biochemical characterization across isoforms Journal of biochemistry High 12761194
2004 PRK1/PKN1 exists as an integral plasma membrane pool in mammalian cells. Phosphorylation of Ser377 of PRK1 is required for membrane integration. Only the membrane-associated form of PRK1 can mediate RhoA-dependent androgen receptor transcriptional activation in prostate epithelial cells and RhoA-induced neurite retraction in neuronal cells. Membrane fractionation, site-directed mutagenesis (S377A), functional reporter assays, neurite retraction assay FASEB journal High 15375078
2006 The Salmonella effector SspH1 interacts with PKN1 via its leucine-rich repeat domain. Expression of constitutively active PKN1 decreases NF-κB-dependent reporter gene expression, while siRNA depletion of PKN1 increases NF-κB activity, identifying PKN1 as a negative regulator of NF-κB signaling that is exploited by SspH1. Yeast two-hybrid screen, co-immunoprecipitation, NF-κB luciferase reporter assay, siRNA knockdown Cellular microbiology High 16611232
2007 The HR1b domain of PRK1/PKN1 binds exclusively to Rac1 (not RhoA), while HR1a binds both. NMR solution structure of the HR1b–Rac1 complex reveals that HR1b contacts the C-terminal effector loop, switch 2, and the polybasic C-terminal region of Rac1. The Rac1 polybasic region forms a novel recognition element for effector binding. NMR structure determination, mutational analysis of binding interface The Journal of biological chemistry High 18006505
2007 PKN1 mRNA and protein expression are dramatically increased in pregnant human myometrium, and PKN1 phosphorylates CPI-17 (PPP1R14A) to inhibit myosin phosphatase, contributing to calcium sensitization and uterine contractile activity. Elevated GTP-bound RhoA correlates with increased PKN1 signaling in spontaneous preterm labor. Immunoblotting, phosphorylation assays, immunohistochemistry on human myometrial tissue Biology of reproduction Medium 17301291
2007 Constitutively active PKN1 expressed in transgenic mouse mammary epithelium impairs tight junction sealing at parturition (demonstrated by paracellular sucrose permeability assay) and causes precocious involution, while dominant-negative PKN1 accelerates tight junction sealing in EpH4 cells, revealing PKN1 as a negative regulator of tight junction sealing via glucocorticoid signaling. Transgenic mouse model, intraductal injection permeability assay, EpH4 cell tight junction assay, dominant-negative/constitutively active mutants Journal of cell science High 17591691
2008 PKN1 is cleaved and activated by caspase in SOD1-G93A transgenic mice (ALS model) and by glutamate treatment in neurons. A constitutively active (cleaved) form of PKN1, but not wild-type PKN1, disrupts neurofilament organization and impairs axonal transport in neurons, suggesting that deregulated PKN1 contributes to ALS pathology. Immunoblotting of SOD1G93A mice, neuronal cell culture with glutamate, axonal transport assay, expression of cleaved vs. wild-type PKN1 FEBS letters Medium 18519042
2009 A 15-amino-acid peptide (PRL) derived from residues 485–499 of the C2-like domain of PKN1 selectively inhibits all PKN isoforms (Ki = 0.7 µM) in vitro without inhibiting PKC. Cell-permeable delivery of PRL inhibited PKN1-mediated tau phosphorylation at the PKN1-specific site Ser320 in vivo. In vitro kinase assay with peptide inhibitor, cell-based phosphorylation assay with phospho-specific antibody, cell-penetrating peptide delivery The Biochemical journal High 19857203
2010 PKN1 is activated during myocardial ischemia/reperfusion (I/R), evidenced by Thr774 phosphorylation. Cardiac-specific overexpression of constitutively active PKN1 in transgenic mice significantly reduces myocardial infarct size and apoptosis after I/R, while dominant-negative PKN1 worsens injury. PKN1 mediates phosphorylation of αB-crystallin and stimulates proteasome activity as part of its cytoprotective mechanism. Transgenic mouse I/R model, TUNEL assay, in vivo and in vitro kinase assays, proteasome activity assay, pharmacological proteasome inhibition Circulation research High 20595653
2010 PKN1 is activated by hypotonic swelling in cardiac myocytes through a Src→RhoA→PKN1 cascade, and PKN1 in turn activates ERK via MEK to promote cell survival. Knockdown of PKN1 inhibited HS-induced ERK phosphorylation and reduced myocyte survival under hypotonic stress. siRNA knockdown, constitutively active PKN1 overexpression, co-immunoprecipitation (PKN1–RhoA), kinase activity assays, cell viability assay American journal of physiology. Heart and circulatory physiology Medium 21037231
2011 PKN1 and PKN2 substrate recognition requires an arginine at position −3 relative to the phosphoserine, while arginines at +1 (PKN1) or −1 (PKN3) are not tolerated. Using a peptide library and protein array approach, 22 novel PKN1 substrates were identified, and EGFR Thr654 was confirmed as a PKN1 phosphorylation site in vitro and in vivo. Oriented peptide library screen, protein array, in vitro kinase assay, in vivo phosphorylation with PKN modulation The Biochemical journal High 21749319
2011 PKN2 but not PKN1 or PKN3 is required for cell migration and invasion in 5637 bladder tumor cells. Using chimeric PKN constructs swapping regulatory domains between isoforms, PKN isoform-specific migration functions are conferred by their distinct N-terminal regulatory domains, indicating that different upstream signals are selectively coupled to PKN isoforms. siRNA knockdown, rescue with wild-type and chimeric PKN constructs, migration and invasion assays PloS one Medium 21754995
2013 PKN1 represses Wnt/β-catenin signaling in melanoma cells. siRNA depletion of PKN1 enhances β-catenin-activated reporter activity and increases WNT3A-induced apoptosis. Affinity purification–mass spectrometry revealed that PKN1 resides in a protein complex with Frizzled 7 and associated proteins, placing PKN1 upstream of β-catenin as a signaling repressor. siRNA screen, β-catenin luciferase reporter assay, affinity purification–mass spectrometry The Journal of biological chemistry Medium 24114839
2014 PRK1/PKN1 kinase activity is required for migration and invasion of androgen-independent prostate cancer cells. PKN1 regulates migration-relevant gene expression via interaction with scaffold protein SPAG9/JIP4, leading to p38 phosphorylation; depletion of ELK1 (p38 effector) or p38 recapitulates PKN1 depletion phenotypes. A PRK1 inhibitor prevented metastasis in mice. siRNA knockdown, transcriptome and interactome analysis, co-immunoprecipitation, in vivo mouse metastasis model with pharmacological inhibitor Oncotarget High 25504435
2016 PKN2 knockout in mice causes lethality at embryonic day 10 due to failure of embryonic mesoderm expansion and cardiovascular defects. PKN1 and PKN3 single knockouts are viable, establishing PKN2 as specifically non-redundant. Mouse embryonic fibroblasts (mesodermal origin) require PKN2 for proliferation and motility, and PKN2 is required for neural crest migration in vivo. Conditional and constitutive knockout mice, embryonic phenotyping, MEF proliferation/motility assays, in vivo neural crest migration analysis Cell reports High 26774483
2017 PKN1 phosphorylates RPH3A, which enhances RPH3A binding to GTP-bound RAB21. This PKN1→RPH3A→RAB21 phosphorylation cascade drives polarized vesicle trafficking in neutrophils, leading to PIP5K1C90 polarization, integrin activation, and adhesion to endothelial cells. Myeloid-specific loss of PKN1 decreases tissue injury in renal ischemia-reperfusion in vivo. In vitro kinase assay, co-immunoprecipitation, neutrophil polarization/adhesion assay, conditional PKN1 knockout mice, ischemia-reperfusion model Cell reports High 28636945
2010 PKCβI is recruited to AR target gene promoters by PRK1/PKN1 as a 'gatekeeper kinase,' and this PKCβI phosphorylates histone H3 at threonine 6 (H3T6ph) to prevent LSD1 from demethylating H3K4 during androgen-dependent gene expression. PRK1 activation is required for the androgen-stimulated recruitment of PKCβI to promoters. ChIP, RNAi knockdown, in vitro histone phosphorylation assay, prostate cancer xenograft model Nature High 20228790
2023 In GNAQ-mutant uveal melanoma, PKN/PRK (downstream of the Gαq–RhoA axis) converges with ROCK to control FAK activity. Darovasertib inhibits both PKC and PKN/PRK and synergizes with FAK inhibitors to halt uveal melanoma growth in vitro and in preclinical metastatic mouse models, identifying PKN as part of a non-canonical Gαq signaling vulnerability. High-throughput chemogenetic drug screen, kinase inhibitor profiling, in vitro cell viability assays, preclinical mouse metastasis models Cell reports. Medicine Medium 37858338

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1997 Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Current biology : CB 609 9395435
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science (New York, N.Y.) 388 8571127
1998 New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer's disease brain using nanoelectrospray mass spectrometry. Journal of neurochemistry 348 9832145
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1999 p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. The Journal of cell biology 332 10330410
1998 Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. European journal of biochemistry 285 9546672
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
1996 Interaction of the Nck adapter protein with p21-activated kinase (PAK1). The Journal of biological chemistry 273 8824201
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
1997 Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS letters 256 9199504
2003 Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. The Journal of neuroscience : the official journal of the Society for Neuroscience 250 12716939
2003 RhoE binds to ROCK I and inhibits downstream signaling. Molecular and cellular biology 244 12773565
2010 Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4. Nature 243 20228790
1999 Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the golgi apparatus. The Journal of biological chemistry 216 10358086
1997 Localization of p21-activated kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells. The Journal of cell biology 200 9298982
2011 Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proceedings of the National Academy of Sciences of the United States of America 172 21482786
2020 Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5. Autophagy 137 32186433
2003 The structure and function of PKN, a protein kinase having a catalytic domain homologous to that of PKC. Journal of biochemistry 135 12761194
2014 A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly. Nature cell biology 134 24859002
1998 Proteolytic activation of PKN by caspase-3 or related protease during apoptosis. Proceedings of the National Academy of Sciences of the United States of America 126 9751706
2003 Yeast Pak1 kinase associates with and activates Snf1. Molecular and cellular biology 124 12748292
2011 Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo. The Journal of biological chemistry 117 21969371
2002 Association of PI-3 kinase with PAK1 leads to actin phosphorylation and cytoskeletal reorganization. Molecular biology of the cell 110 12181358
1999 The Drosophila Pkn protein kinase is a Rho/Rac effector target required for dorsal closure during embryogenesis. Genes & development 109 10323867
1997 Interaction of PKN with alpha-actinin. The Journal of biological chemistry 109 9030526
2008 Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms. Molecular and cellular biology 108 18411304
2006 A Salmonella type III secretion effector interacts with the mammalian serine/threonine protein kinase PKN1. Cellular microbiology 107 16611232
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2001 Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1. The Journal of biological chemistry 106 11733498
1998 A Nck-Pak1 signaling module is required for T-cell receptor-mediated activation of NFAT, but not of JNK. The EMBO journal 105 9755165
2021 DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome. The Journal of clinical investigation 104 33945512
2003 The Ark1/Prk1 family of protein kinases. Regulators of endocytosis and the actin skeleton. EMBO reports 97 12634840
2001 Etk/Bmx tyrosine kinase activates Pak1 and regulates tumorigenicity of breast cancer cells. The Journal of biological chemistry 97 11382770
1998 Multiple interactions of PRK1 with RhoA. Functional assignment of the Hr1 repeat motif. The Journal of biological chemistry 95 9446575
2012 CYK4 inhibits Rac1-dependent PAK1 and ARHGEF7 effector pathways during cytokinesis. The Journal of cell biology 90 22945935
2013 HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases. Molecular cell 85 23317503
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2013 p21-activated kinase 1 (PAK1) can promote ERK activation in a kinase-independent manner. The Journal of biological chemistry 62 23653349
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2007 Pak1 regulates dendritic branching and spine formation. Developmental neurobiology 58 17443815
1999 Mutational analysis of the regulatory mechanism of PKN: the regulatory region of PKN contains an arachidonic acid-sensitive autoinhibitory domain. Journal of biochemistry 58 10467162
2019 PKC and PKN in heart disease. Journal of molecular and cellular cardiology 56 30742812
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1997 Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN. Biochemical and biophysical research communications 56 9175763
2004 Adhesion stimulates direct PAK1/ERK2 association and leads to ERK-dependent PAK1 Thr212 phosphorylation. The Journal of biological chemistry 55 15542607
2014 Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. Cell reports 51 25456130
2015 Overexpression of PAK1 promotes cell survival in inflammatory bowel diseases and colitis-associated cancer. Inflammatory bowel diseases 50 25569743
2014 Thymoquinone-induced conformational changes of PAK1 interrupt prosurvival MEK-ERK signaling in colorectal cancer. Molecular cancer 49 25174975
2007 The Rac1 polybasic region is required for interaction with its effector PRK1. The Journal of biological chemistry 49 18006505
2000 The Rho effector, PKN, regulates ANF gene transcription in cardiomyocytes through a serum response element. American journal of physiology. Heart and circulatory physiology 49 10843871
2014 Erk5 inhibits endothelial migration via KLF2-dependent down-regulation of PAK1. Cardiovascular research 48 25388666
2014 PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition. The Journal of pathology 47 25074413
2015 PAK1 regulates RUFY3-mediated gastric cancer cell migration and invasion. Cell death & disease 45 25766321
2012 PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 45 22252525
2008 The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain. Molecular neurobiology 45 18649038
2008 Biochemical and structural characterization of the Pak1-LC8 interaction. The Journal of biological chemistry 44 18650427
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2023 Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK. Biophysical reviews 42 37124926
2016 Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion. Cell reports 42 26774483
2010 Activation of PKN mediates survival of cardiac myocytes in the heart during ischemia/reperfusion. Circulation research 42 20595653
1996 Translocation of PKN from the cytosol to the nucleus induced by stresses. Proceedings of the National Academy of Sciences of the United States of America 41 8816775
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2014 PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells. Oncotarget 35 25504435
2013 Axl gene knockdown inhibits the metastasis properties of hepatocellular carcinoma via PI3K/Akt-PAK1 signal pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 35 24347489
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2017 PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury. Cell reports 30 28636945
2013 Protein kinase PKN1 represses Wnt/β-catenin signaling in human melanoma cells. The Journal of biological chemistry 30 24114839
2007 Up-regulation of myometrial RHO effector proteins (PKN1 and DIAPH1) and CPI-17 (PPP1R14A) phosphorylation in human pregnancy is associated with increased GTP-RHOA in spontaneous preterm labor. Biology of reproduction 30 17301291
2021 PAK1 Positively Regulates Oligodendrocyte Morphology and Myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 33478987
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2003 Identification of two eukaryote-like serine/threonine kinases encoded by Chlamydia trachomatis serovar L2 and characterization of interacting partners of Pkn1. Infection and immunity 26 14500499
2021 p21-Activated kinase 1 (PAK1) in aging and longevity: An overview. Ageing research reviews 25 34390849
2020 Fission yeast Pak1 phosphorylates anillin-like Mid1 for spatial control of cytokinesis. The Journal of cell biology 25 32421151
2016 GIT1/βPIX signaling proteins and PAK1 kinase regulate microtubule nucleation. Biochimica et biophysica acta 25 27012601
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2007 Impaired tight junction sealing and precocious involution in mammary glands of PKN1 transgenic mice. Journal of cell science 25 17591691
2001 PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division. Proceedings of the National Academy of Sciences of the United States of America 25 11134534
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2023 High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma. Cell reports. Medicine 22 37858338
2018 NCK1 promotes the angiogenesis of cervical squamous carcinoma via Rac1/PAK1/MMP2 signal pathway. Gynecologic oncology 22 30442385
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2019 Effect of P21-activated kinase 1 (PAK-1) inhibition on cancer cell growth, migration, and invasion. Pharmacology research & perspectives 21 31516713
2023 The HOXD9-mediated PAXIP1-AS1 regulates gastric cancer progression through PABPC1/PAK1 modulation. Cell death & disease 20 37225681
2010 Hypotonic swelling-induced activation of PKN1 mediates cell survival in cardiac myocytes. American journal of physiology. Heart and circulatory physiology 20 21037231
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2000 Induction of a 55-kDa PKN cleavage product by ischemia/reperfusion model in the rat retina. Investigative ophthalmology & visual science 20 10634597
2019 PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions. Scientific reports 19 31748572
2020 Ivermectin suppresses tumour growth and metastasis through degradation of PAK1 in oesophageal squamous cell carcinoma. Journal of cellular and molecular medicine 18 32237037
2014 Protein Kinase C-Related Kinase (PKN/PRK). Potential Key-Role for PKN1 in Protection of Hypoxic Neurons. Current neuropharmacology 18 24851086
2023 PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis. Cell reports 17 37967011
2021 Fibrinogen Activates PAK1/Cofilin Signaling Pathway to Protect Endothelial Barrier Integrity. Shock (Augusta, Ga.) 17 32433215
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1998 Characterization of the Prk1 protein kinase from Schizosaccharomyces pombe. Yeast (Chichester, England) 17 9559556