Affinage

PLEKHO1

Pleckstrin homology domain-containing family O member 1 · UniProt Q53GL0

Length
409 aa
Mass
46.2 kDa
Annotated
2026-06-10
77 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLEKHO1 (CKIP-1) is a pleckstrin homology (PH) domain scaffold protein that shuttles between the plasma membrane and nucleus to integrate kinase, ubiquitin-ligase, and cytoskeletal signaling across bone, muscle, immune, cardiac, and metabolic tissues (PMID:10799509, PMID:14729969, PMID:20171213). Its PH domain binds phosphoinositides (PI3-phosphate) and directs PI3K-dependent membrane translocation, while basic and serine-rich motifs in the PH domain drive nuclear import that is counteracted by an auto-inhibitory C-terminal region (PMID:14729969, PMID:20171213). At the membrane it organizes actin dynamics: identified originally through its selective binding to CK2α (PMID:10799509), CKIP-1 bridges CK2α to actin capping protein subunits CPα/CPβ and to PAK1, and recruits the Arp2/3 complex via ARPC1, thereby controlling barbed-end capping, lamellipodia formation, cell migration, and myoblast fusion (PMID:15831458, PMID:16987810, PMID:22553210, PMID:26160174). A second major function is regulation of the HECT E3 ligase Smurf1: CKIP-1 binds the inter-WW linker of Smurf1 to augment its ligase activity toward Smad1/5, and loss of CKIP-1 elevates BMP/Smad signaling, with genetic epistasis establishing this axis as a controller of age-related bone formation and neural crest induction (PMID:18641638, PMID:28083909, PMID:29949573). CKIP-1 further acts as a negative regulator of multiple signaling outputs by scaffolding effector enzymes onto their substrates—recruiting PP2A to HDAC4 to dephosphorylate it and suppress MEF2C-driven cardiac hypertrophy (PMID:23151343), directing Oct-1 to REGγ-dependent proteasomal degradation to limit LOX-1 transcription and atherosclerotic foam-cell formation (PMID:30683852), competing with PKCθ for CARMA1 to dampen T-cell NF-κB (PMID:24465689), and terminating TRAF6-mediated Akt activation to restrain macrophage proliferation (PMID:24777252). CKIP-1 abundance is itself tightly controlled by ubiquitin-dependent degradation through GSK3β-primed, Src/c-Cbl-, and VHL-directed pathways (PMID:24777252, PMID:36347273, PMID:39201556).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2000 High

    Establishing CKIP-1 as a dedicated CK2α partner with dual membrane/nuclear localization defined it as a kinase-associated scaffold rather than a freely diffusing protein.

    Evidence Yeast two-hybrid, reciprocal co-IP, and EGFP imaging with PH-domain deletion

    PMID:10799509

    Open questions at the time
    • Functional consequence of CK2α binding not yet defined
    • No substrate or pathway placement at this stage
  2. 2004 High

    Showing PH-domain binding to PI3-phosphate and PI3K-dependent membrane translocation placed CKIP-1 within PI3K signaling and linked it to muscle differentiation.

    Evidence PI3K inhibitor/construct manipulation, RNAi, and fusion assays in C2C12 myoblasts

    PMID:14729969

    Open questions at the time
    • Membrane effectors downstream of recruitment not identified here
    • Mechanism connecting localization to myogenin expression unresolved
  3. 2005 High

    Identifying actin capping protein as a partner and CK2 phosphorylation of CPα connected CKIP-1 to direct regulation of actin barbed-end dynamics.

    Evidence TAP-MS, co-IP, barbed-end capping assay, and in vitro kinase assay

    PMID:15831458

    Open questions at the time
    • Interface residues for CP binding not yet mapped
    • In vivo relevance to migration not yet tested
  4. 2005 High

    Demonstrating caspase-3 cleavage, nuclear relocalization, and AP-1 repression revealed a stress-regulated nuclear function for CKIP-1 in apoptosis.

    Evidence Caspase cleavage assay, fractionation, AP-1 reporter, and RNAi

    PMID:15706351

    Open questions at the time
    • Direct mechanism of AP-1 repression by cleavage fragments unclear
    • Physiological apoptotic context untested
  5. 2005 Medium

    Linking membrane-bound CKIP-1 to ATM recruitment and p53 stabilization extended its scaffold role into the DNA-damage/p53 axis.

    Evidence Co-IP, fractionation, cycloheximide chase, and phospho-p53 immunoblotting

    PMID:16325375

    Open questions at the time
    • No in vitro reconstitution of ATM recruitment
    • Single-lab observation without genetic confirmation
  6. 2006 High

    Mapping the CP-binding interface to Arg-155/Arg-157 separated CKIP-1's actin-remodeling function from its CK2 binding and membrane targeting.

    Evidence Peptide-walking arrays, point mutagenesis, inducible expression, and phalloidin staining

    PMID:16987810

    Open questions at the time
    • Quantitative contribution of CP versus Arp2/3 to morphology not parsed
    • No structural model of the interface
  7. 2006 Medium

    Showing CKIP-1 destabilizes IFP35 by disrupting the IFP35–Nmi interaction added a stoichiometry-dependent role in cytokine signaling and confirmed self-oligomerization.

    Evidence Reciprocal co-IP, yeast two-hybrid, and domain mapping

    PMID:17197158

    Open questions at the time
    • Cellular cytokine readouts not directly measured
    • Single-lab interaction data
  8. 2008 High

    Identifying CKIP-1 as the first activator of a HECT E3 ligase (Smurf1) and showing increased bone mass in knockouts defined its central role in BMP/bone regulation.

    Evidence Co-IP, in vitro ubiquitylation, domain mapping, and KO mouse histomorphometry

    PMID:18641638

    Open questions at the time
    • Structural basis of WW-linker binding not resolved
    • Whether Smurf1 activation extends to all Smurf1 substrates unclear
  9. 2010 Medium

    Defining a PH-domain nuclear-targeting motif opposed by a C-terminal auto-inhibitory region explained how CKIP-1 partitions between membrane and nuclear pools.

    Evidence Deletion/point-mutant localization imaging

    PMID:20171213

    Open questions at the time
    • Signals that toggle auto-inhibition in vivo not identified
    • No interacting nuclear import machinery defined
  10. 2012 High

    Showing CKIP-1 recruits PP2A to HDAC4 to suppress MEF2C and that knockouts develop hypertrophy established a protective cardiac signaling role.

    Evidence GST pull-down, co-IP, and KO plus transgenic mouse hypertrophy models

    PMID:23151343

    Open questions at the time
    • How CKIP-1 selects HDAC4 over other substrates unclear
    • Membrane-versus-nuclear pool responsible not dissected
  11. 2012 High

    Demonstrating PH-domain-mediated recruitment of Arp2/3 (via ARPC1) to the membrane connected CKIP-1's phosphoinositide binding to cortical actin and myoblast fusion in two model systems.

    Evidence siRNA and zebrafish morpholino knockdown, co-IP, live imaging, and PH-domain binding assays

    PMID:22553210

    Open questions at the time
    • Coordination between CP and Arp2/3 binding not resolved
    • Direct ARPC1 binding interface unmapped
  12. 2013 Medium

    Showing CKIP-1 suppresses Smurf1 levels via mTOR-dependent translation and autodegradation extended the CKIP-1–Smurf1 axis into tumor growth and migration control.

    Evidence Gain/loss of function in colon cancer lines, rapamycin treatment, and xenograft assays

    PMID:23995790

    Open questions at the time
    • Reconciliation with Smurf1 activation reported elsewhere not addressed
    • Single tumor type
  13. 2014 High

    Defining the TRAF6 interaction and GSK3β/Ser-342-primed degradation of CKIP-1 established a feedback loop terminating M-CSF–driven Akt activation and restraining myeloproliferation.

    Evidence Co-IP, phospho-mutagenesis, ubiquitination assay, and KO mouse phenotyping

    PMID:24777252

    Open questions at the time
    • Ubiquitin ligase acting on phosphorylated CKIP-1 not identified
    • Direct effect on TRAF6 catalytic activity unresolved
  14. 2014 Medium

    Showing nuclear CKIP-1 enhances HDAC1 repression of the C/EBPα promoter assigned it a transcriptional role suppressing adipogenesis.

    Evidence Co-IP, ChIP, KO mouse differentiation and high-fat-diet assays

    PMID:25240053

    Open questions at the time
    • Direct CKIP-1 DNA contact versus HDAC1 bridging unclear
    • Single-lab mechanism
  15. 2014 Medium

    Demonstrating PH-domain competition with PKCθ for CARMA1 placed CKIP-1 as an intrinsic brake on T-cell NF-κB signaling controlled by lipid-raft dynamics.

    Evidence Complementation screen, co-IP, raft fractionation, and NF-κB reporter

    PMID:24465689

    Open questions at the time
    • In vivo T-cell phenotype not established
    • Stoichiometry of competition not quantified
  16. 2015 Medium

    Showing EGF-induced co-translocation of CK2α–CKIP-1–PAK1 to ruffles, with CKIP-1 bridging CK2-mediated PAK1 Ser-223 phosphorylation, linked the scaffold to migration/invasion.

    Evidence Co-IP, fractionation/imaging, PI3K inhibition, knockdown, and migration assays

    PMID:26160174

    Open questions at the time
    • Direct versus indirect PAK1 phosphorylation effects on motility not separated
    • Single-lab finding
  17. 2017 High

    In vivo osteoblast-specific epistasis showed age-rising PLEKHO1 suppresses BMP/Smad signaling, identifying it as a driver of age-related bone loss and a therapeutic siRNA target.

    Evidence Conditional KO/overexpression mice, histomorphometry, pSmad immunoblotting, and in vivo siRNA

    PMID:28083909

    Open questions at the time
    • Trigger for age-dependent PLEKHO1 upregulation unknown
    • Translation to human bone disease untested
  18. 2017 Medium

    Defining linkage-specific Nrf2/Keap1/Smurf1 ubiquitination changes placed CKIP-1 as an activator of Nrf2/ARE antioxidant defense protecting against renal fibrosis.

    Evidence K48/K63 ubiquitination assays, Nrf2 reporter, and KO mice

    PMID:29248720

    Open questions at the time
    • Direct enzymatic basis for altered ubiquitin linkages unclear
    • Single-lab mechanism
  19. 2017 Medium

    Identifying a CKIP-1–JNK1 interaction tied CKIP-1 loss to enhanced JNK1/IRS-1 phosphorylation and hepatic lipid accumulation.

    Evidence In vitro pull-down/co-IP and KO mouse high-fat-diet phenotyping

    PMID:28351752

    Open questions at the time
    • Whether CKIP-1 directly inhibits JNK1 activity unresolved
    • Single-lab observation
  20. 2018 High

    In vivo epistasis in chick embryos showed CKIP-1 restrains Smurf1-mediated Smad degradation to maintain BMP levels required for neural crest induction, extending the bone axis to development.

    Evidence Morpholino/siRNA knockdown, Smurf1 overexpression rescue, BMP reporter, and pSmad immunostaining

    PMID:29949573

    Open questions at the time
    • Spatial control of CKIP-1 at the neural plate border not defined
    • Whether other Smurf1 substrates contribute unclear
  21. 2019 High

    Demonstrating CKIP-1–REGγ-dependent degradation of Oct-1 to suppress LOX-1 established a hematopoietic-cell-autonomous anti-atherosclerotic function.

    Evidence Co-IP, degradation assay, LOX-1 promoter reporter, KO mouse atherosclerosis model, and bone marrow transplant

    PMID:30683852

    Open questions at the time
    • Whether REGγ recruitment is direct or scaffolded unclear
    • Generality of Oct-1 targeting beyond macrophages untested
  22. 2020 Medium

    Placing CKIP-1 downstream of Cx43 in Nrf2 activation linked gap-junction signaling to CKIP-1–dependent antioxidant defense.

    Evidence Co-IP, immunofluorescence, knockdown, Cx43 overexpression in KO mice, and Nrf2 reporter

    PMID:33276097

    Open questions at the time
    • How Cx43 CT regulates CKIP-1 expression mechanistically unclear
    • Single-lab finding
  23. 2022 Medium

    Defining Src-driven, c-Cbl-mediated K48 ubiquitination at Lys252 explained CKIP-1 downregulation in diabetic kidney, adding a second degradation route beyond GSK3β priming.

    Evidence Co-IP, Lys252 mutagenesis, K48-specific ubiquitination assay, and KO mice

    PMID:36347273

    Open questions at the time
    • Relative contribution of Src/c-Cbl versus other ligases not quantified
    • Single-lab mechanism
  24. 2024 Medium

    Showing CKIP-1 drives CK2 nuclear-to-cytoplasmic translocation and SAP97 phosphorylation connected the scaffold to cardiac ion channel complex assembly.

    Evidence In vitro CK2 kinase assay, overexpression, fractionation, and patch-clamp of Nav1.5/Kir2.1 currents

    PMID:39056188

    Open questions at the time
    • In vivo cardiac electrophysiological relevance untested
    • Single-lab, single-paper finding
  25. 2024 Medium

    Identifying VHL-mediated CKIP-1 degradation and a direct-binding ligand (C77) opened a route to pharmacological PROTAC-based CKIP-1 degradation.

    Evidence DNA-encoded library screen, SPR, CETSA, and ubiquitination assay

    PMID:39201556

    Open questions at the time
    • No functional cellular consequence of C77 demonstrated
    • PROTAC efficacy not yet shown
  26. 2025 Medium

    Showing ATF2-driven PLEKHO1 expression and a PLEKHO1–NUS1 interaction implicated the gene as a progression factor in clear cell renal carcinoma.

    Evidence Dual-luciferase reporter, co-IP, knockdown, and xenograft models

    PMID:39777695

    Open questions at the time
    • Mechanism by which NUS1 binding promotes progression unresolved
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CKIP-1 selects among its many context-specific partners (Smurf1, PP2A/HDAC4, CARMA1, TRAF6, REGγ, capping protein/Arp2/3) and how localization and competing degradation pathways are coordinated to specify a given output remains unresolved.
  • No structural model of the scaffold engaging distinct partners
  • Quantitative rules for nuclear/membrane partitioning per stimulus undefined
  • Cross-talk between the multiple CKIP-1 degradation routes unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 6 GO:0005634 nucleus 4 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ARPC1BCAPZA1CSNK2A1HDAC4PAK1PSME3SMURF1TRAF6

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CKIP-1 (PLEKHO1) was identified as a novel CK2α-interacting protein that binds CK2α but not CK2α' in yeast two-hybrid and co-immunoprecipitation assays; CK2 kinase activity is detected in anti-CKIP-1 immunoprecipitates from non-transfected cells. EGFP-CKIP-1 localizes to the nucleus and plasma membrane, with plasma membrane localization dependent on the N-terminal pleckstrin homology (PH) domain. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, EGFP fusion live-cell imaging, deletion analysis The Journal of biological chemistry High 10799509
2004 CKIP-1 binds phosphatidylinositol 3-phosphate through its PH domain and translocates to the plasma membrane in a PI3K-dependent manner. In C2C12 myoblasts, CKIP-1 overexpression promotes proliferation and then stimulates myogenin expression and cell fusion; siRNA silencing of CKIP-1 abolishes proliferation and delays myogenin expression, implicating CKIP-1 as a component of PI3K signaling in muscle differentiation. PI3K inhibitors (LY294002, wortmannin), active/dominant-negative PI3K constructs, RNA interference, immunofluorescence, cell fusion assay Molecular and cellular biology High 14729969
2005 CKIP-1 overexpression causes distinct changes in cell morphology and increases F-actin levels. Tandem affinity purification and mass spectrometry identified actin capping protein subunits CPα and CPβ as CKIP-1 interaction partners; co-immunoprecipitation and colocalization confirmed the interaction. CKIP-1 and CK2 together inhibit capping protein activity at barbed ends of actin filaments. CK2 phosphorylates Ser9 of CPα in vitro and in vivo. Tandem affinity purification, mass spectrometry, co-immunoprecipitation, immunofluorescence, quantitative phalloidin binding, in vitro kinase assay, CK2 inhibitor treatment Molecular and cellular biology High 15831458
2005 CKIP-1 functions as a plasma membrane-bound AP-1 regulator. During apoptosis, CKIP-1 is cleaved by caspase-3 and translocates from plasma membrane to cytoplasm and then nucleus; C-terminal cleavage fragments strongly repress AP-1 transcriptional activity. CKIP-1 overexpression promotes apoptosis via a positive feedback loop with caspase-3; RNAi knockdown of CKIP-1 attenuates apoptosis sensitivity. Caspase-3 cleavage assay, subcellular fractionation and live imaging, AP-1 reporter assay, RNA interference, overexpression in cells The EMBO journal High 15706351
2005 CKIP-1 recruits nuclear ATM kinase partially to the plasma membrane through direct interaction with ATM; only the plasma membrane-localized CKIP-1 forms a complex with ATM. CKIP-1 overexpression prevents p53 degradation by increasing p53 Ser-15 phosphorylation, consistent with enhanced ATM activity toward p53. Co-immunoprecipitation, subcellular fractionation, immunofluorescence, cycloheximide chase assay, phospho-specific immunoblotting Cellular signalling Medium 16325375
2006 Arg-155 and Arg-157 of CKIP-1 are required for interaction with actin capping protein (CP). CKIP-1 R155E/R157E mutants lose CP binding while retaining CK2 interaction, plasma membrane localization, and self-association, but fail to induce the cell morphology and actin cytoskeleton changes characteristic of wild-type CKIP-1, demonstrating that the CKIP-1–CP interaction is required for these cellular effects. Peptide walking arrays, site-directed mutagenesis, co-immunoprecipitation, tetracycline-inducible expression, immunofluorescence, phalloidin staining The Journal of biological chemistry High 16987810
2006 CKIP-1 interacts with the IFN-induced proteins IFP35 and Nmi via their NID domains; CKIP-1 forms homodimers and homotrimers in vivo. CKIP-1 destabilizes IFP35 by inhibiting the IFP35–Nmi interaction, with the Nmi:CKIP-1 ratio determining IFP35 stability and thereby modulating cytokine signaling. Co-immunoprecipitation, yeast two-hybrid, domain-mapping, overexpression and knockdown with immunoblot Cellular signalling Medium 17197158
2008 CKIP-1 specifically interacts with the linker region between the WW domains of Smurf1 (but not Smurf2), augments Smurf1 E3 ligase activity, and enhances Smurf1 affinity for its substrates, promoting ubiquitylation. CKIP-1-deficient mice show age-dependent increase in bone mass due to decreased Smurf1 activity, establishing CKIP-1 as the first auxiliary factor to activate a HECT-type E3 ligase. Co-immunoprecipitation, in vitro ubiquitylation assay, domain-mapping, CKIP-1 knockout mouse phenotyping, bone histomorphometry Nature cell biology High 18641638
2010 The N-terminal PH domain of CKIP-1 contains basic residues and a serine-rich motif that control nuclear versus plasma membrane localization; when isolated, the PH domain localizes predominantly to the nucleus. The C-terminal region of CKIP-1 acts as an auto-inhibitory domain that counteracts PH domain-mediated nuclear localization, coordinating the nucleus-plasma membrane shuttling of CKIP-1. Deletion and point-mutant constructs, fluorescence microscopy/localization assay in cells FEBS letters Medium 20171213
2012 CKIP-1 inhibits cardiac hypertrophy by interacting with HDAC4 (GST pull-down and co-IP confirmed), recruits the catalytic subunit of PP2A to HDAC4, enhances HDAC4 dephosphorylation, and thereby synergistically inhibits MEF2C transcriptional activity. CKIP-1 KO mice develop spontaneous cardiac hypertrophy; cardiac-specific CKIP-1 transgenic mice are resistant to pressure-overload hypertrophy. GST pull-down, co-immunoprecipitation, CKIP-1 KO and transgenic mouse models, echocardiography, histology, phosphorylation immunoblotting Circulation High 23151343
2012 CKIP-1 depletion severely impairs myoblast fusion in C2C12 cells in vitro and in zebrafish fast-twitch muscle in vivo. CKIP-1 binds the ARPC1 subunit of the Arp2/3 complex; through its PH domain binding to plasma membrane phosphoinositides, CKIP-1 recruits Arp2/3 to the plasma membrane, regulating cortical actin, lamellipodia formation, and myoblast elongation/fusion. siRNA knockdown, zebrafish morpholino knockdown, co-immunoprecipitation, immunofluorescence, live imaging, PH domain binding assay Journal of cell science High 22553210
2013 In colon cancer cells, CKIP-1 suppresses Smurf1 protein levels by two mechanisms: suppressing PI3K/Akt/mTOR-dependent translational upregulation of Smurf1 and enhancing Smurf1 autodegradation. CKIP-1 overexpression inhibits cell growth and migration in a Smurf1-dependent manner, and CKIP-1 downregulation correlates with Smurf1 upregulation in colon carcinogenesis. Overexpression and knockdown in HCT116 and SW480 cells, rapamycin treatment, in vivo tumor formation assay, immunoblotting Oncogene Medium 23995790
2014 CKIP-1 inhibits macrophage proliferation by interacting with TRAF6, a K63-ubiquitin E3 ligase required for Akt plasma membrane recruitment. In resting macrophages, GSK3β phosphorylates CKIP-1 at Ser-342, triggering its polyubiquitination and proteasomal degradation. Upon M-CSF stimulation, Akt inactivates GSK3β, stabilizing CKIP-1, which then terminates TRAF6-mediated Akt activation. CKIP-1-deficient mice develop splenomegaly and myeloproliferation. Co-immunoprecipitation, phosphorylation mutagenesis, ubiquitination assay, CKIP-1 KO mouse phenotyping, flow cytometry, immunoblotting Cell research High 24777252
2014 CKIP-1 interacts with HDAC1 in the nucleus and enhances HDAC1-mediated repression of the C/EBPα promoter, thereby suppressing adipogenesis in mesenchymal stem cells. MSCs from CKIP-1-deficient mice show enhanced adipogenesis; CKIP-1-deficient mice on a high-fat diet accumulate more white adipose tissue. Co-immunoprecipitation, chromatin immunoprecipitation (inferred from context), CKIP-1 KO mouse model, differentiation assay, immunoblotting Journal of molecular cell biology Medium 25240053
2014 CKIP-1 is an intrinsic negative regulator of T-cell NF-κB activation: CKIP-1 interacts with CARMA1 via its PH domain and competes with PKCθ for CARMA1 association, suppressing the PKCθ–CBM–NF-κB signaling axis. CKIP-1 represses NF-κB in unstimulated cells; CD3/CD28 costimulation causes CKIP-1 dissociation from lipid rafts, relieving inhibition. Cell-based mutagenesis/complementation screen, co-immunoprecipitation, lipid raft fractionation, NF-κB reporter assay, PH domain deletion mutants PloS one Medium 24465689
2015 CKIP-1 mediates the activation of PAK1 at the plasma membrane: upon EGF stimulation, CK2α, CKIP-1, and PAK1 co-translocate to membrane ruffles in a PI3K-dependent manner, where CKIP-1 bridges the interaction between CK2α and PAK1, facilitating CK2-mediated phosphorylation of PAK1 at Ser-223 and downstream phosphorylation of p41-Arc. CKIP-1 knockdown or PI3K inhibition suppresses PAK1-mediated cell migration and invasion. Co-immunoprecipitation, subcellular fractionation/imaging, PI3K inhibitor treatment, siRNA knockdown, migration/invasion assay, phospho-specific immunoblotting The Journal of biological chemistry Medium 26160174
2017 PLEKHO1/CKIP-1 expression increases in bone with age in both human fracture patients and aging rodents. Osteoblast-specific loss of Plekho1 promotes Smad-dependent BMP signaling (increased pSmad1/5/8) and alleviates age-related bone formation reduction; osteoblast-specific Smad1 overexpression is counteracted by Plekho1 overexpression, confirming epistatic relationship. Osteoblast-targeted Plekho1 siRNA enhances BMP signaling and bone formation in aging rodents. Conditional/osteoblast-specific knockout and overexpression mouse models, bone histomorphometry, pSmad1/5/8 immunoblotting, BMP reporter assay, siRNA treatment in vivo Aging cell High 28083909
2017 CKIP-1 overexpression decreases K48-linked polyubiquitination of Nrf2 and increases K63-linked polyubiquitination of Nrf2, while increasing K48-linked polyubiquitination of Keap1, thereby activating the Nrf2/ARE pathway. CKIP-1 promotes degradation of Smurf1 through increased Smurf1 ubiquitination; Smurf1 in turn ubiquitinates Nrf2 for K48-linked degradation. This axis protects against high glucose-induced renal fibrosis in glomerular mesangial cells. Overexpression, knockdown (siRNA/adenovirus), ubiquitination assay (K48/K63 linkage-specific), Nrf2 nuclear accumulation and reporter assay, CKIP-1 KO mice Free radical biology & medicine Medium 29248720
2017 CKIP-1 interacts with JNK1 in vitro; CKIP-1 deficiency in mice fed a high-fat diet leads to increased JNK1 phosphorylation and downstream IRS-1 phosphorylation, aggravating hepatic lipid accumulation. In vitro pull-down/co-IP, CKIP-1 KO mouse model, immunoblotting for phospho-JNK1 and phospho-IRS-1 Experimental cell research Medium 28351752
2018 CKIP-1 (CKIP-1/Smurf1 axis) is required for neural crest induction in chick embryos: CKIP-1 knockdown at the neural plate border suppresses pSmad1/5/8 and BMP reporter output, causing neural crest loss without affecting Wnt signaling. Epistasis experiments show CKIP-1 rescues Smurf1 overexpression-mediated neural crest loss, establishing that CKIP-1 suppresses Smurf1-mediated Smad degradation to maintain intermediate BMP levels required for neural crest induction. Morpholino/siRNA knockdown in chick embryo, Smurf1 overexpression, BMP reporter assay, pSmad1/5/8 immunostaining, epistasis rescue experiments PLoS biology High 29949573
2019 CKIP-1 interacts with the proteasome activator REGγ and targets the transcription factor Oct-1 for proteasomal degradation in a REGγ-dependent manner, thereby suppressing Oct-1-driven transcription of the scavenger receptor LOX-1. Ckip-1-deficient mice show increased LOX-1 expression, enhanced foam cell formation, and accelerated atherosclerosis; bone marrow transplantation demonstrates the effect is hematopoietic cell-autonomous. Co-immunoprecipitation, ubiquitination/degradation assay, luciferase reporter for LOX-1 promoter, CKIP-1 KO mouse with atherosclerosis model, bone marrow transplantation Nature communications High 30683852
2020 CKIP-1 acts downstream of Cx43 to activate the Nrf2 signaling pathway: Cx43 interacts with CKIP-1 (confirmed by co-IP and immunofluorescence), and Cx43-mediated Nrf2 activation requires CKIP-1. The Cx43 carboxyl terminus (CT) domain regulates CKIP-1 expression and the CKIP-1–Nrf2 interaction. High glucose treatment weakens Cx43–CKIP-1 interaction. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, Cx43 overexpression in CKIP-1 KO mice, Nrf2 reporter assay Pharmacological research Medium 33276097
2022 Activated Src kinase interacts with CKIP-1 at Lys252, promotes c-Cbl binding to CKIP-1 (via c-Cbl phosphorylation by Src), and thereby increases K48-linked polyubiquitination and proteasomal degradation of CKIP-1. This mechanism accounts for CKIP-1 downregulation in high-glucose-induced glomerular mesangial cells and diabetic kidneys. Co-immunoprecipitation, site-directed mutagenesis (Lys252), ubiquitination assay (K48-specific), CKIP-1 KO mouse, immunoblotting Biochemical pharmacology Medium 36347273
2024 CKIP-1 mediates translocation of CK2 from the nucleus to the cytoplasm in cardiomyocytes, increasing SAP97 phosphorylation by CK2, which enhances Nav1.5 and Kir2.1 channel complex formation and ion current activity. CK2 phosphorylates SAP97 in vitro. In vitro kinase assay (CK2 phosphorylation of SAP97), transfection-driven CKIP-1 overexpression, subcellular fractionation, whole-cell patch-clamp recording for Nav1.5 and Kir2.1 currents Journal of biochemical and molecular toxicology Medium 39056188
2024 VHL enhances CKIP-1 degradation through the ubiquitin-proteasome system. A small-molecule ligand C77 was identified by DNA-encoded library screening that binds CKIP-1 both in vitro (Surface Plasmon Resonance) and in cells (CETSA), providing a basis for PROTAC-based CKIP-1 degradation. DNA-encoded library screening, Surface Plasmon Resonance (SPR), Cellular Thermal Shift Assay (CETSA), ubiquitination assay International journal of molecular sciences Medium 39201556
2025 ATF2 transcriptionally activates PLEKHO1 expression (validated by dual-luciferase reporter assay); PLEKHO1 directly binds NUS1 (confirmed by co-IP), and PLEKHO1 depletion restrains ccRCC progression via NUS1 regulation in vitro and in xenograft models. Dual-luciferase reporter assay, co-immunoprecipitation, siRNA knockdown, xenograft mouse model Molecular carcinogenesis Medium 39777695

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1. Nature cell biology 136 18641638
2000 Identification and characterization of CKIP-1, a novel pleckstrin homology domain-containing protein that interacts with protein kinase CK2. The Journal of biological chemistry 96 10799509
2016 The pseudogene derived long noncoding RNA DUXAP8 promotes gastric cancer cell proliferation and migration via epigenetically silencing PLEKHO1 expression. Oncotarget 83 28881724
2014 CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation. Cell research 67 24777252
2017 Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating CKIP-1 to resist HG-induced up-regulation of FN and ICAM-1 in GMCs and diabetic mice kidneys. Free radical biology & medicine 66 28286065
2005 Role for the pleckstrin homology domain-containing protein CKIP-1 in AP-1 regulation and apoptosis. The EMBO journal 65 15706351
2005 The pleckstrin homology domain-containing protein CKIP-1 is involved in regulation of cell morphology and the actin cytoskeleton and interaction with actin capping protein. Molecular and cellular biology 65 15831458
2012 CKIP-1 inhibits cardiac hypertrophy by regulating class II histone deacetylase phosphorylation through recruiting PP2A. Circulation 63 23151343
2019 CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ. Nature communications 57 30683852
2006 The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling. Cellular signalling 55 17197158
2004 Role for the pleckstrin homology domain-containing protein CKIP-1 in phosphatidylinositol 3-kinase-regulated muscle differentiation. Molecular and cellular biology 55 14729969
2017 CKIP-1 affects the polyubiquitination of Nrf2 and Keap1 via mediating Smurf1 to resist HG-induced renal fibrosis in GMCs and diabetic mice kidneys. Free radical biology & medicine 52 29248720
2006 The role of CKIP-1 in cell morphology depends on its interaction with actin-capping protein. The Journal of biological chemistry 52 16987810
2012 CKIP-1: a scaffold protein and potential therapeutic target integrating multiple signaling pathways and physiological functions. Ageing research reviews 40 22878216
2017 Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging. Aging cell 38 28083909
2013 CKIP-1 acts as a colonic tumor suppressor by repressing oncogenic Smurf1 synthesis and promoting Smurf1 autodegradation. Oncogene 38 23995790
2005 CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM. Cellular signalling 37 16325375
2019 Physiological functions of CKIP-1: From molecular mechanisms to therapy implications. Ageing research reviews 31 31082489
2018 Intracellular attenuation of BMP signaling via CKIP-1/Smurf1 is essential during neural crest induction. PLoS biology 31 29949573
2013 Therapeutic RNA interference targeting CKIP-1 with a cross-species sequence to stimulate bone formation. Bone 31 24246247
2018 The role of CKIP-1 in osteoporosis development and treatment. Bone & joint research 30 29682283
2016 CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells. Biochemical pharmacology 26 27481061
2014 CKIP-1 suppresses the adipogenesis of mesenchymal stem cells by enhancing HDAC1-associated repression of C/EBPα. Journal of molecular cell biology 26 25240053
2018 Let-7a promotes microglia M2 polarization by targeting CKIP-1 following ICH. Immunology letters 25 30053453
2018 Myocardial CKIP-1 Overexpression Protects from Simulated Microgravity-Induced Cardiac Remodeling. Frontiers in physiology 23 29422872
2012 CKIP-1 regulates mammalian and zebrafish myoblast fusion. Journal of cell science 23 22553210
2019 Upregulation of CKIP-1 inhibits high-glucose induced inflammation and oxidative stress in HRECs and attenuates diabetic retinopathy by modulating Nrf2/ARE signaling pathway: an in vitro study. Cell & bioscience 22 31462987
2019 Fisetin, via CKIP-1/REGγ, limits oxidized LDL-induced lipid accumulation and senescence in RAW264.7 macrophage-derived foam cells. European journal of pharmacology 20 31655030
2015 The Role of the Pleckstrin Homology Domain-containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1). The Journal of biological chemistry 20 26160174
2021 Ckip-1 Mediates P. gingivalis-Suppressed Cementoblast Mineralization. Journal of dental research 19 34875910
2016 Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkin's lymphoma. Oncology reports 19 27840970
2021 The construction of a novel xenograft bovine bone scaffold, (DSS)6-liposome/CKIP-1 siRNA/calcine bone and its osteogenesis evaluation on skull defect in rats. Journal of orthopaedic translation 18 33738240
2021 3' untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein. European heart journal 18 34347073
2022 The effect of QiangGuYin on osteoporosis through the AKT/mTOR/autophagy signaling pathway mediated by CKIP-1. Aging 16 35073518
2014 CKIP-1 is an intrinsic negative regulator of T-cell activation through an interaction with CARMA1. PloS one 16 24465689
2018 miR‑98‑5p promotes osteoblast differentiation in MC3T3‑E1 cells by targeting CKIP‑1. Molecular medicine reports 15 29328483
2016 CKIP-1 knockout offsets osteoporosis induced by simulated microgravity. Progress in biophysics and molecular biology 15 27666961
2016 CKIP-1 silencing promotes new bone formation in rat mandibular distraction osteogenesis. Oral surgery, oral medicine, oral pathology and oral radiology 15 27727105
2022 The ubiquitination of CKIP-1 mediated by Src aggravates diabetic renal fibrosis (original article). Biochemical pharmacology 14 36347273
2010 N-terminal PH domain and C-terminal auto-inhibitory region of CKIP-1 coordinate to determine its nucleus-plasma membrane shuttling. FEBS letters 14 20171213
2023 CKIP-1 Promotes P. gingivalis-Induced Inflammation of Periodontal Soft Tissues by Inhibiting Autophagy. Inflammation 13 37351817
2019 PLEKHO1 knockdown inhibits RCC cell viability in vitro and in vivo, potentially by the Hippo and MAPK/JNK pathways. International journal of oncology 13 31180521
2013 Integrated analysis of genomics and proteomics reveals that CKIP-1 is a novel macrophage migration regulator. Biochemical and biophysical research communications 13 23747421
2022 Exploratory study of sea buckthorn enhancing QiangGuYin efficacy by inhibiting CKIP-1 and Notum activating the Wnt/β-catenin signaling pathway and analysis of active ingredients by molecular docking. Frontiers in pharmacology 12 36304155
2021 Let-7i-5p functions as a putative osteogenic differentiation promoter by targeting CKIP-1. Cytotechnology 11 33505116
2020 CKIP-1 acts downstream to Cx43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes. Pharmacological research 11 33276097
2022 Ckip-1 3'-UTR Attenuates Simulated Microgravity-Induced Cardiac Atrophy. Frontiers in cell and developmental biology 10 35186951
2020 Superior CKIP-1 sensitivity of orofacial bone-derived mesenchymal stem cells in proliferation and osteogenic differentiation compared to long bone-derived mesenchymal stem cells. Molecular medicine reports 9 32626993
2018 Effects of constrained dynamic loading, CKIP‑1 gene knockout and combination stimulations on bone loss caused by mechanical unloading. Molecular medicine reports 9 29956799
2017 Deficiency of CKIP-1 aggravates high-fat diet-induced fatty liver in mice. Experimental cell research 9 28351752
2024 CKIP-1 silencing suppresses OSCC via mitochondrial homeostasis-associated TFAM/cGAS-STING signalling axis. Journal of cellular and molecular medicine 8 39169452
2019 CKIP-1 alleviates oxygen-glucose deprivation/reoxygenation-induced apoptosis and oxidative stress in cultured hippocampal neurons by downregulating Keap1 and activating Nrf2/ARE signaling. European journal of pharmacology 8 30658115
2018 CKIP-1 suppresses odontoblastic differentiation of dental pulp stem cells via BMP2 pathway and can interact with NRP1. Connective tissue research 8 29852799
2019 Overexpression of CKIP-1 alleviates hypoxia-induced cardiomyocyte injury by up-regulating Nrf2 antioxidant signaling via Keap1 inhibition. Biochimie 7 31201843
2017 Association of CKIP-1 P21A polymorphism with risk of chronic heart failure in a Chinese population. Oncotarget 7 28402261
2020 High expression of the CKIP-1 gene might promote apoptosis through downregulation of the Ras/ERK signalling pathway in the intestinal type of gastric cancer. The Journal of international medical research 6 32223671
2020 CKIP-1 augments autophagy in steatotic hepatocytes by inhibiting Akt/mTOR signal pathway. Experimental cell research 6 33191205
2019 CKIP-1 regulates the immunomodulatory function of mesenchymal stem cells. Molecular biology reports 6 31168669
2017 A novel role of CKIP-1 in promoting megakaryocytic differentiation. Oncotarget 6 28404913
2017 CKIP-1 serves as a negative regulator and correlates with the degree of differentiation in gastric cancer. International journal of clinical and experimental pathology 5 31966411
2024 Ckip-1 3'UTR alleviates prolonged sleep deprivation induced cardiac dysfunction by activating CaMKK2/AMPK/cTNI pathway. Molecular biomedicine 4 38871861
2022 A novel CKIP-1 SiRNA slow-release coating on porous titanium implants for enhanced osseointegration. Biomaterials advances 4 35929282
2021 CKIP-1 contributes to osteogenic differentiation of mouse bone marrow mesenchymal stem cells. Regenerative medicine 4 34498492
2017 [MicroRNA-20a Promotes Osteogenic Differentiation of C3H/10T1/2 Cells through Regulating CKIP-1 Expression]. Zhongguo shi yan xue ye xue za zhi 4 28245404
2024 CKIP-1-Loaded Cartilage-Affinitive Nanoliposomes Reverse Osteoarthritis by Restoring Chondrocyte Homeostasis. ACS biomaterials science & engineering 3 38885017
2024 Paeonol can improve hypoxic-induced H9c2 cells injury and ion channel activity by up-regulating the expression of CKIP-1. Tissue & cell 2 38593570
2024 The Discovery of a Specific CKIP-1 Ligand for the Potential Treatment of Disuse Osteoporosis. International journal of molecular sciences 2 39201556
2024 CKIP-1 inhibits M2 macrophage polarization to suppress the progression of gastric cancer by inactivating JAK/STAT3 signaling. Cell biochemistry and biophysics 2 39470944
2023 CKIP-1 mediates P. gingivalis-suppressed osteogenic/cementogenic differentiation of periodontal ligament cells partially via p38 signaling pathway. Journal of oral microbiology 2 37483640
2021 Ckip-1 regulates C3H10T1/2 mesenchymal cell proliferation and osteogenic differentiation via Lrp5. Experimental and therapeutic medicine 2 33732315
2013 Crystallization and preliminary X-ray crystallographic analysis of the human CKIP-1 pleckstrin homology domain. Acta crystallographica. Section F, Structural biology and crystallization communications 2 23519814
2025 The Transcription Factor ATF2 Accelerates Clear Cell Renal Cell Carcinoma Progression Through Activating the PLEKHO1/NUS1 Pathway. Molecular carcinogenesis 1 39777695
2023 [Effect of CKIP-1 on hepatocyte apoptosis in nonalcoholic fatty liver disease]. Zhonghua nei ke za zhi 1 36631036
2023 Associations of CKIP-1 and LOX-1 polymorphisms with the risk of type 2 diabetes mellitus with hypertension among Chinese adults. Acta diabetologica 1 37668684
2026 LncRNA MIAT inhibits osteoblast differentiation and function in rheumatoid arthritis via let-7i-5p/ CKIP-1 axis. Arthritis research & therapy 0 41862966
2025 MicroRNA-6069 ASO inhibits the growth of hepatocellular carcinoma by PLEKHO1. Biochimica et biophysica acta. General subjects 0 39956470
2024 CKIP-1 mediates CK2 translocation to regulate Nav1.5 and Kir2.1 channel complexes in cardiomyocytes. Journal of biochemical and molecular toxicology 0 39056188

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