Affinage

KLF2

Krueppel-like factor 2 · UniProt Q9Y5W3

Length
355 aa
Mass
37.4 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLF2 is a mechanosensitive Krüppel-like zinc finger transcription factor that serves as a master regulator of endothelial quiescence, vascular homeostasis, and lymphocyte fate. In endothelial cells, KLF2 is induced by laminar shear stress via a PIEZO1–CaMKII–MEKK3–MEK5–ERK5–MEF2 signaling cascade and by statins through inhibition of geranylgeranylation; it transcriptionally activates thrombomodulin, eNOS, and miR-30-5p while repressing PAI-1, PFKFB3, and proinflammatory genes through inhibition of NF-κB/AP-1 and ATF2, thereby coordinating antithrombotic, anti-inflammatory, and metabolic programs (PMID:15718498, PMID:25359860, PMID:17244683, PMID:35883633, PMID:15878865). In lymphocytes, KLF2 programs T cell quiescence via c-Myc repression, controls naive T cell and Treg homing by regulating chemokine receptors and S1PR1, restrains T follicular helper differentiation through Blimp-1/Bcl-6, and maintains CD8 effector lineage fidelity by suppressing TOX and enabling TBET (PMID:9302292, PMID:11477405, PMID:18246069, PMID:25692701, PMID:39946463). KLF2 also directly binds embryonic β-globin promoters to regulate primitive erythropoiesis, and gain-of-function MEKK3–KLF2/4 signaling upon loss of the CCM complex drives cerebral cavernous malformation lesion formation (PMID:21610079, PMID:27027284).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    Establishing that KLF2 is essential for two fundamental processes — T cell quiescence and vascular integrity — resolved the question of what biological functions this Krüppel-like factor controls in vivo.

    Evidence KLF2-knockout mice showed spontaneously activated T cells dying by Fas-mediated apoptosis, and separately, embryonic lethality from hemorrhage with defective tunica media formation

    PMID:9302292 PMID:9367982

    Open questions at the time
    • Molecular targets downstream of KLF2 in both contexts unknown
    • Cell-autonomous vs. non-autonomous vascular role unresolved
  2. 2001 High

    Demonstrating that KLF2 programs quiescence through c-Myc repression identified the first downstream transcriptional target linking KLF2 to cell cycle control in T cells.

    Evidence Forced KLF2 expression in Jurkat cells decreased c-Myc; dominant-negative MadMyc mimicked KLF2 effects and c-Myc overexpression rescued them

    PMID:11477405

    Open questions at the time
    • Whether c-Myc is a direct or indirect target of KLF2 not determined
    • Mechanism of KLF2 downregulation upon T cell activation unknown
  3. 2005 High

    Identification of KLF2 as a shear-stress-responsive, atheroprotective transcription factor that induces eNOS and thrombomodulin while repressing PAI-1 and tissue factor established its central role in endothelial antithrombotic and anti-inflammatory programs.

    Evidence KLF2 overexpression/siRNA in endothelial cells altered clotting times; in vivo expression mapped to high-shear regions; laminar flow induced KLF2 while cyclic stretch did not

    PMID:15718498 PMID:16049344

    Open questions at the time
    • Mechanosensor converting shear to KLF2 transcription not yet identified
    • Relative contribution of KLF2 vs. KLF4 to overlapping targets unclear
  4. 2005 High

    Statin-mediated induction of KLF2 via inhibition of geranylgeranylation revealed a pharmacologically targetable pathway upstream of KLF2 independent of shear stress.

    Evidence Geranylgeranyl transferase inhibitor GGTI-298 replicated statin effect; mevalonate reversed it; KLF2 siRNA blocked statin-mediated gene regulation in endothelial cells

    PMID:15878865

    Open questions at the time
    • Which geranylgeranylated GTPase mediates repression of KLF2 not identified
    • Whether statin-KLF2 axis operates identically in vivo uncertain
  5. 2005 High

    Direct regulation of embryonic β-globin promoters by KLF2 established a developmental-stage-specific transcriptional role in primitive erythropoiesis distinct from adult globin regulation.

    Evidence KLF2-KO mice lacked embryonic β-like globin expression; later confirmed by ChIP showing direct KLF2 binding to ε- and γ-globin promoters and locus control region

    PMID:15947087 PMID:21610079

    Open questions at the time
    • How KLF2 is silenced at the switch to definitive erythropoiesis unknown
    • Cooperativity with KLF1 at individual globin promoters not fully dissected
  6. 2006 High

    Discovery that KLF2 suppresses monocyte inflammation by inhibiting NF-κB/AP-1 via PCAF recruitment, and that shear-induced KLF2 suppresses endothelial inflammation by inhibiting ATF2, defined the anti-inflammatory transcriptional mechanisms downstream of KLF2.

    Evidence Co-IP showed KLF2–PCAF interaction; KLF2 overexpression/siRNA in monocytes and endothelial cells plus in vivo edema model; EMSA demonstrated ATF2 inhibition

    PMID:16617118 PMID:17244683

    Open questions at the time
    • Whether PCAF sequestration is stoichiometric or catalytic unclear
    • Genome-wide map of KLF2-repressed inflammatory enhancers absent
  7. 2006 High

    Identification of nucleolin as a PI3K-dependent factor binding the KLF2 promoter in response to shear stress provided the first upstream transcriptional mechanism for flow-induced KLF2 expression.

    Evidence DNA affinity chromatography/mass spectrometry identified nucleolin; validated by ChIP, siRNA, and PI3K inhibitor in HUVECs

    PMID:16571724

    Open questions at the time
    • Relationship between nucleolin–PI3K axis and MEK5–ERK5 pathway not integrated
    • Whether nucleolin acts as a pioneer factor or co-activator undetermined
  8. 2008 High

    Conditional T cell KLF2 deletion showed that KLF2 transcriptionally represses inflammatory chemokine receptors to maintain naive T cell homing to lymphoid organs, establishing KLF2 as a lymphocyte trafficking regulator.

    Evidence Lineage-specific KLF2 knockout in mice caused redistribution of naive T cells to non-lymphoid tissues with upregulation of CCR3/CCR5

    PMID:18246069

    Open questions at the time
    • Direct versus indirect regulation of individual chemokine receptor promoters unresolved
    • Whether KLF2 similarly controls B cell trafficking not addressed
  9. 2014 High

    Multiple studies converged to show KLF2 controls endothelial metabolic reprogramming (repressing PFKFB3/glycolysis), cell migration (downregulating PAK1), and liver sinusoidal homeostasis (paracrine NO–sGC signaling to deactivate stellate cells), broadening KLF2's endothelial roles beyond inflammation and thrombosis.

    Evidence EC-specific KLF2 KO with Seahorse metabolic flux for PFKFB3; MEK5-ERK5/siRNA epistasis for PAK1; coculture and statin treatment for LSEC-stellate cell paracrine axis

    PMID:22989565 PMID:25359860 PMID:25388666

    Open questions at the time
    • Whether PFKFB3 repression is direct promoter binding or indirect unclear
    • Full secretome of KLF2-overexpressing endothelial cells not characterized
  10. 2015 High

    KLF2 was shown to restrain CD4 T follicular helper differentiation by promoting S1PR1 and inducing Blimp-1 to repress Bcl-6, revealing a dual mechanism controlling T helper subset fate decisions.

    Evidence Inducible KLF2 deficiency and overexpression in activated CD4 T cells with flow cytometry and gene expression

    PMID:25692701

    Open questions at the time
    • Direct binding of KLF2 to S1PR1 and Blimp-1 promoters not shown by ChIP
    • Role of KLF2 in Tfh responses during chronic infection unexplored
  11. 2016 High

    Demonstration that CCM lesion formation requires gain-of-function MEKK3–KLF2/4 signaling, with endothelial KLF2/4 deletion rescuing CCM pathology, established KLF2 as a disease driver in cerebral cavernous malformations.

    Evidence Neonatal CCM mouse models with endothelial-specific conditional Klf2/Klf4 KO rescuing lethality; human CCM2 mutation abrogating MEKK3 interaction

    PMID:27027284

    Open questions at the time
    • Which KLF2 target genes mediate cavernoma formation not identified
    • Relative contribution of KLF2 vs. KLF4 to lesion formation not separated
  12. 2016 High

    KDM3A-mediated H3K9 demethylation was identified as an epigenetic mechanism maintaining KLF2 expression, and a KLF2–IRF4 positive autoregulatory loop was defined in multiple myeloma, linking KLF2 to B cell malignancy adhesion and homing.

    Evidence ChIP for H3K9me2 at KLF2 locus after KDM3A knockdown; KLF2 ChIP at IRF4 promoter; in vivo myeloma homing assays

    PMID:26728187

    Open questions at the time
    • Whether KDM3A–KLF2 axis operates in normal B cells unknown
    • Kinase responsible for KLF2 phosphorylation in myeloma context not identified
  13. 2016 High

    KLF2 was shown to control NK cell and Treg homeostasis by regulating homing receptors that enable access to survival cytokine niches, unifying KLF2's lymphocyte trafficking function across multiple immune lineages.

    Evidence Conditional KLF2 KO in NK cells and Tregs; apoptosis from IL-15 starvation in NK cells; autoimmunity from failed Treg SLO migration

    PMID:27114551 PMID:27462110

    Open questions at the time
    • Identity of all homing receptors directly regulated by KLF2 in NK and Treg cells incomplete
    • Whether KLF2 controls innate lymphoid cell trafficking unknown
  14. 2017 High

    Endothelial KLF2 was found to negatively regulate liver regeneration through activin A secretion, and combined EC-specific KLF2/KLF4 deletion caused acute vascular catastrophe, establishing the non-redundant yet overlapping requirement for both factors in adult vascular integrity.

    Evidence EC-specific KLF2 KO in CCl4 liver injury; inducible EC-specific double KLF2/KLF4 KO with myocardial infarction and stroke phenotype

    PMID:28239661 PMID:28348240

    Open questions at the time
    • Genome-wide identification of KLF2-unique vs. KLF2/4-shared target genes in endothelium lacking
    • Whether activin A is a direct KLF2 transcriptional target not confirmed by ChIP
  15. 2022 High

    Identification of PIEZO1 as the mechanosensor upstream of KLF2, signaling through CaMKII–MEKK3–ERK5, completed the mechanotransduction pathway from shear force to KLF2 transcription.

    Evidence Endothelial-specific Piezo1 KO reduced KLF2/4 in vivo; co-IP showed CaMKII–MEKK3 interaction; PIEZO1 agonist/inhibitor confirmed calcium-dependent activation

    PMID:35883633

    Open questions at the time
    • How HEG1/KRIT1 integrates with PIEZO1 signaling at the membrane not resolved
    • Whether other mechanosensors contribute redundantly to KLF2 induction in specific vascular beds unknown
  16. 2021 Medium

    SPHK2-mediated phosphorylation of KLF2 protein was shown to trigger its ubiquitin-proteasomal degradation, and METTL3-mediated m6A modification of KLF2 mRNA was found to regulate its expression, revealing post-translational and epitranscriptomic layers of KLF2 regulation.

    Evidence Phosphorylation/ubiquitination assays in gastric cancer cells; MeRIP-qPCR and m6A site mutations in endothelial cells with Mettl3 KO mice

    PMID:33758320 PMID:38741032

    Open questions at the time
    • Specific phosphorylation site(s) on KLF2 not mapped
    • E3 ubiquitin ligase responsible for KLF2 degradation not identified
    • Whether SPHK2-mediated degradation operates in endothelial or immune contexts unknown
  17. 2025 High

    KLF2 was established as a CD8 T cell lineage fidelity factor that suppresses the exhaustion program by repressing TOX and enabling TBET-driven effector differentiation, extending KLF2's immune role from quiescence/trafficking to active lineage fate control.

    Evidence In vivo CRISPR-Cas9 perturbation sequencing in LCMV infection, conditional KLF2 KO, single-cell multi-omics

    PMID:39946463

    Open questions at the time
    • Whether KLF2 directly binds TOX regulatory elements not shown
    • Role of KLF2 in chronic infection and tumor exhaustion programs not fully tested in therapeutic settings

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for KLF2's selective promoter recognition, the identity of the E3 ligase mediating KLF2 ubiquitination, the full partition of KLF2- versus KLF4-specific target genes in endothelium, and whether KLF2's CD8 lineage-fidelity function can be therapeutically leveraged in cancer immunotherapy.
  • No crystal structure of KLF2 zinc fingers bound to DNA
  • E3 ubiquitin ligase unknown
  • Genome-wide KLF2 vs. KLF4 ChIP-seq comparison in matched endothelial conditions absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 14 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 7
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 7 R-HSA-109582 Hemostasis 3 R-HSA-1643685 Disease 3
Partners
ERK5HEG1IRF4KDM3AMEKK3NUCLEOLINPCAFSPHK2

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 KLF2 (LKLF) is a Krüppel-like zinc finger transcription factor required to program the quiescent state of single-positive T cells; KLF2-deficient T cells show spontaneously activated phenotype and die from Fas ligand-induced apoptosis in peripheral lymphoid organs. Gene targeting (knockout mouse), flow cytometry, loss-of-function with defined phenotypic readout Science High 9302292
1997 KLF2 (LKLF) is expressed in vascular endothelial cells and is required for tunica media formation and blood vessel stabilization; KLF2-null embryos die from hemorrhaging with thin tunica media, reduced pericytes, and decreased extracellular matrix deposition. Homologous recombination knockout in mice, in situ hybridization, immunohistochemistry, electron microscopy Genes & development High 9367982
2001 KLF2 (LKLF) is sufficient to program T cell quiescence via a c-Myc-dependent pathway; forced KLF2 expression decreases c-Myc expression, and many KLF2 effects are mimicked by dominant-negative MadMyc or rescued by c-Myc overexpression. Forced expression in Jurkat T cells, gene targeting knockout, dominant-negative/rescue experiments Nature immunology High 11477405
2004 KLF2 inhibits T leukemia cell growth by upregulating the CDK inhibitor p21WAF1/CIP1; the KLF2-responsive element in the p21 promoter is an Sp1-3 binding site, not the CACCC motif, and both activation and inhibitory domains of KLF2 are required. Tetracycline-inducible expression, luciferase reporter assay, promoter deletion analysis, 3H-thymidine incorporation Oncogene High 15361832
2005 KLF2 transcriptionally regulates endothelial thrombotic function by inducing thrombomodulin and eNOS, reducing PAI-1, and inhibiting cytokine-induced tissue factor expression; KLF2 overexpression increases blood clotting time while siRNA knockdown reduces it. Adenoviral overexpression, siRNA knockdown, in vitro clotting assays, gene expression analysis Circulation research High 15718498
2005 Statins induce endothelial KLF2 expression via inhibition of geranylgeranylation (not farnesylation); this KLF2 induction is necessary for statin-mediated regulation of atheroprotective endothelial genes. siRNA knockdown, pharmacological inhibitors (GGTI-298, mevalonate), mRNA expression analysis The Journal of biological chemistry High 15878865
2005 KLF2 is expressed in endothelial cells in regions of high shear stress in vivo and is induced by steady and pulsatile laminar flow but not cyclic stretch; KLF2 repression by siRNA suppresses flow-induced regulation of endothelin-1, adrenomedullin, and eNOS. In situ hybridization, laser microdissection, carotid artery collar model, siRNA knockdown, flow chamber experiments The American journal of pathology High 16049344
2005 KLF2 is essential for primitive erythropoiesis and positively regulates embryonic beta-like globin genes (murine Ey, βh1 and human ε-globin) but not adult beta-globin, demonstrating developmental-stage-specific transcriptional regulation. KLF2 knockout mouse model, transgenic human globin locus mice, gene expression analysis Blood High 15947087
2006 KLF2 inhibits proinflammatory activation of monocytes by inhibiting the transcriptional activity of both NF-κB and AP-1, in part through recruitment of transcriptional coactivator p300/CBP-associated factor (PCAF). Adenoviral overexpression, siRNA knockdown, transcription factor activity assays, co-immunoprecipitation, in vivo carrageenan edema model Proceedings of the National Academy of Sciences of the United States of America High 16617118
2006 KLF2 promoter induction by fluid shear stress requires nucleolin, which binds a palindromic response region in the KLF2 promoter in a PI3K-dependent manner; shear stress induces nucleolin interaction with the p85 regulatory subunit of PI3K. DNA affinity chromatography, mass spectrometry, EMSA, ChIP, siRNA, co-immunoprecipitation, PI3K inhibitor The Journal of biological chemistry High 16571724
2007 KLF2 and shear stress suppress constitutive proinflammatory endothelial gene expression by inhibiting nuclear binding activity of ATF2; KLF2 knockdown prevents shear-mediated reduction of ATF2 activity. Genome-wide expression profiling, siRNA knockdown, EMSA for ATF2 binding, promoter analysis, immunostaining in atherosclerotic tissue Blood High 17244683
2008 KLF2 maintains naive T cell migration patterns by transcriptionally repressing inflammatory chemokine receptors including CCR3 and CCR5; lineage-specific KLF2 deletion results in altered chemokine receptor expression and redistribution of naive T cells to nonlymphoid tissues. Conditional (lineage-specific) KLF2 knockout mice, flow cytometry, gene expression analysis Nature immunology High 18246069
2011 KLF2 and KLF1 directly bind the promoters of human ε- and γ-globin genes, murine Ey- and βh1-globin genes, and the β-globin locus control region to positively regulate embryonic and fetal beta-globin gene expression; KLF2 effect is at least partly erythroid cell-autonomous. ChIP assays in mouse embryonic blood cells, conditional KO mice, dual transgenic (human globin locus + KLF KO) mouse model, histone modification analysis The Journal of biological chemistry High 21610079
2013 KLF2 expression in CD8 T cells is downregulated by antigen receptor engagement in a graded manner determined by TCR ligand affinity and integrated PKB/ERK1/2 activation; KLF2 negatively controls CXCR3 expression and maximum clonal expansion in an analogue (dose-dependent) fashion. T cell stimulation assays, pharmacological inhibitors, retroviral overexpression/knockdown, flow cytometry, CXCL10 chemotaxis assay PloS one Medium 24155966
2014 Laminar shear stress inhibits endothelial cell glycolysis via KLF2-mediated transcriptional repression of PFKFB3; PFKFB3 knockdown reduces glycolysis and partially reverses KLF2-mediated reduction in angiogenic sprouting. KLF2 endothelial-specific knockout mice, siRNA, RNA sequencing, Seahorse flux analysis, glucose uptake measurements, promoter activity assay Arteriosclerosis, thrombosis, and vascular biology High 25359860
2014 Endothelial KLF2 induces a vasoprotective transcriptional program in liver sinusoidal endothelial cells (LSECs) via statins; KLF2-overexpressing LSECs deactivate hepatic stellate cells through a KLF2-nitric oxide-guanylate cyclase-mediated paracrine mechanism. siRNA knockdown, adenoviral overexpression, coculture experiments, shear stress application, gene expression analysis Journal of hepatology High 22989565
2014 KLF2 overexpression in cirrhotic rats activates the KLF2-Nrf2 pathway to deactivate hepatic stellate cells, reduce liver fibrosis, and improve portal hypertension; KLF2 activates Nrf2 which reduces α-SMA, procollagen I, and oxidative stress in HSCs. Adenoviral KLF2 overexpression in vivo, simvastatin treatment, inhibitor studies, liver hemodynamic measurements Gut Medium 25500203
2014 KLF2 inhibits endothelial cell migration via KLF2-dependent downregulation of PAK1 (p21-activated kinase 1) downstream of the MEK5/Erk5 pathway; KLF2 siRNA but not KLF4 siRNA prevented Erk5-mediated PAK1 mRNA inhibition, and PAK1 re-expression restored migration. Constitutively active MEK5 expression, siRNA knockdown of KLF2/KLF4, PAK1 re-expression rescue, migration assays Cardiovascular research High 25388666
2015 KLF2 restrains CD4+ T follicular helper (Tfh) cell differentiation through two mechanisms: (1) promoting S1PR1 expression to control T cell localization, and (2) inducing Blimp-1 expression to repress Bcl-6, thereby impeding Tfh differentiation; KLF2 also promotes T-bet and GATA3 expression to enhance Th1 differentiation. Inducible KLF2 deficiency, KLF2 overexpression, flow cytometry, gene expression analysis in activated CD4+ T cells Immunity High 25692701
2015 KLF2 and shear stress induce expression of miR-30-5p family members in endothelial cells; miR-30 targets angiopoietin 2 (Ang2) to reduce basal and TNF-α-induced expression of inflammatory adhesion molecules E-selectin, ICAM1, and VCAM1. KLF2 overexpression, shear stress in vitro and in vivo, LNA antimiR inhibition, luciferase target validation, rescue with exogenous Ang2 Journal of molecular and cellular cardiology Medium 26456066
2015 In zebrafish, loss of CCM proteins upregulates klf2 mRNA via β1 integrin signaling (in the absence of blood flow), driving EGFL7-dependent angiogenesis; downregulation of β1 integrin rescues ccm mutant cardiovascular malformations. siRNA knockdown in HUVECs, zebrafish genetic models, epistasis by β1 integrin downregulation rescue Developmental cell High 25625207
2016 Cerebral cavernous malformations (CCMs) arise from endothelial gain of MEKK3-KLF2/4 signaling; loss of CCM complex (KRIT1/CCM2/PDCD10) increases MEKK3 activity, elevating KLF2/4 and Rho/ADAMTS activity; endothelial-specific loss of Klf2 or Klf4 markedly prevents CCM lesion formation and rescues lethality. Neonatal mouse CCM model, endothelial-specific conditional knockout of Mekk3/Klf2/Klf4, gene expression analysis in CCM lesions, disease-causing human CCM2 mutation abrogating MEKK3 interaction Nature High 27027284
2016 KDM3A (H3K9 demethylase) maintains KLF2 expression in multiple myeloma cells through H3K9 demethylation at the KLF2 locus; KLF2 directly activates IRF4, which reciprocally upregulates KLF2 forming a positive autoregulatory circuit; KLF2 regulates MM cell adhesion to bone marrow stromal cells and homing via ITGB7. siRNA/shRNA knockdown, ChIP for H3K9 demethylation, in vitro and in vivo MM models, bone marrow homing assays Nature communications High 26728187
2016 KLF2 controls homeostatic NK cell proliferation and survival by regulating homeostatic homing receptors (but not inflammatory receptors), allowing mature NK cells to access IL-15-rich microenvironments; KLF2-deficient NK cells undergo apoptosis due to IL-15 starvation. Gene-targeted mouse models (Klf2 excision), ex vivo proliferation assays, homing receptor expression analysis, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 27114551
2016 KLF2 controls naive Treg migration to secondary lymphoid organs via regulation of homeostatic and inflammatory homing receptors; KLF2-deficient Tregs fail to migrate efficiently to SLOs, initiating autoimmunity, and stabilizing KLF2 in Tregs diverts them to SLOs to enhance peripheral tolerance. Conditional Treg-specific KLF2 KO mice, adoptive transfer experiments, homing receptor analysis, autoimmunity disease models Proceedings of the National Academy of Sciences of the United States of America High 27462110
2017 Endothelial KLF2 negatively regulates liver regeneration by inducing activin A expression and secretion from endothelial cells, which inhibits hepatocyte proliferation; EC-specific KLF2 deletion reduces liver damage and augments hepatocyte proliferation after CCl4 injury. EC-specific KLF2 knockout mice, KLF2 transgenic overexpression, activin A measurement in vitro and in vivo, CCl4 liver injury model Proceedings of the National Academy of Sciences of the United States of America High 28348240
2017 Inducible endothelial-specific deletion of Klf2 and Klf4 together (EC-DKO) causes acute death from myocardial infarction, heart failure, and stroke with profound dysregulation of coagulation, establishing an absolute requirement for KLF2/4 for vascular integrity in the adult animal. Inducible endothelial-specific double knockout mice (Klf2/Klf4), physiological phenotyping, coagulation assays JCI insight High 28239661
2014 KLF2 mutations (frameshift, nonsense, and missense clustering in C-terminal zinc finger domains) found in splenic marginal zone lymphoma inactivate the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR, and TNFR signaling. Whole exome sequencing, functional NF-κB suppression assays with mutant KLF2 constructs Leukemia Medium 25428260
2003 TRAF2 regulates KLF2 expression through the p38 MAP kinase pathway; ectopic KLF2 expression in TRAF2-null cells protects against TNF-induced apoptosis, establishing KLF2 as a downstream anti-apoptotic effector of TRAF2. Microarray comparison of TRAF2-/- vs wild-type cells, ectopic KLF2 expression rescue, pharmacological p38 pathway analysis Molecular and cellular biology Medium 12897154
2015 Shear stress activates P2X4 receptor (via ATP release) to regulate endothelial KLF2 expression; P2X4 mediates shear stress-induced phosphorylation of ERK5, a known upstream regulator of KLF2; a loss-of-function P2X4 mutant (Tyr315>Cys) blocks ATP-induced KLF2 expression. Apyrase treatment, P2X4 siRNA, P2X4 antagonist, mutant P2X4 transfection, ERK5 phosphorylation measurement in HUVECs Purinergic signalling Medium 25563726
2019 AMPK activation by metformin phosphorylates HDAC5 at serine 498, leading to KLF2 upregulation and suppression of VCAM1 in endothelial cells exposed to LPS/TNFα; this AMPK-HDAC5-KLF2 axis is confirmed in vivo in endotoxic mice. HDAC5 phosphorylation assays, KLF2 expression analysis, siRNA knockdown, in vivo LPS endotoxemia model Biochimica et biophysica acta. Molecular basis of disease Medium 31002870
2022 PIEZO1 mechanosensitive channel senses shear force and activates KLF2/4 expression via a CaMKII-MEKK3-ERK5 signaling cascade; PIEZO1 activation causes calcium influx, activating CaMKII which interacts with and activates MEKK3; endothelial-specific Piezo1 deletion reduces KLF2/4 expression in vivo. Endothelial-specific Piezo1 knockout mice, PIEZO1 agonist/inhibitor, calcium imaging, co-immunoprecipitation of CaMKII-MEKK3, gene expression analysis Cells High 35883633
2022 KLF2 in neutrophils regulates a KLF2/NETosis pathway; chronic angiotensin II infusion activates neutrophil KLF2 downregulation leading to NETosis, sporadic thrombosis in myocardial vessels, and heart failure; KLF2 regulates neutrophil activation partly through crosstalk with HIF1 signaling. Mouse model of angiotensin II-induced cardiac dysfunction, neutrophil-specific intervention, NETosis and thrombosis assays, HIF1 pathway analysis The Journal of clinical investigation Medium 34793333
2021 SPHK2 promotes phosphorylation of KLF2 protein, which triggers ubiquitination and degradation of KLF2 in gastric cancer cells; METTL3 promotes SPHK2 translation via m6A-YTHDF1-dependent manner to suppress KLF2. Phosphorylation and ubiquitination assays, MeRIP, western blot, gain/loss-of-function in gastric cancer cells Oncogene Medium 33758320
2020 KLF2 regulates osteoblast differentiation of dental pulp-derived stem cells by modulating autophagy; KLF2 directly binds to the ATG7 promoter (confirmed by ChIP with active histone marks H3K27Ac and H3K4me3) and induces mitophagy and metabolic shift from oxidative phosphorylation to glycolysis. Gain/loss-of-function of KLF2, ChIP analysis, autophagy knockdown (ATG7/BECN1 siRNA), Seahorse flux analysis, mitochondrial ROS/potential measurements Redox biology Medium 32777717
2014 IKKβ inhibition increases KLF2 expression and KLF2 binding to the thrombomodulin (TM) promoter to upregulate TM expression; KLF2 knockdown completely abrogates IKKβ inhibition-mediated TM upregulation. IKKβ chemical inhibitors/siRNA/shRNA, KLF2 ChIP on TM promoter, luciferase reporter, KLF2 siRNA rescue, flow cytometry Journal of thrombosis and haemostasis Medium 25039491
2023 HEG1 mediates flow-induced KLF2/4 expression by regulating its intracellular binding partner KRIT1 and the MEKK3-MEK5-ERK5-MEF2 pathway in endothelial cells; HEG1 knockdown prevents s-flow-induced KLF2/4 expression; endothelial HEG1 KO mice develop advanced atherosclerosis. siRNA knockdown, inducible endothelial-specific HEG1 KO mice, flow-induced gene expression, pathway analysis in HAECs Circulation High 38099436
2020 KLF2-induced exosomal microRNAs miR-181a-5p and miR-324-5p attenuate pulmonary vascular remodeling by targeting Notch4 and ETS1; KLF2 signaling is reduced in PAH and a disease-causing missense KLF2 mutation (p.H288Y) reduces this microRNA-mediated signaling. Exosome isolation, microRNA profiling, target gene validation, patient-derived cell functional assays, PAH mouse model therapeutic supplementation Nature communications Medium 32132543
2014 KLF2 inhibits TGF-β signaling in hepatocellular carcinoma cells by inhibiting the transcriptional activity of Smad2/3 and Smad4, creating a negative feedback loop that attenuates TGF-β-induced MMP2 upregulation and cancer cell motility. Luciferase reporter assay, stable KLF2 overexpression, TGF-β stimulation, wound-healing and transwell assays Acta biochimica et biophysica Sinica Medium 32318691
2019 The IRF2BP2-KLF2 axis regulates bone homeostasis: IRF2BP2 upregulates KLF2, which inhibits osteoclast differentiation (downregulating c-Fos, NFATc1, TRAP) and enhances osteoblast differentiation (upregulating Runx2, ALP, BSP); KLF2 knockdown reverses IRF2BP2 effects. Overexpression and siRNA knockdown of KLF2 and IRF2BP2 in osteoclast precursors and osteoblasts, differentiation marker analysis BMB reports Medium 31186082
2024 METTL3-mediated m6A modification of KLF2 mRNA is required for KLF2 expression and protection against endothelial-to-mesenchymal transition (EndMT); mutations in the m6A site of KLF2 mRNA compromise KLF2 expression, and KLF2 modulates SM22 expression through direct binding to its promoter. MeRIP-qPCR, mRNA stability assay, m6A site mutations, dual-luciferase assays, endothelial-specific Mettl3 KO mice, KLF2 overexpression Cellular & molecular biology letters Medium 38741032
2025 KLF2 is required in CD8 T cells to maintain effector lineage fidelity during acute infection by suppressing the exhaustion-promoting TF TOX and enabling TBET to drive effector differentiation; KLF2 knockout leads to aberrant differentiation toward exhausted-like CD8 T cells and is necessary to maintain a polyfunctional tumor-specific progenitor state. In vivo CRISPR-Cas9 perturbation sequencing, LCMV infection model, KLF2 conditional KO, single-cell chromatin + transcriptome profiling Science High 39946463

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science (New York, N.Y.) 350 9302292
2005 Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circulation research 322 15718498
1997 The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes & development 306 9367982
2005 Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. The American journal of pathology 290 16049344
2016 Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature 254 27027284
2014 Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arteriosclerosis, thrombosis, and vascular biology 246 25359860
2006 Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proceedings of the National Academy of Sciences of the United States of America 245 16617118
2005 Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. The Journal of biological chemistry 204 15878865
2017 KLF2 and KLF4 control endothelial identity and vascular integrity. JCI insight 194 28239661
2012 The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. Journal of hepatology 193 22989565
2001 Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway. Nature immunology 182 11477405
2014 KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 170 25500203
2015 The transcription factor KLF2 restrains CD4⁺ T follicular helper cell differentiation. Immunity 162 25692701
2008 Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nature immunology 162 18246069
2017 KLF2 in Regulation of NF-κB-Mediated Immune Cell Function and Inflammation. International journal of molecular sciences 139 29125549
2014 KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype. Leukemia 137 25428260
1998 Loss of LKLF function results in embryonic lethality in mice. Transgenic research 123 9859212
2015 Regulation of β1 integrin-Klf2-mediated angiogenesis by CCM proteins. Developmental cell 122 25625207
2007 Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2. Blood 122 17244683
2004 KLF2 inhibits Jurkat T leukemia cell growth via upregulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1. Oncogene 104 15361832
2014 The role of the transcription factor KLF2 in vascular development and disease. Progress in molecular biology and translational science 95 24751430
2016 The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nature communications 91 26728187
2007 The role of shear stress on ET-1, KLF2, and NOS-3 expression in the developing cardiovascular system of chicken embryos in a venous ligation model. Physiology (Bethesda, Md.) 90 18073411
2022 KLF2 regulates neutrophil activation and thrombosis in cardiac hypertrophy and heart failure progression. The Journal of clinical investigation 83 34793333
2009 N-Myc regulates expression of pluripotency genes in neuroblastoma including lif, klf2, klf4, and lin28b. PloS one 78 19495417
2005 KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo. Blood 78 15947087
2020 Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension. Nature communications 76 32132543
2015 Klf2 and Tfcp2l1, Two Wnt/β-Catenin Targets, Act Synergistically to Induce and Maintain Naive Pluripotency. Stem cell reports 76 26321140
2021 METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2. Oncogene 75 33758320
2022 The Role of KLF2 in the Regulation of Atherosclerosis Development and Potential Use of KLF2-Targeted Therapy. Biomedicines 63 35203463
2018 LncRNA GAS5 Overexpression Reverses LPS-Induced Inflammatory Injury and Apoptosis Through Up-Regulating KLF2 Expression in ATDC5 Chondrocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 63 29448248
2020 KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism. Redox biology 62 32777717
2020 BDNF corrects NLRP3 inflammasome-induced pyroptosis and glucose metabolism reprogramming through KLF2/HK1 pathway in vascular endothelial cells. Cellular signalling 61 33253911
2020 Transcription Factor KLF2 and Its Role in the Regulation of Inflammatory Processes. Biochemistry. Biokhimiia 60 32079517
2023 FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells. Nature immunology 56 38012417
2016 Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival. Proceedings of the National Academy of Sciences of the United States of America 54 27114551
2018 LncRNA SNHG3 enhances the malignant progress of glioma through silencing KLF2 and p21. Bioscience reports 53 30042166
2019 Metformin ameliorates endotoxemia-induced endothelial pro-inflammatory responses via AMPK-dependent mediation of HDAC5 and KLF2. Biochimica et biophysica acta. Molecular basis of disease 51 31002870
2015 MicroRNA-30 mediates anti-inflammatory effects of shear stress and KLF2 via repression of angiopoietin 2. Journal of molecular and cellular cardiology 51 26456066
2014 Erk5 inhibits endothelial migration via KLF2-dependent down-regulation of PAK1. Cardiovascular research 48 25388666
2006 Up-regulation of the KLF2 transcription factor by fluid shear stress requires nucleolin. The Journal of biological chemistry 48 16571724
2005 Identification of LKLF-regulated genes in quiescent CD4+ T lymphocytes. Molecular immunology 48 15607822
2021 The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction. Signal transduction and targeted therapy 47 34253708
2020 Epigenetic silencing of KLF2 by long non-coding RNA SNHG1 inhibits periodontal ligament stem cell osteogenesis differentiation. Stem cell research & therapy 47 33028420
2019 The GLP-1 receptor agonist liraglutide protects against oxidized LDL-induced endothelial inflammation and dysfunction via KLF2. IUBMB life 46 30969479
2025 KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection. Science (New York, N.Y.) 45 39946463
2019 KLF2 regulates eNOS uncoupling via Nrf2/HO-1 in endothelial cells under hypoxia and reoxygenation. Chemico-biological interactions 45 30928399
2023 KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway. The journal of pathology. Clinical research 44 37147883
2022 Ferutinin induces osteoblast differentiation of DPSCs via induction of KLF2 and autophagy/mitophagy. Cell death & disease 44 35552354
2021 Krüppel-like Factor 2 (KLF2) in Immune Cell Migration. Vaccines 43 34696279
2023 HEG1 Protects Against Atherosclerosis by Regulating Stable Flow-Induced KLF2/4 Expression in Endothelial Cells. Circulation 42 38099436
2022 Mechanosensitive Channel PIEZO1 Senses Shear Force to Induce KLF2/4 Expression via CaMKII/MEKK3/ERK5 Axis in Endothelial Cells. Cells 42 35883633
2022 LncRNA Airn maintains LSEC differentiation to alleviate liver fibrosis via the KLF2-eNOS-sGC pathway. BMC medicine 41 36171606
2016 A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability. Circulation research 41 27756792
2015 Shear stress modulates endothelial KLF2 through activation of P2X4. Purinergic signalling 40 25563726
2013 The impact of KLF2 modulation on the transcriptional program and function of CD8 T cells. PloS one 40 24155966
2021 Calycosin ameliorates atherosclerosis by enhancing autophagy via regulating the interaction between KLF2 and MLKL in apolipoprotein E gene-deleted mice. British journal of pharmacology 39 34713437
2020 Primary cilia mediate Klf2-dependant Notch activation in regenerating heart. Protein & cell 39 32249387
2019 Knockdown of LncRNA GHET1 suppresses prostate cancer cell proliferation by inhibiting HIF-1α/Notch-1 signaling pathway via KLF2. BioFactors (Oxford, England) 39 30609158
2011 Transcription factors KLF1 and KLF2 positively regulate embryonic and fetal beta-globin genes through direct promoter binding. The Journal of biological chemistry 39 21610079
2018 Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2. Molecular immunology 38 30029058
2017 Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A. Proceedings of the National Academy of Sciences of the United States of America 36 28348240
2016 Peripheral tolerance can be modified by altering KLF2-regulated Treg migration. Proceedings of the National Academy of Sciences of the United States of America 33 27462110
2021 Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish. Cell reports 32 34610316
2020 KLF2 regulates neutrophil migration by modulating CXCR1 and CXCR2 in asthma. Biochimica et biophysica acta. Molecular basis of disease 31 32800946
2017 KLF2 inhibits cell growth via regulating HIF-1α/Notch-1 signal pathway in human colorectal cancer HCT116 cells. Oncology reports 31 28628187
2020 KLF2 inhibits TGF-β-mediated cancer cell motility in hepatocellular carcinoma. Acta biochimica et biophysica Sinica 29 32318691
2019 Klf4, Klf2, and Zfp148 activate autophagy-related genes in smooth muscle cells during aortic aneurysm formation. Physiological reports 29 31025534
2018 KLF2 Inhibits the Migration and Invasion of Prostate Cancer Cells by Downregulating MMP2. American journal of men's health 29 30520325
2017 KLF2 attenuates bleomycin-induced pulmonary fibrosis and inflammation with regulation of AP-1. Biochemical and biophysical research communications 29 29079188
2023 FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses. International journal of biological sciences 28 37705747
2021 Metformin attenuates atherosclerosis and plaque vulnerability by upregulating KLF2-mediated autophagy in apoE-/- mice. Biochemical and biophysical research communications 28 33915432
2019 The IRF2BP2-KLF2 axis regulates osteoclast and osteoblast differentiation. BMB reports 28 31186082
2017 KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure. The Journal of physiology 28 29023738
2023 Induction of KLF2 by Exercise Activates eNOS to Improve Vasodilatation in Diabetic Mice. Diabetes 27 37347764
2021 Chrysin boosts KLF2 expression through suppression of endothelial cell-derived exosomal microRNA-92a in the model of atheroprotection. European journal of nutrition 27 34041583
2019 KLF2 protects BV2 microglial cells against oxygen and glucose deprivation injury by modulating BDNF/TrkB pathway. Gene 27 31821872
2018 MiRNA-92a protects pancreatic B-cell function by targeting KLF2 in diabetes mellitus. Biochemical and biophysical research communications 27 29660330
2015 KLF2 is downregulated in pancreatic ductal adenocarcinoma and inhibits the growth and migration of cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 27 26449825
2015 Disturbed shear stress reduces Klf2 expression in arterial-venous fistulae in vivo. Physiological reports 26 25780089
2003 TRAF2 exerts its antiapoptotic effect by regulating the expression of Krüppel-like factor LKLF. Molecular and cellular biology 26 12897154
2016 Scutellarin attenuates vasospasm through the Erk5-KLF2-eNOS pathway after subarachnoid hemorrhage in rats. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 25 27742373
2024 N6-methyladenosine modification of KLF2 may contribute to endothelial-to-mesenchymal transition in pulmonary hypertension. Cellular & molecular biology letters 24 38741032
2020 The EGFL7-ITGB3-KLF2 axis enhances survival of multiple myeloma in preclinical models. Blood advances 23 32191808
2020 DT-13 induced apoptosis and promoted differentiation of acute myeloid leukemia cells by activating AMPK-KLF2 pathway. Pharmacological research 23 32416217
2020 Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway. European journal of pharmacology 23 32739175
2014 Klf2 contributes to the stemness and self-renewal of human bone marrow stromal cells. Cytotechnology 23 25550041
2011 Krüppel-like factors KLF2 and 6 and Ki-67 are direct targets of zoledronic acid in MCF-7 cells. Bone 22 22166808
2017 Vascular protective effects of KLF2 on Aβ-induced toxicity: Implications for Alzheimer's disease. Brain research 21 28130053
2014 IKKβ regulates endothelial thrombomodulin in a Klf2-dependent manner. Journal of thrombosis and haemostasis : JTH 21 25039491
2024 Engineering microvascular networks using a KLF2 reporter to probe flow-dependent endothelial cell function. Biomaterials 20 38971122
2023 Down-regulation of KLF2 in lung fibroblasts is linked with COVID-19 immunofibrosis and restored by combined inhibition of NETs, JAK-1/2 and IL-6 signaling. Clinical immunology (Orlando, Fla.) 20 36693535
2021 Azilsartan ameliorates ox-LDL-induced endothelial dysfunction via promoting the expression of KLF2. Aging 20 33946046
2015 Expression of Nitric Oxide-Transporting Aquaporin-1 Is Controlled by KLF2 and Marks Non-Activated Endothelium In Vivo. PloS one 20 26717516
2014 Krüppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation. Haematologica 20 25150253
2013 Aβ(1-42) disrupts the expression and function of KLF2 in Alzheimer's disease mediated by p53. Biochemical and biophysical research communications 20 23313511
2017 AMPK-KLF2 signaling pathway mediates the proangiogenic effect of erythropoietin in endothelial colony-forming cells. American journal of physiology. Cell physiology 19 28978525
2014 Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin. PloS one 19 24801208
2024 CircFndc3b Mediates Exercise-Induced Neuroprotection by Mitigating Microglial/Macrophage Pyroptosis via the ENO1/KLF2 Axis in Stroke Mice. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 39467260
2020 Long non-coding RNA AFAP1-AS1 promotes proliferation and migration of gastric cancer by downregulating KLF2. European review for medical and pharmacological sciences 18 32016968