# KLF2

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Protein-coding gene in the species Homo sapiens

KLF2 Identifiers Aliases KLF2, LKLF, Kruppel-like factor 2, Kruppel like factor 2 External IDs OMIM: 602016; MGI: 1342772; HomoloGene: 133978; GeneCards: KLF2; OMA:KLF2 - orthologs Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.11 Start 16,324,826 bp[1] End 16,328,685 bp[1] Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 B3.3 Start 73,072,877 bp[2] End 73,075,500 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in urethra vena cava trachea saphenous vein gastric mucosa granulocyte nipple pericardium cardia pylorus Top expressed in granulocyte right lung ankle joint right lung lobe mesenteric lymph nodes spleen subcutaneous adipose tissue ankle endocardial cushion left lung More reference expression data BioGPS More reference expression data Gene ontology Molecular function sequence-specific DNA binding DNA-binding transcription factor activity metal ion binding protein binding nucleic acid binding DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component nucleus Biological process cellular response to peptide regulation of transcription, DNA-templated regulation of gene expression, epigenetic multicellular organism growth cellular response to laminar fluid shear stress positive regulation of transcription from RNA polymerase II promoter in response to stress positive regulation of nitric oxide biosynthetic process negative regulation of interleukin-6 production cellular response to tumor necrosis factor cellular response to organic cyclic compound response to laminar fluid shear stress in utero embryonic development transcription, DNA-templated positive regulation of transcription, DNA-templated erythrocyte homeostasis type I pneumocyte differentiation cellular response to interleukin-1 cell morphogenesis cellular response to cycloheximide cellular response to hydrogen peroxide erythrocyte maturation positive regulation of transcription by RNA polymerase II cellular response to fluid shear stress negative regulation of transcription by RNA polymerase II cellular stress response to acid chemical negative regulation of sprouting angiogenesis regulation of transcription by RNA polymerase II Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 10365 16598 Ensembl ENSG00000127528 ENSMUSG00000055148 UniProt Q9Y5W3 Q60843 RefSeq (mRNA) NM_016270 NM_006075 NM_016198 NM_008452 RefSeq (protein) NP_057354 NP_032478 Location (UCSC) Chr 19: 16.32 – 16.33 Mb Chr 8: 73.07 – 73.08 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**Krüppel-like Factor 2 (KLF2)**, also known as **lung Krüppel-like Factor (LKLF)**, is a [protein](/source/Protein) that in humans is encoded by the *KLF2* [gene](/source/Gene) on [chromosome 19](/source/Chromosome_19).[5][6] It is in the [Krüppel-like factor](/source/Kruppel-like_factors) family of [zinc finger transcription factors](/source/Zinc_finger_transcription_factors), and it has been implicated in a variety of biochemical processes in the human body, including [lung development](/source/Development_of_human_lung), embryonic [erythropoiesis](/source/Erythropoiesis), [epithelial](/source/Epithelial) integrity, [T-cell](/source/T-cell) viability, and [adipogenesis](/source/Adipogenesis).[7]

## Discovery

Erythroid Krüppel-like Factor ([EKLF](/source/EKLF) or KLF1) was the first Krüppel-like Factor discovered. It is vital for embryonic erythropoiesis in promoting the switch from fetal [hemoglobin](/source/Hemoglobin) ([Hemoglobin F](/source/Hemoglobin_F)) to adult hemoglobin (Hemoglobin A) [gene expression](/source/Gene_expression) by binding to highly conserved CACCC domains.[8] *EKLF* [ablation](/source/Gene_knockout) in mouse embryos produces a lethal [anemic](/source/Anemic) [phenotype](/source/Phenotype), causing death by embryonic day 14, and natural [mutations](/source/Mutations) lead to [β+ thalassemia](/source/Thalassemia) in humans.[9] However, expression of [embryonic hemoglobin](/source/Embryonic_hemoglobin) and fetal hemoglobin genes is normal in *EKLF*-deficient mice, and since all genes on the [human β-globin locus](/source/Human_%CE%B2-globin_locus) exhibit the CACCC elements, researchers began searching for other Krüppel-like factors.[10]

KLF2, initially called lung Krüppel-like Factor due to its high expression in the adult mouse lung, was first isolated in 1995 by using the [zinc finger](/source/Zinc_finger) domain of EKLF as a [hybridization probe](/source/Hybridization_probe).[11] By [transactivation](/source/Transactivation) [assay](/source/Assay) in mouse [fibroblasts](/source/Fibroblasts), KLF2 was also noticed to bind to the [β-globin](/source/Beta_globin) [gene promoter](/source/Gene_promoter) containing the CACCC sequence shown to be the binding site for EKLF, confirming KLF2 as a member of the Krüppel-like Factor family.[11] Since then, many other KLF proteins have been discovered.

## Structure

The main feature of the KLF family is the presence of three highly conserved [Cysteine](/source/Cysteine)2/[Histidine](/source/Histidine)2 zinc fingers of either 21 or 23 [amino acid residues](/source/Amino_acid) in length, located at the [C-terminus](/source/C-terminus) of the protein. These amino acid sequences each [chelate](/source/Chelate) a single [zinc ion](/source/Zinc#Other_proteins), [coordinated](/source/Coordination_complex) between the two cysteine and two histidine residues. These zinc fingers are joined by a conserved seven-amino acid sequence; [T](/source/Threonine)[G](/source/Glycine)[E](/source/Glutamic_acid)[K](/source/Lysine)[P](/source/Proline)([Y](/source/Tyrosine)/[F](/source/Phenylalanine))X. The zinc fingers enable all KLF proteins to bind to CACCC [gene promoters](/source/Promoter_(genetics)), so although they may complete varied functions (due to lack of [homology](/source/Homology_(biology)) away from the zinc fingers), they all recognize similar [binding domains](/source/Binding_domains).[7]

KLF2 also exhibits these structural features. The [mRNA](/source/MRNA) transcript is approximately 1.5 [kilobases](/source/Kilobase) in length, and the 37.7 [kDa](/source/Kilodalton) protein contains 354 amino acids.[11] KLF2 also shares some homology with EKLF at the [N-terminus](/source/N-terminus) with a [proline](/source/Proline)-rich region presumed to function as the [transactivation domain](/source/Transactivation_domain).[11]

## Gene expression

*KLF2* was first discovered, and is highly expressed in, the adult mouse [lung](/source/Lung), but it is also expressed temporally during [embryogenesis](/source/Embryogenesis) in [erythroid cells](/source/Erythrocyte), [endothelium](/source/Endothelium), [lymphoid cells](/source/Lymphocyte), the [spleen](/source/Spleen), and [white adipose tissue](/source/White_adipose_tissue).[7][11] It is expressed as early as embryonic day 9.5 in the endothelium.

*KLF2* has a particularly interesting expression profile in erythroid cells. It is minimally expressed in the primitive and fetal definitive erythroid cells, but is highly expressed in adult definitive erythroid cells, particularly in the [proerythroblast](/source/Proerythroblast) and the [polychromatic](/source/Normoblast) and [orthochromatic normoblasts](/source/Normoblast).[12]

## Mouse knockout

[Homologous recombination](/source/Homologous_recombination) of [embryonic stem cells](/source/Embryonic_stem_cells) was used to generate *KLF2*-deficient mouse embryos. Both [vasculogenesis](/source/Vasculogenesis) and [angiogenesis](/source/Angiogenesis) were normal in the embryos, but they died by embryonic day 14.5 from severe [hemorrhaging](/source/Hemorrhaging). The [vasculature](/source/Vasculature) displayed defective morphology, with thin [tunica media](/source/Tunica_media) and [aneurysmal dilation](/source/Aneurysm) that led to rupturing. Aortic vascular smooth muscle cells failed to organize into a normal tunica media, and [pericytes](/source/Pericytes) were low in number. These *KLF2*-deficient mice thus demonstrated the important role of *KLF2* in blood vessel stabilization during embryogenesis.[13]

Due to embryonic lethality in *KLF2*-deficient embryos, it is difficult to examine the role of *KLF2* in normal [post-natal](/source/Post-natal) [physiology](/source/Physiology), such as in [lung](/source/Lung) development and function.[14]

## Function

### Lung development

Lung buds removed from *KLF2*-deficient mouse embryos and cultured from normal [tracheobronchial trees](/source/Tracheobronchial_tree). In order to circumvent embryonic lethality usually observed in *KLF2*-deficient embryos, *KLF2* [homozygous](/source/Homozygous) null mouse embryonic stem cells were constructed and used to produce [chimeric animals](/source/Chimera_(genetics)). These *KLF2*-deficient embryonic stem cells contribute significantly to development of skeletal muscle, spleen, heart, liver, kidney, stomach, brain, uterus, testis, and skin, but not to the development of the lung. These embryos had lungs arrested in the [late canalicular stage](/source/Development_of_human_lung) of lung development, with undilated [acinar tubules](/source/Acinus). In contrast, [wild type](/source/Wild_type) embryos are born in the [saccular stage](/source/Saccular_stage) of lung development with expanded alveoli. This suggests that KLF2 is an important [transcription factor](/source/Transcription_factor) required in late gestation for lung development.[7]

### Embryonic erythropoiesis

KLF2 is now believed to play an important role in embryonic erythropoiesis, specifically in regulating embryonic and [fetal](/source/Hemoglobin_F) β-like globin gene expression. In a [murine](/source/Murine) *KLF2*-deficient embryo, expression of β-like globin genes normally expressed in primitive erythroid cells was significantly decreased, although [adult](/source/Hemoglobin_A) β-globin gene expression was unaffected.[15]

The role of KLF2 in human β-like globin gene expression was further elucidated by [transfection](/source/Transfection) of a murine *KLF2*-deficient embryo with the human β-globin locus. It was found that KLF2 was important for [ε-globin](/source/HBE1) (found in embryonic hemoglobin) and [γ-globin](/source/HBG1) (found in [fetal hemoglobin](/source/Fetal_hemoglobin)) gene expression. However, as before, KLF2 plays no role in adult β-globin gene expression; this is [regulated](/source/Transcription_factor) by EKLF.[15]

However, KLF2 and EKLF have been found to interact in embryonic erythropoiesis. [Deletion](/source/Genetic_deletion) of both *KLF2* and *EKLF* in mouse embryos results in fatal anemia earlier than in either single deletion at embryonic day 10.5. This indicates that KLF2 and EKLF interact in [embryonic](/source/HBE1) and fetal β-like globin gene expression.[16] It has been shown using [conditional knockout](/source/Conditional_gene_knockout) mice that both KLF2 and EKLF bind directly to β-like globin [promoters](/source/Promoter_(genetics)).[17] There is also evidence to suggest that KLF2 and EKLF [synergistically](/source/Synergistically) bind to the *[Myc](/source/Myc)* [promoter](/source/Gene_promoter), a [transcription factor](/source/Transcription_factor) that is associated with gene expression of [α-globin](/source/Alpha_globin) and β-globin in embryonic [proerythroblasts](/source/Proerythroblast).[18]

### Endothelial physiology

*KLF2* expression is induced by [fluid laminar flow](/source/Laminar_flow) [shear stress](/source/Shear_stress), as is caused by blood flow in normal endothelium.[19][20]

This activates [mechanosensitive channels](/source/Mechanosensitive_channels), which in turn activates two pathways; the [MEK5](/source/MAP2K)/[ERK5](/source/MAPK7) pathway, which activates [MEF2](/source/MEF2), a [transcription factor](/source/Transcription_factor) that upregulates *KLF2* gene expression; and [PI3K](/source/PI3K) inhibition, which increases the stability of *KLF2* mRNA. Binding of cytokines such as [TNFα](/source/TNF%CE%B1) and [IL-1β](/source/IL-1%CE%B2) to their [receptors](/source/Receptor_(biochemistry)) activates [transcription factor](/source/Transcription_factor) [p65](/source/RELA), which also induces *KLF2* expression. KLF2 then has four key functions in endothelium:

- By inhibiting activation of [p65](/source/RELA) by transcription coactivator [p300](/source/EP300), *[VCAM1](/source/VCAM1)* and *[SELE](/source/SELE)* expression is downregulated, genes that encode endothelial [cell adhesion molecules](/source/Cell_adhesion_molecule), causing decreased [lymphocyte](/source/Lymphocyte) and [leukocyte](/source/Leukocyte) activation and hence decreasing inflammation

- It upregulates *[THBD](/source/THBD)* (thrombomodulin) and *[NOS3](/source/NOS3)* (endothelial [nitric oxide](/source/Nitric_oxide) [synthase](/source/Synthase)) expression, having an anti-[thrombotic](/source/Thrombotic) effect

- Through the upregulation of *NOS3*, as well as *[NPPC](/source/Natriuretic_peptide_precursor_C)* (natriuretic precursor peptide C), KLF2 has a [vasodilatory](/source/Vasodilatory) effect

- KLF2 also inhibits *[VEGFR2](/source/VEGFR2)* (VEGF receptor 2) expression, having an anti-[angiogenic](/source/Angiogenic) effect[21]

Thus KLF2 has an important role in regulating normal endothelium physiology. It is hypothesized that [myeloid](/source/Myeloid)-specific KLF2 plays a protective role in [atherosclerosis](/source/Atherosclerosis).[22] Gene expression changes in endothelial cells induced by KLF2 have been demonstrated to be atheroprotective.[20]

### T-cell differentiation

KLF2 has an important function in [T-lymphocyte](/source/T-lymphocyte) [differentiation](/source/Cellular_differentiation). T-cells are activated and more prone to [apoptosis](/source/Apoptosis) without KLF2, suggesting that KLF2 regulates T-cell [quiescence](/source/G0_phase) and survival.[7] *KLF2*-deficient [thymocytes](/source/Thymocytes) also do not express several receptors required for thymus [emigration](/source/Chemorepulsion#Thymic_emigration) and differentiation into mature T-cells, such as [sphingosine-1 phosphate receptor 1](/source/S1PR1).[23]

### Adipogenesis

KLF2 is a [negative regulator](/source/Downregulation_and_upregulation) of [adipocyte](/source/Adipocyte) differentiation. KLF2 is expressed in [preadipocytes](/source/Preadipocytes), but not mature adipocytes, and it potently inhibits [PPAR-γ](/source/PPAR-%CE%B3) ([peroxisome](/source/Peroxisome) proliferator-activated receptor-γ) expression by inhibiting [promoter](/source/Gene_promoter) activity. This prevents differentiation of preadipocytes into adipocytes, and thus prevents adipogenesis.[24]

## See also

- [Krüppel-like factors](/source/Kr%C3%BCppel-like_factors)

- [Erythroid Krüppel-like factor](/source/EKLF)

- [Zinc finger transcription factors](/source/Zinc_finger_transcription_factors)

## References

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## External links

- [KLF2+protein,+human](https://meshb.nlm.nih.gov/record/ui?name=KLF2+protein%2C+human) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- [*KLF2*](https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&singleSearch=knownCanonical&position=KLF2) human gene location in the [UCSC Genome Browser](/source/UCSC_Genome_Browser).

- [*KLF2*](https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=KLF2) human gene details in the [UCSC Genome Browser](/source/UCSC_Genome_Browser).

*This article incorporates text from the [United States National Library of Medicine](/source/United_States_National_Library_of_Medicine), which is in the [public domain](/source/Public_domain).*

v t e Transcription factors and intracellular receptors (1) Basic domains (1.1) Basic leucine zipper (bZIP) Activating transcription factor AATF 1 2 3 4 5 6 7 AP-1 c-Fos FOSB FOSL1 FOSL2 JDP2 c-Jun JUNB JunD BACH 1 2 BATF BLZF1 C/EBP α β γ δ ε ζ CREB 1 3 L1 CREM DBP DDIT3 GABPA GCN4 HLF MAF B sMaf F G K NFE 2 L1 L2 L3 NFIL3 NRL NRF 1 2 3 XBP1 (1.2) Basic helix–loop–helix (bHLH) Group A AS-C ASCL1 ASCL2 ATOH1 HAND 1 2 MESP2 Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 NeuroD 1 2 Neurogenins 1 2 3 OLIG 1 2 Paraxis TCF15 Scleraxis SLC LYL1 TAL 1 2 Twist Group B FIGLA Myc c-Myc l-Myc n-Myc MXD4 TCF4 Group C bHLH-PAS AhR AHRR ARNT ARNTL ARNTL2 CLOCK HIF 1A EPAS1 3A NPAS 1 2 3 PER 1 2 3 Period SIM 1 2 Group D DEC 1 2 BHLHA9 Pho4 ID 1 2 3 4 Group E HES 1 2 3 4 5 6 7 HEY 1 2 L Group F bHLH-COE EBF1 (1.3) bHLH-ZIP AP-4 MAX MXD1 MXD3 MITF MNT MLX MLXIPL MXI1 Myc SREBP 1 2 USF1 (1.4) NF-1 NFI A B C X SMAD R-SMAD 1 2 3 5 9 I-SMAD 6 7 4) (1.5) RF-X RFX 1 2 3 4 5 6 ANK (1.6) Basic helix-span-helix (bHSH) AP-2 α β γ δ ε (2) Zinc finger DNA-binding domains (2.1) Nuclear receptor (Cys4) subfamily 1 Thyroid hormone α β CAR FXR LXR α β PPAR α β/δ γ PXR RAR α β γ ROR α β γ Rev-ErbA α β VDR subfamily 2 COUP-TF (I II Ear-2 HNF4 α γ PNR RXR α β γ Testicular receptor 2 4 TLX subfamily 3 Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ subfamily 4 NUR NGFIB NOR1 NURR1 subfamily 5 LRH-1 SF1 subfamily 6 GCNF subfamily 0 DAX1 SHP (2.2) Other Cys4 GATA 1 2 3 4 5 6 MTA 1 2 3 TRPS1 (2.3) Cys2His2 General transcription factors TFIIA TFIIB TFIID TFIIE 1 2 TFIIF 1 2 TFIIH 1 2 4 2I 3A 3C1 3C2 ATBF1 BCL 6 11A 11B CTCF E4F1 EGR 1 2 3 4 ERV3 GFI1 GLI family 1 2 3 REST S1 S2 YY1 HIC 1 2 HIVEP 1 2 3 IKZF 1 2 3 ILF 2 3 Sp/KLF family KLF 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 SP 1 2 4 7 8 MTF1 MYT1 OSR1 PRDM9 SALL 1 2 3 4 TSHZ3 WT1 Zbtb7 7A 7B ZBTB 11 16 17 20 21 32 33 40 zinc finger 3 7 9 10 19 22 24 33B 34 35 41 43 44 51 74 143 146 148 165 202 217 219 238 239 259 267 268 281 300 318 330 346 350 365 366 384 423 451 452 471 593 638 644 649 655 804A (2.4) Cys6 HIVEP1 (2.5) Alternating composition AIRE DIDO1 GRLF1 ING 1 2 4 JARID 1A 1B 1C 1D 2 JMJD1B (2.6) WRKY WRKY (3) Helix-turn-helix domains (3.1) Homeodomain Antennapedia ANTP class protoHOX Hox-like ParaHox Gsx 1 2 Xlox PDX1 Cdx 1 2 4 extended Hox: Evx1 Evx2 MEOX1 MEOX2 Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 GBX1 GBX2 MNX1 metaHOX NK-like BARHL1 BARHL2 BARX1 BARX2 BSX DBX 1 2 DLX 1 2 3 4 5 6 EMX 1 2 EN 1 2 HHEX HLX LBX1 LBX2 MSX 1 2 NANOG NKX 2-1 2-2 2-3 2-5 3-1 3-2 HMX1 HMX2 HMX3 6-1 6-2 NOTO TLX1 TLX2 TLX3 VAX1 VAX2 other ARX CRX CUTL1 FHL 1 2 3 HESX1 HOPX LMX 1A 1B NOBOX TALE IRX 1 2 3 4 5 6 MKX MEIS 1 2 PBX 1 2 3 PKNOX 1 2 SIX 1 2 3 4 5 PHF 1 3 6 8 10 16 17 20 21A POU domain PIT-1 BRN-3: A B C Octamer transcription factor: 1 2 3/4 6 7 11 SATB2 ZEB 1 2 (3.2) Paired box PAX 1 2 3 4 5 6 7 8 9 PRRX 1 2 PROP1 PHOX 2A 2B RAX SHOX SHOX2 VSX1 VSX2 Bicoid GSC BICD2 OTX 1 2 PITX 1 2 3 (3.3) Fork head / winged helix E2F 1 2 3 4 5 FOX proteins A1 A2 A3 B1 B2 C1 C2 D1 D2 D3 D4 D4L1 D4L3 D4L4 D4L5 D4L6 E1 E3 F1 F2 G1 H1 I1 I2 I3 J1 J2 J3 K1 K2 L1 L2 M1 N1 N2 N3 N4 O1 O3 O4 O6 P1 P2 P3 P4 Q1 R1 R2 S1 (3.4) Heat shock factors HSF 1 2 4 (3.5) Tryptophan clusters ELF 2 4 5 EHF ELK 1 3 4 ERF ETS 1 2 ERG SPIB ETV 1 4 5 6 FLI1 Interferon regulatory factors 1 2 3 4 5 6 7 8 MYB MYBL2 (3.6) TEA domain transcriptional enhancer factor 1 2 3 4 (4) β-Scaffold factors with minor groove contacts (4.1) Rel homology region NF-κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5 (4.2) STAT STAT 1 2 3 4 5 6 (4.3) p53-like p53 p63 p73 family p53 TP63 p73 TBX 1 2 3 5 19 21 22 TBR1 TBR2 TFT MYRF (4.4) MADS box Mef2 A B C D SRF (4.6) TATA-binding proteins TBP TBPL1 (4.7) High-mobility group BBX HMGB 1 2 3 4 HMGN 1 2 3 4 HNF 1A 1B SOX 1 2 3 4 5 6 8 9 10 11 12 13 14 15 17 18 21 SRY SSRP1 TCF/LEF TCF 1 3 4 LEF1 TOX 1 2 3 4 (4.9) Grainyhead TFCP2 (4.10) Cold-shock domain CSDA YBX1 (4.11) Runt CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1 (0) Other transcription factors (0.2) HMGI(Y) HMGA 1 2 HBP1 (0.3) Pocket domain Rb RBL1 RBL2 (0.5) AP-2/EREBP-related factors Apetala 2 EREBP B3 (0.6) Miscellaneous ARID 1A 1B 2 3A 3B 4A CAP IFI 16 35 MLL 2 3 T1 MNDA NFY A B C Rho/Sigma see also transcription factor/coregulator deficiencies

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Adapted from the Wikipedia article [KLF2](https://en.wikipedia.org/wiki/KLF2) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/KLF2?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.