KLF2

Summary

KLF2 (KLF transcription factor 2, HGNC:6347) is a protein-coding gene on chromosome 19p13.11, encoding Krueppel-like factor 2 (Q9Y5W3). Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription.

This gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is expressed early in mammalian development and is found in many different cell types. The protein acts to bind the CACCC box found in the promoter of target genes to activate their transcription. It plays a role in many processes during development and disease including adipogenesis, embryonic erythropoiesis, epithelial integrity, inflammation and t-cell viability.

Source: NCBI Gene 10365 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (Limited, ClinGen)
• GWAS associations: 15
• Clinical variants (ClinVar): 66 total
• Transcription factor: yes — 70 downstream targets (CollecTRI)
• MANE Select transcript: NM_016270

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6347
Approved symbol	KLF2
Name	KLF transcription factor 2
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	LKLF
Ensembl gene	ENSG00000127528
Ensembl biotype	protein_coding
OMIM	602016
Entrez	10365

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000248071, ENST00000592003

RefSeq mRNA: 1 — MANE Select: NM_016270 NM_016270

CCDS: CCDS12343

Canonical transcript exons

ENST00000248071 — 3 exons

Exon	Start	End
ENSE00000873433	16325216	16326032
ENSE00000873434	16326856	16328685
ENSE00002835925	16324826	16324998

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 106.6031 / max 3493.5770, expressed in 1605 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174401	103.8314	1580
174405	0.8763	247
174406	0.5579	187
174403	0.5224	196
174402	0.4865	190
174408	0.2147	100
174404	0.0637	33
174407	0.0502	24

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
urethra	UBERON:0000057	99.70	gold quality
vena cava	UBERON:0004087	99.40	gold quality
trachea	UBERON:0003126	99.30	gold quality
saphenous vein	UBERON:0007318	99.29	gold quality
mucosa of stomach	UBERON:0001199	99.16	gold quality
granulocyte	CL:0000094	99.14	gold quality
nipple	UBERON:0002030	99.01	gold quality
cardia of stomach	UBERON:0001162	98.91	gold quality
pericardium	UBERON:0002407	98.91	gold quality
pylorus	UBERON:0001166	98.71	gold quality
trigeminal ganglion	UBERON:0001675	98.64	gold quality
lower lobe of lung	UBERON:0008949	98.47	gold quality
blood	UBERON:0000178	98.26	gold quality
body of tongue	UBERON:0011876	98.21	gold quality
bone marrow cell	CL:0002092	98.10	gold quality
olfactory bulb	UBERON:0002264	98.03	gold quality
dorsal root ganglion	UBERON:0000044	97.98	gold quality
superficial temporal artery	UBERON:0001614	97.93	gold quality
leukocyte	CL:0000738	97.84	gold quality
right lung	UBERON:0002167	97.83	gold quality
left uterine tube	UBERON:0001303	97.78	gold quality
mononuclear cell	CL:0000842	97.71	gold quality
periodontal ligament	UBERON:0008266	97.70	gold quality
penis	UBERON:0000989	97.68	gold quality
monocyte	CL:0000576	97.67	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.48	gold quality
parietal pleura	UBERON:0002400	97.47	gold quality
right ovary	UBERON:0002118	97.40	gold quality
synovial joint	UBERON:0002217	97.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.38	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	2532.00
E-HCAD-4	yes	97.66
E-MTAB-10287	yes	83.56
E-HCAD-8	yes	57.41
E-GEOD-134144	yes	41.37
E-CURD-46	yes	33.84
E-HCAD-1	yes	33.37
E-ANND-3	yes	24.46
E-MTAB-8410	yes	21.35
E-HCAD-9	yes	12.81
E-MTAB-9467	no	1232.56

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

70 targets.

Target	Regulation
ACE	Unknown
ADM	Unknown
CCN3
CCR5	Activation
CCR7	Unknown
CD36
CDH1
CDH17
CDKN1A	Activation
CEBPA	Repression
CXCR4	Repression
DLK1
DPP7	Activation
EDN1	Repression
F3	Repression
FABP5	Repression
FOXP3
GAST
GATA4
GJA4
GPS2
HBB	Activation
HBD
HBE1	Activation
HBG1
HDC
HIF1A	Repression
HMOX1	Activation
IFNG	Repression
IL2	Unknown

JASPAR motifs

Motif	Name	Family
MA1515.1	KLF2	Three-zinc finger Kruppel-related
MA1515.2	KLF2	Three-zinc finger Kruppel-related

JASPAR matrix evidence (PMIDs): PMID:11443140

Upstream regulators (CollecTRI, top): APLNR, CXXC1, EZH2, FOXO1, HNRNPD, IL17A, KLF2, MAP2K5, MAPK7, MEF2A, MEF2C, NANOG, NR1I2, RELA, SRF, TP53

miRNA regulators (miRDB)

89 targeting KLF2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-338-5P	99.92	72.34	2951

Literature-anchored findings (GeneRIF, showing 40)

• LKLF is the first endothelial transcription factor that is uniquely induced by flow and might therefore be at the molecular basis of the physiological healthy, flow-exposed state of the endothelial cell (PMID:12176889)
• KLF2 has a role as a negative regulator of adipogenesis (PMID:12426306)
• KLF2 is a novel regulator of endothelial activation in response to proinflammatory stimuli. (PMID:15136591)
• LKLF may establish a phenotype that primes quiescent cells for responses to specific extracellular stimuli. (PMID:15607822)
• The ability to differentially modulate key molecules such as TM, eNOS, PAI-1, & TF identifies KLF2 as an important regulator of endothelial coagulant function. KLF2 is a “molecular switch” regulating important aspects of vascular function. (PMID:15718498)
• Level of WEE1 is regulated by KLF2 and enhanced KLF2 expression sensitizes cells to DNA damage-induced apoptosis. (PMID:15735666)
• a promoter element activated by a PI3kinase-dependent chromatin-remodeling pathway induces KLF2 (PMID:15834135)
• demonstrated that KLF2 transcription factor is necessary for the statin-mediated regulation of several pathophysiologically relevant genes (PMID:15878865)
• KLF2 has roles in primitive erythropoiesis and regulating human and murine embryonic beta-like globin genes (PMID:15947087)
• KLF2 is a regulator of VEGFR2/KDR and has a role in regulating angiogenesis (PMID:15980434)
• In co-transfection assays in K562 cells, it was demonstrated that KLF2, 5 and 13 positively regulate, and KLF8 negatively regulates, the gamma-globin gene through the CACCC promoter element. (PMID:16023392)
• Statin-dependent induction of eNOS and thrombomodulin requires KLF2 and thereby provides a novel molecular target for modulating endothelial function in vascular disease. (PMID:16043642)
• KLF2 regulates IL-2 promoter activity in the earliest stages of T cell activation. (PMID:16116194)
• KLF2 is selectively induced in endotheliums by atheroprotective flow via a MEK5/ERK5/MEF2 signaling pathway. Expression of KLF2 results in the regulation of endothelial programs controlling inflammation, thrombosis, vascular tone, and angiogenesis. (PMID:16341264)
• KLF2 acts as a central transcriptional switch point between the quiescent and activated states of the adult endothelial cell (PMID:16455954)
• findings demonstrate that different flow patterns differentially regulate the expression of KLF2 and that KLF2 has an anti-apoptotic effect (PMID:16466697)
• nucleolin binds the KLF2 promoter (PMID:16571724)
• KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. (PMID:16617118)
• Human transcription factors KLF2 and KLF6 are targets of the P. aeruginosa type III exoenzymes S and Y, with potential importance in host cell death. (PMID:16988269)
• Shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expression. (PMID:17244683)
• analysis of SNPs, located in the KLF2, KLF4 and KLF5 gene did not show an association with Type 2 diabetes in this French population (PMID:17688680)
• Atorvastatin-mediated HO-1 upregulation, and its associated antioxidant effect, are KLF2-dependent. (PMID:17927807)
• Simvastatin has a strong anti-inflammatory effect on monocytes including upregulation of the atheroprotective factor KLF-2. (PMID:18192240)
• Data suggest that, in neutrophil-dominated airway environments, such as that seen in cystic fibrosis, reduced LKLF activity releases a brake on pro-inflammatory cytokine production and may contribute to the inflammatory responses seen in CF. (PMID:18218994)
• up-regulation of CD59 via ERK5/KLF2 activation leads to endothelial resistance to complement-mediated injury and protects from atherogenesis in regions of laminar shear stress (PMID:18362151)
• KLF2 substantially enhances antioxidant activity of Nrf2 by increasing its nuclear localization and activation. (PMID:18467642)
• downregulation of antiinflammatory factors, such as TNFAIP3, KLF2, ZFP36, and BTG1, seems to be involved in acceleration of immune response, thus exacerbation of acute GVHD. (PMID:18814951)
• KLF2-expressing EC co-cultured with SMC significantly reduce SMC migration compared with control EC and that this reduction can be rescued by the addition of exogenous connective tissue growth factor. (PMID:19047056)
• KLF2 is a novel inhibitor of HIF-1alpha expression and function. (PMID:19491109)
• N-Myc regulates expression of pluripotency genes in neuroblastoma including lif, klf2, klf4, and lin28b (PMID:19495417)
• Data show that the use of siRNA against KLF2 led to an upregulation of CXCR4 mRNA. (PMID:19671192)
• These findings illustrate a novel mechanism by which p66shc promotes cellular oxidative stress, through suppression of MEF2A expression and consequent repression of KLF2 transcription. (PMID:19696221)
• Short hairpin RNA-mediated inactivation of RhoA and its effector rhophilin 1 is sufficient to induce long-term klf2 expression by several bacterial toxins. (PMID:19786564)
• The ratio of proinflammatory factor RelA (NFkappaB/p65) to anti-inflammatory factor KLF2 (Kruppel-like factor 2) was greater in blood outgrowth endothelial cells of Sickle cell patients at risk of stroke (PMID:19957349)
• these data identify a significant degree of mechanistic and functional conservation between KLF2 and KLF4, and importantly, provide further insights into the complex regulatory networks governing endothelial vasoprotection. (PMID:19968965)
• findings link the specific effects of shear-induced KLF2 on endothelial morphology to the suppression of JNK MAPK signaling in vascular homeostasis via novel actin shear fibers (PMID:20032497)
• phosphorylation-dependent derepression of HDAC5 mediates flow-induced KLF2 and eNOS expression as well as flow anti-inflammation, and suggest that HDAC5 could be a potential therapeutic target for the prevention of atherosclerosis. (PMID:20042720)
• Bacterial pneumococci induce KLF2 expression in human epithelial BEAS-2B cells in vitro, thus contributing to the control of proinflammatory gene expression. (PMID:20525885)
• KLF2 confers barrier-protection via differential effects on the expression of key junction protein occludin and modification of a signaling molecule (myosin light chain) that regulate endothelial barrier integrity. (PMID:20651277)
• Data suggest that inhibition of differentiation of human adipose tissue-derived stem cells by UVA occurs primarily through reduced expression of PPAR gamma, which is mediated by up-regulation of KLF2 via activation of MIF-AMP-activated protein kinase. (PMID:20693579)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klf2	ENSMUSG00000055148
rattus_norvegicus	Klf2	ENSRNOG00000075360
drosophila_melanogaster	CG3065	FBGN0034946
drosophila_melanogaster	luna	FBGN0040765

Paralogs (22): KLF6 (ENSG00000067082), KLF8 (ENSG00000102349), KLF5 (ENSG00000102554), KLF1 (ENSG00000105610), KLF3 (ENSG00000109787), KLF7 (ENSG00000118263), KLF12 (ENSG00000118922), KLF9 (ENSG00000119138), KLF16 (ENSG00000129911), KLF4 (ENSG00000136826), KLF10 (ENSG00000155090), KLF15 (ENSG00000163884), SP8 (ENSG00000164651), KLF13 (ENSG00000169926), SP7 (ENSG00000170374), KLF17 (ENSG00000171872), KLF11 (ENSG00000172059), SP6 (ENSG00000189120), SP5 (ENSG00000204335), SP9 (ENSG00000217236), KLF14 (ENSG00000266265), KLF18 (ENSG00000283039)

Protein

Protein identifiers

Krueppel-like factor 2 — Q9Y5W3 (reviewed: Q9Y5W3)

Alternative names: Lung krueppel-like factor

All UniProt accessions (2): Q9Y5W3, K7EJ60

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. Might be involved in transcriptional regulation by modulating the binding of the RARA nuclear receptor to RARE DNA elements.

Subunit / interactions. Interacts with WWP1.

Subcellular location. Nucleus.

Post-translational modifications. Ubiquitinated. Polyubiquitination involves WWP1 and leads to proteasomal degradation of this protein.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family.

RefSeq proteins (1): NP_057354* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (19 total): region of interest 4, zinc finger region 3, compositionally biased region 3, sequence conflict 3, modified residue 2, sequence variant 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5W3-F1	57.81	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 173, 244

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 460 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, WWTAAGGC_UNKNOWN, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_LUNG_CELL_DIFFERENTIATION

GO Biological Process (25): negative regulation of transcription by RNA polymerase II (GO:0000122), cell morphogenesis (GO:0000902), in utero embryonic development (GO:0001701), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of interleukin-6 production (GO:0032715), multicellular organism growth (GO:0035264), epigenetic regulation of gene expression (GO:0040029), vasodilation (GO:0042311), erythrocyte maturation (GO:0043249), positive regulation of nitric oxide biosynthetic process (GO:0045429), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of retinoic acid receptor signaling pathway (GO:0048386), positive regulation of protein metabolic process (GO:0051247), type I pneumocyte differentiation (GO:0060509), cellular response to hydrogen peroxide (GO:0070301), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to fluid shear stress (GO:0071498), cellular response to laminar fluid shear stress (GO:0071499), cellular stress response to acid chemical (GO:0097533), negative regulation of sprouting angiogenesis (GO:1903671), cellular response to endothelin (GO:1990859), erythrocyte homeostasis (GO:0034101), response to laminar fluid shear stress (GO:0034616)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
cellular response to cytokine stimulus	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
negative regulation of DNA-templated transcription	1
anatomical structure morphogenesis	1
chordate embryonic development	1
negative regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
multicellular organismal process	1
developmental growth	1
chromatin remodeling	1
regulation of gene expression	1
blood vessel diameter maintenance	1
cell maturation	1
erythrocyte development	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
retinoic acid receptor signaling pathway	1
regulation of retinoic acid receptor signaling pathway	1
positive regulation of intracellular signal transduction	1
positive regulation of macromolecule metabolic process	1
protein metabolic process	1
regulation of protein metabolic process	1
lung epithelial cell differentiation	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
response to interleukin-1	1
response to tumor necrosis factor	1
cellular response to stress	1
response to fluid shear stress	1
response to laminar fluid shear stress	1
cellular response to fluid shear stress	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

3022 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLF2	S1PR1	P21453	822
KLF2	SOX2	P48431	786
KLF2	CCR7	P32248	782
KLF2	GZMB	P10144	758
KLF2	NANOG	Q9H9S0	758
KLF2	POU5F1	P31359	757
KLF2	SELL	P14151	746
KLF2	MAPK7	Q13164	729
KLF2	CD8A	P01732	712
KLF2	EOMES	O95936	698
KLF2	MYC	P01106	693
KLF2	MAP2K5	Q13163	673
KLF2	ESRRB	O95718	659
KLF2	ELF4	Q99607	649
KLF2	DPPA3	Q6W0C5	640

IntAct

19 interactions, top by confidence:

A	B	Type	Score
KLF2	SMURF1	psi-mi:“MI:0407”(direct interaction)	0.570
SMURF1	KLF2	psi-mi:“MI:0915”(physical association)	0.570
SMURF1	KLF2	psi-mi:“MI:0403”(colocalization)	0.570
KLF2	SMURF1	psi-mi:“MI:0915”(physical association)	0.570
KLF2	KAT2B	psi-mi:“MI:0407”(direct interaction)	0.540
KLF2	KAT2B	psi-mi:“MI:0915”(physical association)	0.540
SMURF1	KLF2	psi-mi:“MI:0915”(physical association)	0.510
	KLF2	psi-mi:“MI:0915”(physical association)	0.370
CXCL3	KLF2	psi-mi:“MI:0915”(physical association)	0.370
IL31	KLF2	psi-mi:“MI:0915”(physical association)	0.370
TNFSF10	KLF2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (26): KLF2 (Co-localization), KLF2 (Co-localization), KAT2B (Reconstituted Complex), KLF2 (Affinity Capture-Western), KLF2 (Reconstituted Complex), KLF2 (Affinity Capture-Western), PSME3 (Affinity Capture-Western), KLF2 (Reconstituted Complex), KLF2 (Biochemical Activity), KLF2 (Reconstituted Complex), MYC (Affinity Capture-Western), KLF2 (Two-hybrid), KLF2 (Two-hybrid), KLF2 (Two-hybrid), WWP1 (Affinity Capture-Western)

ESM2 similar proteins: A0A8I6AGW3, A2A9A2, A6NMB9, A8MYZ6, E9PZZ1, J3QK54, O02755, O02756, O35392, O35767, O60548, O70220, P05554, P17676, P21272, P28033, P35713, P42582, P49715, P49716, P52952, P53566, P58012, Q12952, Q13461, Q14526, Q60843, Q61345, Q63244, Q63250, Q6BEB4, Q6VFT5, Q6VFT6, Q6ZQN5, Q70KY4, Q8IU81, Q8MIP2, Q8NDY6, Q8R2I0, Q98937

Diamond homologs: O08584, O08876, O14901, O35738, O35819, O43474, O62259, O70494, O75840, O89090, O89091, O95600, P08047, P0CG40, P46099, P57682, P58334, Q01714, Q02446, Q02447, Q0VA40, Q13118, Q13351, Q13887, Q14V87, Q19A40, Q19A41, Q22678, Q24266, Q3SY56, Q5XGT8, Q60793, Q60843, Q60980, Q62445, Q64HY3, Q64HY5, Q65ZG6, Q6BEB4, Q6NW96

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
IL17A	“up-regulates quantity by expression”	KLF2	“transcriptional regulation”
KLF2	down-regulates	PPARG	“transcriptional regulation”
IL17A	up-regulates	KLF2	“transcriptional regulation”
KLF2	“up-regulates quantity by expression”	THBD	“transcriptional regulation”
MAPK7	“up-regulates quantity by expression”	KLF2	“transcriptional regulation”
KLF2	“up-regulates quantity by expression”	NPNT	“transcriptional regulation”
KLF2	“up-regulates quantity”	mir-143	“transcriptional regulation”
KLF2	“up-regulates quantity by expression”	RELN	“transcriptional regulation”
KLF2	“down-regulates quantity by repression”	PPARG	“transcriptional regulation”
KLF2	“up-regulates quantity by expression”	HBE1	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

66 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	1
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

235 predictions. Top by Δscore:

Variant	Effect	Δscore
19:16324996:G:GT	donor_gain	1.0000
19:16326028:CACAG:C	donor_loss	1.0000
19:16326029:ACAG:A	donor_loss	1.0000
19:16326030:CAG:C	donor_loss	1.0000
19:16326031:AG:A	donor_loss	1.0000
19:16326032:GG:G	donor_loss	1.0000
19:16326853:CA:C	acceptor_loss	1.0000
19:16326854:A:AG	acceptor_gain	1.0000
19:16326854:AG:A	acceptor_gain	1.0000
19:16326855:G:GA	acceptor_gain	1.0000
19:16326855:GG:G	acceptor_gain	1.0000
19:16326855:GGT:G	acceptor_gain	1.0000
19:16326855:GGTGA:G	acceptor_gain	1.0000
19:16324995:GGAG:G	donor_gain	0.9900
19:16325214:A:AG	acceptor_gain	0.9900
19:16325215:G:GG	acceptor_gain	0.9900
19:16325215:GC:G	acceptor_gain	0.9900
19:16325215:GCGCT:G	acceptor_gain	0.9900
19:16326033:G:GC	donor_loss	0.9900
19:16326851:T:TA	acceptor_gain	0.9900
19:16326854:AGGT:A	acceptor_gain	0.9900
19:16326855:GGTG:G	acceptor_gain	0.9900
19:16324997:AGG:A	donor_loss	0.9800
19:16324999:G:A	donor_loss	0.9800
19:16325000:T:G	donor_loss	0.9800
19:16325210:CCGCA:C	acceptor_loss	0.9700
19:16325211:CGCAG:C	acceptor_loss	0.9700
19:16325212:GCAGC:G	acceptor_loss	0.9700
19:16325213:CA:C	acceptor_loss	0.9700
19:16325214:A:AC	acceptor_loss	0.9700

AlphaMissense

2241 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:16325987:T:G	Y283D	1.000
19:16326900:T:C	F313L	1.000
19:16326902:T:A	F313L	1.000
19:16326902:T:G	F313L	1.000
19:16326963:T:C	C334R	1.000
19:16326984:T:C	F341L	1.000
19:16326986:C:A	F341L	1.000
19:16326986:C:G	F341L	1.000
19:16325960:T:C	C274R	0.999
19:16325975:T:A	C279S	0.999
19:16325975:T:C	C279R	0.999
19:16325976:G:A	C279Y	0.999
19:16325976:G:C	C279S	0.999
19:16325987:T:A	Y283N	0.999
19:16326006:T:C	L289P	0.999
19:16326014:C:A	H292N	0.999
19:16326014:C:G	H292D	0.999
19:16326016:T:A	H292Q	0.999
19:16326016:T:G	H292Q	0.999
19:16326018:T:C	L293P	0.999
19:16326021:G:C	R294P	0.999
19:16326867:T:G	Y302D	0.999
19:16326873:T:A	C304S	0.999
19:16326873:T:C	C304R	0.999
19:16326874:G:A	C304Y	0.999
19:16326874:G:C	C304S	0.999
19:16326875:C:G	C304W	0.999
19:16326888:T:A	C309S	0.999
19:16326889:G:C	C309S	0.999
19:16326901:T:C	F313S	0.999

dbSNP variants (sampled 300 via entrez): RS1000315963 (19:16328316 C>T), RS1000346869 (19:16328670 G>T), RS1000964898 (19:16323370 G>C), RS1001312342 (19:16323580 C>T), RS1001602351 (19:16326751 A>C), RS1002466361 (19:16323132 T>C), RS1002484988 (19:16326434 G>A,C), RS1002665506 (19:16329022 G>A), RS1002976622 (19:16323031 C>T), RS1002985008 (19:16328136 TTGTTAGCCTGCTC>T), RS1003611897 (19:16329165 C>G,T), RS1003613451 (19:16327862 C>T), RS1003669 (19:16326278 G>T), RS1004068911 (19:16325695 C>A,T), RS1004163821 (19:16326010 G>A)

Disease associations

OMIM: gene MIM:602016 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary arterial hypertension	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pulmonary arterial hypertension	Limited	AD

Mondo (1): pulmonary arterial hypertension (MONDO:0015924)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST004627_186	Lymphocyte count	2.000000e-71
GCST004632_20	Lymphocyte percentage of white cells	3.000000e-48
GCST006427_12	Depression in smokers	2.000000e-06
GCST006627_42	Diastolic blood pressure	1.000000e-11
GCST006979_748	Heel bone mineral density	2.000000e-09
GCST010043_71	Asthma	1.000000e-08
GCST010867_21	Coronary artery disease	2.000000e-08
GCST011491_1	Systemic lupus erythematosus	2.000000e-09
GCST011493_1	Systemic lupus erythematosus	7.000000e-07
GCST90002381_250	Eosinophil count	9.000000e-11
GCST90002382_456	Eosinophil percentage of white cells	9.000000e-20
GCST90002388_49	Lymphocyte count	5.000000e-134
GCST90002389_394	Lymphocyte percentage of white cells	4.000000e-49
GCST90002399_225	Neutrophil percentage of white cells	1.000000e-12
GCST90002407_366	White blood cell count	6.000000e-19

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0006336	diastolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

88 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	4
Air Pollutants	affects expression, increases abundance, increases expression, decreases expression	4
Valproic Acid	increases expression, increases methylation, decreases methylation	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Cisplatin	affects expression, affects cotreatment, decreases expression, affects response to substance	3
Cyclosporine	increases expression	3
Simvastatin	decreases reaction, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
bisphenol A	decreases expression, increases expression	2
dorsomorphin	increases expression, decreases expression, decreases reaction	2
Resveratrol	decreases reaction, increases expression, increases reaction, affects binding	2
Acetaminophen	increases expression	2
Arsenic	decreases expression, increases abundance	2
Smoke	decreases expression, increases abundance, increases expression	2
Particulate Matter	increases abundance, increases expression	2
LMK-235	decreases reaction, increases expression	1
yoda-1	affects localization	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bis(tri-n-butyltin)oxide	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
titanium dioxide	decreases expression	1
tributyltin	increases expression	1
trichostatin A	affects expression	1
hydroxyhydroquinone	decreases reaction, increases expression	1
cypermethrin	decreases expression	1
tetrathiomolybdate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
ochratoxin A	decreases expression	1
didecyldimethylammonium	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A3Q2	SEES3-1V human KLF2, clone1	Embryonic stem cell	Male
CVCL_A3Q3	SEES3-1V human KLF2, clone2	Embryonic stem cell	Male
CVCL_A3Q4	SEES3-1V human KLF2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial