CFL1

Summary

CFL1 (cofilin 1, HGNC:1874) is a protein-coding gene on chromosome 11q13.1, encoding Cofilin-1 (P23528). Binds to F-actin and exhibits pH-sensitive F-actin depolymerizing activity. It is a selective cancer dependency (DepMap: 59.5% of cell lines).

The protein encoded by this gene can polymerize and depolymerize F-actin and G-actin in a pH-dependent manner. Increased phosphorylation of this protein by LIM kinase aids in Rho-induced reorganization of the actin cytoskeleton. Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. It is involved in the translocation of actin-cofilin complex from cytoplasm to nucleus.

Source: NCBI Gene 1072 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 23 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 59.5% of screened cell lines
• MANE Select transcript: NM_005507

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1874
Approved symbol	CFL1
Name	cofilin 1
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000172757
Ensembl biotype	protein_coding
OMIM	601442
Entrez	1072

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000308162, ENST00000524553, ENST00000525451, ENST00000525710, ENST00000526975, ENST00000527344, ENST00000527752, ENST00000530157, ENST00000530413, ENST00000530945, ENST00000531407, ENST00000531413, ENST00000532134, ENST00000534769, ENST00000534784

RefSeq mRNA: 1 — MANE Select: NM_005507 NM_005507

CCDS: CCDS8114

Canonical transcript exons

ENST00000308162 — 4 exons

Exon	Start	End
ENSE00001344370	65854673	65855448
ENSE00001376907	65858097	65858180
ENSE00003889230	65855654	65855730
ENSE00003890491	65855935	65856242

Expression profiles

Bgee: expression breadth ubiquitous, 310 present calls, max score 99.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1180.6466 / max 6625.7789, expressed in 1828 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120704	1132.7837	1828
120705	39.1903	1821
120694	4.2005	1579
120699	2.2815	915
120703	0.5685	316
120701	0.5543	264
120702	0.3272	158
206341	0.2422	100
120707	0.2306	64
120706	0.1330	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.96	gold quality
pons	UBERON:0000988	99.92	gold quality
ileum	UBERON:0002116	99.91	silver quality
ventral tegmental area	UBERON:0002691	99.91	gold quality
inferior vagus X ganglion	UBERON:0005363	99.91	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.90	gold quality
medulla oblongata	UBERON:0001896	99.89	gold quality
subthalamic nucleus	UBERON:0001906	99.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.89	gold quality
superior vestibular nucleus	UBERON:0007227	99.89	gold quality
colonic mucosa	UBERON:0000317	99.88	gold quality
pylorus	UBERON:0001166	99.88	gold quality
cervix squamous epithelium	UBERON:0006922	99.88	gold quality
renal medulla	UBERON:0000362	99.87	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.87	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.87	gold quality
pancreatic ductal cell	CL:0002079	99.86	gold quality
trigeminal ganglion	UBERON:0001675	99.86	gold quality
parietal lobe	UBERON:0001872	99.86	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.86	gold quality
prefrontal cortex	UBERON:0000451	99.85	gold quality
cardia of stomach	UBERON:0001162	99.85	gold quality
nipple	UBERON:0002030	99.85	gold quality
postcentral gyrus	UBERON:0002581	99.85	gold quality
entorhinal cortex	UBERON:0002728	99.85	gold quality
CA1 field of hippocampus	UBERON:0003881	99.85	gold quality
mucosa of transverse colon	UBERON:0004991	99.85	gold quality
cranial nerve II	UBERON:0000941	99.83	gold quality
inferior olivary complex	UBERON:0002127	99.83	gold quality
superior frontal gyrus	UBERON:0002661	99.83	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-7606	yes	2191.66
E-HCAD-4	yes	115.37
E-HCAD-1	yes	100.04
E-CURD-122	yes	43.50
E-CURD-46	yes	30.52
E-HCAD-9	yes	22.56
E-CURD-88	yes	21.83
E-HCAD-31	yes	21.05
E-MTAB-10042	yes	18.07
E-MTAB-8410	yes	16.89
E-MTAB-7316	yes	16.26
E-CURD-112	yes	10.10
E-MTAB-10553	yes	8.97
E-HCAD-11	yes	7.42
E-GEOD-130148	yes	6.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EWSR1, NR1I2

miRNA regulators (miRDB)

61 targeting CFL1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4685-5P	99.25	65.99	1563

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 59.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• differences in actin binding by human ADF and cofilin (PMID:11812157)
• cofilin interacts with the serine phosphatases PP1 and PP2A in normal and neoplastic human T lymphocytes [review] (PMID:12791392)
• interaction between the C-terminal tail of ClC-5 and cofilin, an actin-associated protein that is crucial in the regulation of albumin uptake by the proximal tubule (PMID:12904289)
• Important sequence differences between actin-depolymerizing factor/cofilin were correlated with unique structural determinants in the F-actin-binding site to account for differences in biochemical activities of the two proteins. (PMID:14627701)
• After induction of apoptosis, cofilin was translocated to mitochondria before release of cytochrome c. Reduction of cofilin with siRNA resulted in inhibition of both cytochrome c release and apoptosis. (PMID:14634665)
• Cofilin-phosphatase activity of SSH1L increases by association with actin filaments, indicating that actin assembly at the leading edge per se triggers local activation of SSH1L and thereby stimulates cofilin-mediated actin turnover in lamellipodia. (PMID:15159416)
• NMR assignments of human cofilin (PMID:15213453)
• cofilin 1 inhibited glucocorticoid receptor activity; cofilin represents a novel factor that can cause glucocorticoid resistance (PMID:15485906)
• a novel pathway emanating from the TGF-beta type I receptor and leading to regulation of actin assembly, via the kinase LIMK2. (PMID:15647284)
• a multi-protein complex consisting of SSH-1L, LIMK1, actin, and the scaffolding protein, 14-3-3zeta, is involved, along with the kinase, PAK4, in the regulation of ADF/cofilin activity (PMID:15660133)
• Ca2+-induced cofilin dephosphorylation is mediated by calcineurin-dependent activation of SSH1L (PMID:15671020)
• Regulation by cofilin of actin depolymerization is important in the process of neuroblastoma cell motility, and IGF-I regulates cofilin activity in part through PI-3K, rac, and LIM kinase. (PMID:15719172)
• downregulated following UV exposure in epidermis (PMID:15816841)
• cofilin can influence radiosensitivity by altering DNA repair capacity (PMID:16061204)
• excessive cofilin production might have a role in preventing cancer cell invasion (PMID:16301112)
• Increased expression may be important in the regulation of glucocorticoid sensitivity in peripheral blood lymphocytes of patients with severe treatment-insensitive asthma. (PMID:17088134)
• In the absence of any crystal structures of ADF or cofilin in complex with actin, these studies provide further information about the binding sites on F-actin for these important actin regulatory proteins. (PMID:17196218)
• The sequence variation of human CFL1 gene is a genetic modifier for spina bifida risk in California population (PMID:17352815)
• destrin is a significant regulator of various processes important for invasive phenotype of human colon cancer Isreco1 cells whereas cofilin-1 may be involved in only a subset of them (PMID:17583572)
• PDGF participates in actin dynamics by dual regulation of cofilin activity via LIMK and SSH1L in aortic smooth muscle cells (PMID:18096821)
• These studies suggest that CAP1 provides a direct link from the actin cytoskeleton to the mitochondria by functioning as an actin shuttle. (PMID:18716285)
• HIV utilizes the Galphai-dependent signaling from the chemokine coreceptor CXCR4 to activate a cellular actin-depolymerizing factor, cofilin, to overcome the static cortical actin restriction in resting CD4 T cells. (PMID:18775311)
• the conserved SSH-N domain of slingshot-1 plays critical roles in P-cofilin recognition, F-actin-mediated activation, and subcellular localization of SSH1 (PMID:18809681)
• tropomyosin 1 and cofilin play antagonistic roles within the contractile ring and that the balance between tropomyosin 1 and cofilin expression is important for cytokinesis. (PMID:18937355)
• These results strongly support the importance of cofilin in tight-junction opening, suggesting cofilin as a target for tight-junction permeability regulation in epithelial cells. (PMID:18952063)
• Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for melanoma progression. (PMID:18987670)
• Study demonstrates the ATP-sensitive interaction of the cofilin phosphatase chronophin (CIN) with the chaperone hsp90 to form a biosensor that mediates cofilin/actin rod formation. (PMID:19000834)
• This protein has been found differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19110265)
• Memo was detected in complexes with cofilin, ErbB2 and PLCgamma1. (PMID:19223396)
• Results suggest that the formation of ROS by NADPH oxidases engages a SSH-1L-cofilin pathway to regulate cytoskeletal organization and cell migration. (PMID:19339277)
• BPAG1e is required for efficient regulation of keratinocyte polarity and migration by determining the activation of Rac1. (PMID:19403692)
• Cofilin-1 occupies a central position in RhoA-actin pathway mediating nuclear translocation of RelA/p65 and expression of ICAM-1 in endothelial cells. (PMID:19483084)
• Studies showed that three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease. (PMID:19546591)
• These data suggest that cofilin expression and its regulation of p27(kip1) expression is important for the control of G(1) phase progression. (PMID:19556892)
• Data identify PKD as a central regulator of the cofilin signaling network via direct phosphorylation and regulation of SSH1L. (PMID:19567672)
• Coronin 2A and cofilin regulate a subset of focal-adhesion-turnover events. (PMID:19654210)
• The authors conclude that HIV-1 Nef alters Pak2 function, which directly or indirectly inactivates cofilin, thereby restricting migration of infected T lymphocytes as part of a strategy to optimize immune evasion and HIV-1 replication. (PMID:19683683)
• Oxidant-induced apoptosis is mediated by oxidation of CFL. (PMID:19734890)
• Results suggest a novel mechanism by which cofilin is regulated by v-Src through tyrosine phosphorylation that triggers the degradation of cofilin through ubiquitination-proteosome pathway and reducing cellular F-actin contents and cell spreading. (PMID:19802004)
• presence of cofilin also increases the cross-linking of actin filaments by alpha-actinin and hypothesize that this is due to cofilin’s ability to alter the filament twist (PMID:19997845)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cfl1	ENSDARG00000021124
mus_musculus	Cfl1	ENSMUSG00000056201
rattus_norvegicus	Cfl1	ENSRNOG00000020660
drosophila_melanogaster	tsr	FBGN0011726
drosophila_melanogaster	CG6873	FBGN0030951
caenorhabditis_elegans		WBGENE00006794
caenorhabditis_elegans		WBGENE00302980

Paralogs (2): DSTN (ENSG00000125868), CFL2 (ENSG00000165410)

Protein

Protein identifiers

Cofilin-1 — P23528 (reviewed: P23528)

Alternative names: 18 kDa phosphoprotein, Cofilin, non-muscle isoform

All UniProt accessions (8): P23528, E9PK25, E9PLJ3, E9PP50, E9PQB7, E9PS23, G3V1A4, V9HWI5

UniProt curated annotations — full annotation on UniProt →

Function. Binds to F-actin and exhibits pH-sensitive F-actin depolymerizing activity. In conjunction with the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics. Required for the centralization of the mitotic spindle and symmetric division of zygotes. Plays a role in the regulation of cell morphology and cytoskeletal organization in epithelial cells. Required for the up-regulation of atypical chemokine receptor ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. Required for neural tube morphogenesis and neural crest cell migration.

Subunit / interactions. Can bind G- and F-actin in a 1:1 ratio of cofilin to actin. It is a major component of intranuclear and cytoplasmic actin rods. Interacts with the subcortical maternal complex (SCMC) via interaction with TLE6 isoform 1 and NLRP5. Interacts with C9orf72. (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction probably facilitates viral replication.

Subcellular location. Nucleus matrix. Cytoplasm. Cytoskeleton. Cell projection. Ruffle membrane. Lamellipodium membrane. Lamellipodium. Growth cone. Axon.

Tissue specificity. Widely distributed in various tissues.

Post-translational modifications. Inactivated by phosphorylation on Ser-3. Phosphorylated on Ser-3 in resting cells. Dephosphorylated by PDXP/chronophin; this restores its activity in promoting actin filament depolymerization. The phosphorylation of Ser-24 may prevent recognition of the nuclear localization signal. Phosphorylated via a ARRB1-RAC1-LIMK1-PAK1 cascade upon active ligand stimulation of atypical chemokine receptor ACKR2.

Induction. Up-regulated in response to enterovirus 71 (EV71) infection (at protein level).

Similarity. Belongs to the actin-binding proteins ADF family.

RefSeq proteins (1): NP_005498* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002108	ADF-H	Domain
IPR017904	ADF/Cofilin	Family
IPR029006	ADF-H/Gelsolin-like_dom_sf	Homologous_superfamily

Pfam: PF00241

UniProt features (35 total): modified residue 14, helix 8, strand 7, initiator methionine 1, chain 1, cross-link 1, domain 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
9H1F	X-RAY DIFFRACTION	1.8
9QFJ	ELECTRON MICROSCOPY	2.31
5L6W	X-RAY DIFFRACTION	2.53
9QFD	ELECTRON MICROSCOPY	2.61
9QFQ	ELECTRON MICROSCOPY	2.76
4BEX	X-RAY DIFFRACTION	2.8
9QFO	ELECTRON MICROSCOPY	2.96
9QFE	ELECTRON MICROSCOPY	3.12
9QFW	ELECTRON MICROSCOPY	3.16
6VAO	ELECTRON MICROSCOPY	3.4
9QFG	ELECTRON MICROSCOPY	3.49
5HVK	X-RAY DIFFRACTION	3.5
9QFK	ELECTRON MICROSCOPY	3.99
6UBY	ELECTRON MICROSCOPY	7.5
6UC0	ELECTRON MICROSCOPY	7.5
3J0S	ELECTRON MICROSCOPY	9
6UC4	ELECTRON MICROSCOPY	9.2
1Q8G	SOLUTION NMR
1Q8X	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23528-F1	87.86	0.45

Antibody-complex structures (SAbDab): 1 — 9H1F

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 (15): 63, 68, 73, 82, 108, 140, 144, 156, 132, 2, 3, 8, 13, 25, 41

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-399954	Sema3A PAK dependent Axon repulsion
R-HSA-5627117	RHO GTPases Activate ROCKs
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation

MSigDB gene sets: 560 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_MITOTIC_CYTOKINESIS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, HONMA_DOCETAXEL_RESISTANCE, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, WWTAAGGC_UNKNOWN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS

GO Biological Process (54): mitotic cytokinesis (GO:0000281), neural crest cell migration (GO:0001755), neural fold formation (GO:0001842), protein import into nucleus (GO:0006606), cytoskeleton organization (GO:0007010), negative regulation of cell adhesion (GO:0007162), Rho protein signal transduction (GO:0007266), response to virus (GO:0009615), positive regulation of lamellipodium assembly (GO:0010592), negative regulation of lamellipodium assembly (GO:0010593), response to activity (GO:0014823), hippocampus development (GO:0021766), regulation of cell morphogenesis (GO:0022604), establishment of cell polarity (GO:0030010), cell projection organization (GO:0030030), actin cytoskeleton organization (GO:0030036), actin filament depolymerization (GO:0030042), actin filament fragmentation (GO:0030043), positive regulation of cell growth (GO:0030307), negative regulation of actin filament depolymerization (GO:0030835), positive regulation of actin filament depolymerization (GO:0030836), positive regulation of synaptic plasticity (GO:0031915), negative regulation of actin filament bundle assembly (GO:0032232), positive regulation of embryonic development (GO:0040019), negative regulation of apoptotic process (GO:0043066), response to amino acid (GO:0043200), host-mediated activation of viral process (GO:0044794), negative regulation of cell size (GO:0045792), positive regulation of proteolysis (GO:0045862), actin filament severing (GO:0051014), establishment of spindle localization (GO:0051293), negative regulation of unidimensional cell growth (GO:0051511), positive regulation of focal adhesion assembly (GO:0051894), positive regulation of dendritic spine development (GO:0060999), regulation of dendritic spine morphogenesis (GO:0061001), cellular response to hydrogen peroxide (GO:0070301), cellular response to interleukin-1 (GO:0071347), cellular response to interleukin-6 (GO:0071354), cellular response to tumor necrosis factor (GO:0071356), cellular response to ether (GO:0071362)

GO Molecular Function (6): signaling receptor binding (GO:0005102), protein phosphatase binding (GO:0019903), actin filament binding (GO:0051015), phosphatidylinositol bisphosphate binding (GO:1902936), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (29): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), nuclear matrix (GO:0016363), lamellipodium (GO:0030027), filopodium (GO:0030175), growth cone (GO:0030426), cortical actin cytoskeleton (GO:0030864), lamellipodium membrane (GO:0031258), mitochondrial membrane (GO:0031966), vesicle (GO:0031982), ruffle membrane (GO:0032587), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), extracellular exosome (GO:0070062), cofilin-actin rod (GO:0090732), synaptic membrane (GO:0097060), glutamatergic synapse (GO:0098978), postsynaptic density, intracellular component (GO:0099092), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), axon (GO:0030424), cell leading edge (GO:0031252), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
EPH-Ephrin signaling	1
Semaphorin interactions	1
RHO GTPase Effectors	1
Interleukin-12 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of lamellipodium assembly	2
lamellipodium assembly	2
actin filament depolymerization	2
cell projection membrane	2
leading edge membrane	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
neural crest cell development	1
mesenchymal cell migration	1
primary neural tube formation	1
morphogenesis of embryonic epithelium	1
anatomical structure formation involved in morphogenesis	1
morphogenesis of an epithelial fold	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
organelle organization	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
small GTPase-mediated signal transduction	1
response to other organism	1
positive regulation of plasma membrane bounded cell projection assembly	1
positive regulation of lamellipodium organization	1
negative regulation of plasma membrane bounded cell projection assembly	1
negative regulation of lamellipodium organization	1
response to stimulus	1
pallium development	1
limbic system development	1
anatomical structure development	1
cell morphogenesis	1
regulation of anatomical structure morphogenesis	1
establishment or maintenance of cell polarity	1
cellular component organization	1
cytoskeleton organization	1
actin filament-based process	1
actin polymerization or depolymerization	1

Protein interactions and networks

STRING

4526 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFL1	WASL	O00401	997
CFL1	HCLS1	P14317	995
CFL1	CTTN	Q14247	995
CFL1	WDR1	O75083	985
CFL1	LIMK1	P53667	983
CFL1	PFN1	P07737	973
CFL1	PFN4	Q8NHR9	957
CFL1	SSH1	Q8WYL5	949
CFL1	PFN3	P60673	948
CFL1	ACTR2	P61160	920
CFL1	CDC42	P21181	920
CFL1	ACTN1	P12814	908
CFL1	RHOA	P06749	902
CFL1	LIMK2	P53671	900
CFL1	SSH3	Q8TE77	890

IntAct

279 interactions, top by confidence:

A	B	Type	Score
CFL1	ACTB	psi-mi:“MI:0915”(physical association)	0.930
ACTB	CFL1	psi-mi:“MI:0915”(physical association)	0.930
H2AX	PARP1	psi-mi:“MI:0914”(association)	0.840
CFL1	ACTG1	psi-mi:“MI:0915”(physical association)	0.830
ACTG1	CFL1	psi-mi:“MI:0915”(physical association)	0.830
CFL1	LIMK1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFL1	ATXN1	psi-mi:“MI:0915”(physical association)	0.700
EGFR	CFL1	psi-mi:“MI:0915”(physical association)	0.670
CFL1	EGFR	psi-mi:“MI:0915”(physical association)	0.670
YWHAZ	CFL1	psi-mi:“MI:0915”(physical association)	0.660

BioGRID (545): CFL1 (Affinity Capture-MS), CFL1 (Two-hybrid), CFL1 (Two-hybrid), CFL2 (Two-hybrid), CFL1 (Affinity Capture-MS), CFL1 (Affinity Capture-MS), CAP1 (Affinity Capture-MS), CAP2 (Affinity Capture-MS), CFL1 (Two-hybrid), CFL1 (Two-hybrid), CFL1 (Affinity Capture-MS), CFL1 (Affinity Capture-MS), CFL1 (Affinity Capture-MS), ABAT (Co-fractionation), ACAA2 (Co-fractionation)

ESM2 similar proteins: A4FUD6, B0BN93, B5DGH9, O60234, O80526, P10668, P18760, P21566, P23528, P45591, P45592, P60983, P60984, P84169, Q05AY2, Q148F1, Q15437, Q1LUA8, Q28C65, Q2QNG7, Q3B8M3, Q3SZN2, Q3T102, Q4R5C0, Q4R6G8, Q56JZ9, Q5E964, Q5E9F7, Q5G6V9, Q5R5G2, Q5R6P6, Q5RCC1, Q5U4Y2, Q5XHH8, Q5ZK03, Q5ZLA5, Q63228, Q6B7M7, Q6DRI1, Q6GNI4

Diamond homologs: C4LVG4, O49606, P0CM06, P0CM07, P0DJ26, P0DJ27, P10668, P18359, P18760, P23528, P30174, P30175, P37167, P45592, P45594, P46251, P60981, P60982, P78929, P86293, Q03048, Q0D744, Q0DLA3, Q17A58, Q2QLT8, Q337A5, Q39250, Q39251, Q41764, Q43694, Q4I963, Q4P6E9, Q4R5C0, Q54R65, Q570Y6, Q5E9D5, Q5E9F7, Q5I082, Q5ZM35, Q640W2

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
LIMK2	“down-regulates activity”	CFL1	phosphorylation
TESK1	“down-regulates activity”	CFL1	phosphorylation
TESK2	“down-regulates activity”	CFL1	phosphorylation
LIMK1	down-regulates	CFL1	phosphorylation
ILK	down-regulates	CFL1	phosphorylation
SRC	down-regulates	CFL1	phosphorylation
PRKCA	down-regulates	CFL1	phosphorylation
SSH2	“up-regulates activity”	CFL1	dephosphorylation
SSH3	“up-regulates activity”	CFL1	dephosphorylation
SSH1	“up-regulates activity”	CFL1	dephosphorylation
CFL1	“down-regulates quantity”	F-actin_assembly	binding
CFL1	down-regulates	Axonal_growth_cone_formation
PTEN	“up-regulates activity”	CFL1	dephosphorylation
AURKA	“down-regulates activity”	CFL1	phosphorylation
PDXP	“down-regulates activity”	CFL1	dephosphorylation
ROBO2	“up-regulates quantity by expression”	CFL1	“post transcriptional regulation”
ROBO3	“up-regulates quantity by expression”	CFL1	“post transcriptional regulation”
PRKD1	“down-regulates activity”	CFL1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PI3K events in ERBB2 signaling	5	33.6×	2e-05
RHO GTPases activate PAKs	6	32.6×	3e-06
Signaling by ERBB2 TMD/JMD mutants	6	28.6×	6e-06
Signaling by ERBB2 KD Mutants	6	25.4×	1e-05
SHC1 events in ERBB2 signaling	5	23.8×	9e-05
Signaling by RAS mutants	5	21.1×	1e-04
Downregulation of ERBB2 signaling	5	19.0×	2e-04
Sensory processing of sound	6	18.5×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of cell polarity	5	16.2×	3e-03
epidermal growth factor receptor signaling pathway	7	14.0×	7e-04
platelet aggregation	5	13.6×	5e-03
positive regulation of fibroblast proliferation	5	11.9×	6e-03
cellular response to virus	6	9.7×	5e-03
actin filament organization	9	8.6×	7e-04
in utero embryonic development	9	5.2×	6e-03
negative regulation of apoptotic process	13	3.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3531 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65850010:GAGGA:G	donor_gain	1.0000
11:65850012:G:GT	donor_gain	1.0000
11:65850012:GGA:G	donor_gain	1.0000
11:65850013:G:GT	donor_gain	1.0000
11:65850013:GA:G	donor_gain	1.0000
11:65850015:G:GG	donor_gain	1.0000
11:65850031:G:GG	donor_gain	1.0000
11:65850036:G:GT	donor_gain	1.0000
11:65850270:GC:G	donor_gain	1.0000
11:65850272:G:GG	donor_gain	1.0000
11:65850430:GGGA:G	acceptor_gain	1.0000
11:65850551:GGAT:G	donor_gain	1.0000
11:65850552:G:GT	donor_gain	1.0000
11:65850560:C:G	donor_gain	1.0000
11:65850741:T:TA	acceptor_gain	1.0000
11:65850750:GCT:G	acceptor_gain	1.0000
11:65851159:GT:G	donor_gain	1.0000
11:65851161:G:GG	donor_gain	1.0000
11:65851396:C:G	donor_gain	1.0000
11:65851404:G:GG	donor_gain	1.0000
11:65852443:A:AG	acceptor_gain	1.0000
11:65852444:G:GG	acceptor_gain	1.0000
11:65852624:TCCTA:T	acceptor_loss	1.0000
11:65852625:CCTAG:C	acceptor_loss	1.0000
11:65852626:CTAG:C	acceptor_loss	1.0000
11:65852627:TAGG:T	acceptor_loss	1.0000
11:65852628:A:AG	acceptor_gain	1.0000
11:65852628:A:T	acceptor_loss	1.0000
11:65852629:G:GG	acceptor_gain	1.0000
11:65852629:G:T	acceptor_loss	1.0000

AlphaMissense

1096 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65855448:C:T	G130E	1.000
11:65855654:C:G	G130R	1.000
11:65855654:C:T	G130R	1.000
11:65855679:C:A	K121N	1.000
11:65855679:C:G	K121N	1.000
11:65855683:G:A	S120F	1.000
11:65855685:G:C	S119R	1.000
11:65855685:G:T	S119R	1.000
11:65855687:T:G	S119R	1.000
11:65855689:G:T	A118D	1.000
11:65855698:A:C	M115R	1.000
11:65855698:A:G	M115T	1.000
11:65855698:A:T	M115K	1.000
11:65855700:T:A	K114N	1.000
11:65855700:T:G	K114N	1.000
11:65855702:T:C	K114E	1.000
11:65855936:A:G	W104R	1.000
11:65855936:A:T	W104R	1.000
11:65855989:T:A	D86V	1.000
11:65855995:A:G	L84P	1.000
11:65855995:A:T	L84H	1.000
11:65855998:G:T	A83D	1.000
11:65856002:A:G	Y82H	1.000
11:65856006:G:C	C80W	1.000
11:65856007:C:T	C80Y	1.000
11:65856008:A:G	C80R	1.000
11:65856133:A:G	F38S	1.000
11:65856189:C:A	K19N	1.000
11:65856189:C:G	K19N	1.000
11:65856201:G:C	F15L	1.000

dbSNP variants (sampled 300 via entrez): RS1000036052 (11:65856309 G>A,T), RS1000490980 (11:65856144 C>T), RS1000856599 (11:65860136 T>C), RS1000963823 (11:65858287 C>G,T), RS1001567706 (11:65858358 G>C), RS1002591222 (11:65857279 C>T), RS1002667289 (11:65856374 C>G,T), RS1002961084 (11:65856985 A>G), RS1002991371 (11:65857453 T>A,C,G), RS1003296078 (11:65854491 C>A,G), RS1003746710 (11:65854370 G>A,C), RS1004029428 (11:65857761 G>A,C,T), RS1004082043 (11:65857632 C>G), RS1004875474 (11:65858031 T>G), RS1004906503 (11:65857858 G>A)

Disease associations

OMIM: gene MIM:601442 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001937_15	Breast cancer	9.000000e-12
GCST002058_5	DNA methylation (variation)	2.000000e-07
GCST002481_8	Acne (severe)	3.000000e-11
GCST004346_52	Psoriasis	7.000000e-09
GCST008870_46	Keratinocyte cancer (MTAG)	4.000000e-11
GCST008871_9	Basal cell carcinoma	2.000000e-13
GCST90002398_198	Neutrophil count	4.000000e-12
GCST90002402_353	Platelet count	2.000000e-10
GCST90002407_330	White blood cell count	7.000000e-18
GCST90020025_1881	Waist-to-hip ratio adjusted for BMI	7.000000e-12
GCST90020027_1497	Waist-hip index	4.000000e-12
GCST90020029_330	Waist circumference adjusted for body mass index	2.000000e-08
GCST90020029_331	Waist circumference adjusted for body mass index	2.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0022599	DNA methylation
EFO:0010176	keratinocyte carcinoma
EFO:0004833	neutrophil count
EFO:0004309	platelet count
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075129 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.21	Kd	62.37	nM	CHEMBL5653589
7.21	ED50	62.37	nM	CHEMBL5653589
5.14	Kd	7305	nM	CHEMBL3752910
5.14	ED50	7305	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 22 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148063: Binding affinity to human CFL1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0624	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148063: Binding affinity to human CFL1 incubated for 45 mins by Kinobead based pull down assay	kd	7.3049	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	3
Tobacco Smoke Pollution	affects expression, increases expression, increases metabolic processing	3
bisphenol F	increases expression, affects cotreatment	2
chloropicrin	affects expression, decreases expression	2
Arsenic	affects expression, decreases expression	2
Benzo(a)pyrene	decreases expression, increases expression, affects reaction	2
Nickel	increases expression	2
Okadaic Acid	increases expression	2
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	increases expression	1
4-hydroxy-2-nonenal	affects binding	1
potassium hydroxide	increases expression	1
cupric oxide	increases expression	1
artenimol	affects binding	1
methacrylaldehyde	affects cotreatment, increases oxidation	1
myricetin	increases expression	1
dibenzo(a,l)pyrene	decreases expression	1
diallyl trisulfide	decreases expression	1
fasudil	decreases expression, decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
Y 27632	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1109057	Binding	Inhibition of cofilin phosphorylation in human U937 cells after 24 hrs by Western blotting	Cucurbitacin E as a new inhibitor of cofilin phosphorylation in human leukemia U937 cells. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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