PLEK

Summary

PLEK (pleckstrin, HGNC:9070) is a protein-coding gene on chromosome 2p14, encoding Pleckstrin (P08567). Major protein kinase C substrate of platelets.

Enables several functions, including phosphatidylinositol-3,4-bisphosphate binding activity; protein homodimerization activity; and protein kinase C binding activity. Involved in several processes, including G protein-coupled receptor signaling pathway; integrin-mediated signaling pathway; and positive regulation of supramolecular fiber organization. Located in cytoplasm and ruffle membrane.

Source: NCBI Gene 5341 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss 58 (Limited, GenCC)
• GWAS associations: 20
• Clinical variants (ClinVar): 50 total
• GTEx eGene: eQTL in 19 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 0.81 (unconstrained)
• MANE Select transcript: NM_002664
• Interaction hub: 3,820 STRING partners (top 1% of genes corpus-wide)
• Notable: 50 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9070
Approved symbol	PLEK
Name	pleckstrin
Location	2p14
Locus type	gene with protein product
Status	Approved
Aliases	P47, PLEK1
Ensembl gene	ENSG00000115956
Ensembl biotype	protein_coding
OMIM	173570
Entrez	5341

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000234313

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1

ENST00000234313, ENST00000474788, ENST00001049503, ENST00001095838, ENST00001110805, ENST00001118406, ENST00001142524

RefSeq mRNA: 1 — MANE Select: NM_002664 NM_002664

CCDS: CCDS1887

Canonical transcript exons

ENST00000234313 — 9 exons

Exon	Start	End
ENSE00000758794	68380723	68380904
ENSE00000758796	68382542	68382633
ENSE00000758798	68386502	68386686
ENSE00000758800	68388387	68388491
ENSE00000963053	68380328	68380483
ENSE00001163794	68395680	68397453
ENSE00001911788	68365282	68365393
ENSE00003547803	68394107	68394176
ENSE00003577887	68393162	68393245

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 99.08.

FANTOM5 (CAGE): breadth broad, TPM avg 119.7135 / max 9473.8797, expressed in 530 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, granulocyte, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PLEK is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

19 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	eqtl	4.4e-11	+0.45	2:68246325:A:G
Whole Blood	eqtl	1.3e-10	+0.14	2:68371885:C:A
Spleen	eqtl	8.5e-09	+0.21	2:68366013:G:A
Brain Nucleus accumbens basal ganglia	eqtl	3.6e-07	+0.34	2:68276788:A:G
Brain Caudate basal ganglia	eqtl	3.9e-05	-0.28	2:68422497:C:A
Brain Frontal Cortex BA9	eqtl	5.3e-05	-0.25	2:68356037:T:C
Brain Cerebellum	eqtl	6.3e-05	+0.39	2:68259977:A:G
Cells Cultured fibroblasts	eqtl	6.7e-04	+0.28	2:68251787:A:G
Brain Putamen basal ganglia	eqtl	5.1e-03	-0.24	2:68358352:G:A
Adipose Subcutaneous	eqtl	1.1e-02	+0.08	2:68372750:G:A
Esophagus Gastroesophageal Junction	eqtl	1.4e-02	+0.16	2:68419334:G:C
Adipose Visceral Omentum	eqtl	1.9e-02	+0.11	2:68422565:C:T
Small Intestine Terminal Ileum	eqtl	2.0e-02	-0.68	2:67805943:G:A
Testis	eqtl	2.2e-02	+0.66	2:67777734:G:A
Cells EBV-transformed lymphocytes	eqtl	2.3e-02	-0.15	2:68357305:C:A
Pancreas	eqtl	2.7e-02	-0.36	2:69184641:G:T
Colon Transverse	eqtl	3.1e-02	+0.57	2:67506589:C:A
Brain Spinal cord cervical c-1	eqtl	3.5e-02	+0.16	2:68429210:T:C
Heart Left Ventricle	eqtl	3.9e-02	-0.28	2:68522139:T:C

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
20673	114.3031	512
20672	4.3541	335
20686	0.3232	80
20685	0.2758	73
20687	0.1562	58
20689	0.1224	51
20671	0.0997	54
20690	0.0789	38

Top tissues by expression

showing 100 of 277 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.08	gold quality
mononuclear cell	CL:0000842	99.01	gold quality
leukocyte	CL:0000738	99.00	gold quality
granulocyte	CL:0000094	98.83	gold quality
blood	UBERON:0000178	98.02	gold quality
bone marrow	UBERON:0002371	97.66	gold quality
bone marrow cell	CL:0002092	97.16	gold quality
lymph node	UBERON:0000029	96.34	gold quality
vermiform appendix	UBERON:0001154	96.19	gold quality
spleen	UBERON:0002106	95.76	gold quality
periodontal ligament	UBERON:0008266	95.43	gold quality
bone element	UBERON:0001474	95.31	gold quality
trabecular bone tissue	UBERON:0002483	94.56	gold quality
caecum	UBERON:0001153	92.44	gold quality
olfactory bulb	UBERON:0002264	91.98	gold quality
type B pancreatic cell	CL:0000169	91.03	gold quality
gall bladder	UBERON:0002110	89.83	gold quality
tongue squamous epithelium	UBERON:0006919	89.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.25	gold quality
upper lobe of left lung	UBERON:0008952	88.82	gold quality
upper lobe of lung	UBERON:0008948	87.77	gold quality
rectum	UBERON:0001052	87.75	gold quality
superficial temporal artery	UBERON:0001614	86.95	gold quality
tonsil	UBERON:0002372	85.93	gold quality
right lung	UBERON:0002167	85.66	gold quality
smooth muscle tissue	UBERON:0001135	85.50	gold quality
omental fat pad	UBERON:0010414	85.23	gold quality
peritoneum	UBERON:0002358	85.19	gold quality
right coronary artery	UBERON:0001625	85.09	gold quality
lung	UBERON:0002048	84.68	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.63	gold quality
epithelium of nasopharynx	UBERON:0001951	84.44	gold quality
nasopharynx	UBERON:0001728	84.43	gold quality
triceps brachii	UBERON:0001509	83.73	gold quality
upper arm skin	UBERON:0004263	83.48	gold quality
amniotic fluid	UBERON:0000173	83.19	gold quality
gluteal muscle	UBERON:0002000	83.00	gold quality
layer of synovial tissue	UBERON:0007616	82.39	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	82.00	silver quality
nasal cavity epithelium	UBERON:0005384	81.54	silver quality
subcutaneous adipose tissue	UBERON:0002190	81.13	gold quality
germinal epithelium of ovary	UBERON:0001304	80.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.79	gold quality
left uterine tube	UBERON:0001303	80.75	gold quality
adipose tissue	UBERON:0001013	80.72	gold quality
placenta	UBERON:0001987	80.63	gold quality
connective tissue	UBERON:0002384	80.49	gold quality
caudate nucleus	UBERON:0001873	80.22	gold quality
vena cava	UBERON:0004087	80.22	silver quality
putamen	UBERON:0001874	80.01	gold quality
hair follicle	UBERON:0002073	79.86	gold quality
decidua	UBERON:0002450	79.85	gold quality
small intestine	UBERON:0002108	79.78	gold quality
descending thoracic aorta	UBERON:0002345	79.72	gold quality
colonic epithelium	UBERON:0000397	79.64	gold quality
right adrenal gland cortex	UBERON:0035827	79.62	gold quality
mammalian vulva	UBERON:0000997	79.58	gold quality
liver	UBERON:0002107	79.06	gold quality
coronary artery	UBERON:0001621	78.84	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.75	gold quality
left coronary artery	UBERON:0001626	78.69	gold quality
pleura	UBERON:0000977	78.57	gold quality
buccal mucosa cell	CL:0002336	78.56	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	78.44	gold quality
thymus	UBERON:0002370	78.37	gold quality
parietal pleura	UBERON:0002400	78.33	gold quality
thoracic aorta	UBERON:0001515	78.31	gold quality
right lobe of liver	UBERON:0001114	78.27	gold quality
urinary bladder	UBERON:0001255	78.12	gold quality
ascending aorta	UBERON:0001496	78.03	gold quality
right adrenal gland	UBERON:0001233	77.99	gold quality
superior surface of tongue	UBERON:0007371	77.93	gold quality
heart right ventricle	UBERON:0002080	77.91	silver quality
vastus lateralis	UBERON:0001379	77.90	gold quality
gingiva	UBERON:0001828	77.82	silver quality
spinal cord	UBERON:0002240	77.66	gold quality
visceral pleura	UBERON:0002401	77.65	gold quality
mucosa of urinary bladder	UBERON:0001259	77.33	gold quality
intestine	UBERON:0000160	77.23	gold quality
gingival epithelium	UBERON:0001949	77.04	gold quality
mucosa of sigmoid colon	UBERON:0004993	76.88	gold quality
calcaneal tendon	UBERON:0003701	76.80	gold quality
mucosa of transverse colon	UBERON:0004991	76.73	gold quality
large intestine	UBERON:0000059	76.59	gold quality
colonic mucosa	UBERON:0000317	76.39	gold quality
transverse colon	UBERON:0001157	76.36	gold quality
colon	UBERON:0001155	76.30	gold quality
diaphragm	UBERON:0001103	76.19	gold quality
apex of heart	UBERON:0002098	76.13	gold quality
tongue	UBERON:0001723	75.99	silver quality
lower lobe of lung	UBERON:0008949	75.89	silver quality
left adrenal gland	UBERON:0001234	75.68	gold quality
adrenal gland	UBERON:0002369	75.63	gold quality
substantia nigra	UBERON:0002038	75.48	gold quality
muscle tissue	UBERON:0002385	75.44	gold quality
adrenal cortex	UBERON:0001235	75.34	gold quality
pylorus	UBERON:0001166	75.30	gold quality
ileal mucosa	UBERON:0000331	75.24	gold quality
saliva-secreting gland	UBERON:0001044	75.15	gold quality
palpebral conjunctiva	UBERON:0001812	75.13	gold quality

Single-cell (SCXA)

Detected in 31 experiment(s), a significant marker in 29.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	3767.08
E-MTAB-10432	yes	2990.09
E-MTAB-9067	yes	2672.10
E-CURD-98	yes	2281.72
E-MTAB-7407	yes	1880.54
E-GEOD-135922	yes	1745.66
E-CURD-6	yes	1564.42
E-GEOD-130473	yes	1465.43
E-MTAB-8884	yes	1427.00
E-HCAD-6	yes	1327.01
E-GEOD-75688	yes	1021.97
E-ANND-5	yes	619.18
E-HCAD-1	yes	84.78
E-CURD-122	yes	47.35
E-GEOD-84465	yes	39.41

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	571.1	medium
Lymph node	tissue	121.5	high
Tonsil	tissue	110.7	medium
Appendix	tissue	93.8	low
Spleen	tissue	88.1	high
Urinary bladder	tissue	48.7	not detected
Adipose tissue	tissue	34.0	not detected
Lung	tissue	33.6	not detected
Thymus	tissue	31.4
Placenta	tissue	27.5	not detected
Liver	tissue	25.7	not detected
Smooth muscle	tissue	20.7	not detected
Gallbladder	tissue	19.7	not detected
Rectum	tissue	17.7	not detected
Colon	tissue	12.4	low
Small intestine	tissue	12.0	medium
Spinal cord	tissue	11.0
Stomach 1	tissue	10.6	low
Caudate putamen	tissue	10.5
Substantia nigra	tissue	10.2
Periaqueductal gray	tissue	10.2
Hypothalamus	tissue	10.0
Duodenum	tissue	9.8	medium
Medulla oblongata	tissue	9.3
Adrenal gland	tissue	9.2	not detected
Pons	tissue	9.1
Corpus callosum	tissue	9.1
Midbrain	tissue	8.6
Septum	tissue	8.1
Choroid plexus	tissue	8.0
Putamen	tissue	7.8
Breast	tissue	7.7	not detected
Hippocampal formation	tissue	7.4
Frontal cortex	tissue	7.3
Thalamus	tissue	7.2
Cerebral cortex	tissue	7.1	not detected
Somatosensory cortex	tissue	7.1
Occipital cortex	tissue	7.0
Prefrontal cortex	tissue	6.8
Motor cortex	tissue	6.8
Retrosplenial and cingulate cortex	tissue	6.6
Retrosplenial cortex	tissue	6.6
Cervix	tissue	6.4	not detected
Entorhinal cortex	tissue	6.3
Insular cortex	tissue	6.2
Superior colliculi	tissue	6.1
Ventral forebrain	tissue	6.1
Temporal cortex	tissue	6.0
Basal ganglia	tissue	5.8	not detected
Olfactory bulb	tissue	5.8
Amygdala	tissue	5.7
Esophagus	tissue	5.6	not detected
Salivary gland	tissue	5.4	not detected
Heart muscle	tissue	5.0	not detected
Tongue	tissue	4.8
Endometrium 1	tissue	4.4	not detected
Nucleus accumbens	tissue	4.4
Hippocampus	tissue	4.3	not detected
Locus coeruleus	tissue	4.2
Prostate	tissue	4.0	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Lateral funiculus (white matter) (20.1), Area parastriata, superior (15.1), Nucleus gracilis (11.0), Ventral spinal cord (11.0), Medial olivary nucleus (10.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FLI1, GATA1, LMO2, RUNX1, SPI1

miRNA regulators (miRDB)

Targeting PLEK by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 54 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-4460	99.37	68.52	615
HSA-MIR-6128	99.33	67.83	1581

Functional genomics

gnomAD constraint: pLI 0.0123, LOEUF 0.809, missense Z 0.501 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000234313 — one region, missense o/e 0.96.

Literature-anchored findings (GeneRIF, showing 12)

• Translocation requires its phosphorylation and newly formed ligands (PMID:12054651)
• A pleckstrin homology domain located in G protein-coupled receptor kinase-2 (GRK2) residue 548 to 660 plays a significant role in mediating interaction between protein kinase C beta 1 and GRK2. (PMID:12456365)
• The human pleckstrin-1 solution nuclear magnetic resonance structure of the C-terminal pleckstrin homology domain was reported. (PMID:15698571)
• Proteins beta3 integrin, Vav3, Plekhm1, and Src, implicated in attachment defects, had normal exon sequences in a new type of osteopetrosis. (PMID:19546854)
• Idirect associations between plek and actin through 17 beta-hydroxysteroid dehydrogenase 4, alpha-actinin, moesin, radixin and factor XIIIA, is proposed. (PMID:19722192)
• Here they show that the PH domain from Bcr-Abl binds a number of proteins involved in vital cellular processes in leukemogenesis. (PMID:19944685)
• crystallization and preliminary X-ray diffraction analysis of the first 2 domains of pleckstrin (NPHDEP); work demonstrates that NPHDEP behaves as a monomer in solution and suggests that all 3 pleckstrin domains contribute to the dimerization interface (PMID:21393855)
• These findings reveal a novel role of the PLD1-pleckstrin homology domain as a positive regulator of endocytosis and provide a link between PLD1 and HIF-1alpha in the EGFR endocytosis pathway. (PMID:26680696)
• Only one gene, pleckstrin , was significantly overexpressed in periodontitis,cardiovascular disease, rheumatoid arthritis and ulcerative colitis , implicating this gene as an important networking link between these chronic inflammatory diseases (PMID:26686060)
• A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58. (PMID:32337552)
• Pleckstrin Levels Are Increased in Patients with Chronic Periodontitis and Regulated via the MAP Kinase-p38alpha Signaling Pathway in Gingival Fibroblasts. (PMID:35087525)
• Higher expression of PLEK and LY86 as the potential biomarker of carotid atherosclerosis. (PMID:37861500)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	plek	ENSDARG00000104325
mus_musculus	Plek	ENSMUSG00000020120
rattus_norvegicus	Plek	ENSRNOG00000005214

Paralogs (1): PLEK2 (ENSG00000100558)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1860485) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
thrombocytopenia	1
abnormal platelet activation	1
decreased platelet aggregation	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Canis lupus familiaris	Q6Q308	94.0%	Diamond
Bos taurus	P0C1G6	89.9%	Diamond
Gallus gallus	Q5F4B2	80.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PPP3R1-AS1	ncRNA	107985892
CNRIP1	protein-coding	25927
FBXO48	protein-coding	554251
PPP3R1	protein-coding	5534
DNAAF10	protein-coding	116143
PNO1	protein-coding	56902
APLF	protein-coding	200558

Protein

Protein identifiers

Pleckstrin — P08567 (reviewed: P08567)

Alternative names: Platelet 47 kDa protein

All UniProt accessions (1): P08567

UniProt curated annotations — full annotation on UniProt →

Function. Major protein kinase C substrate of platelets.

RefSeq proteins (1): NP_002655* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000591	DEP_dom	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR037370	Pleckstrin	Family
IPR037371	PLEK_DEP	Domain

Pfam: PF00169, PF00610

UniProt features (46 total): strand 23, helix 7, sequence variant 5, domain 3, turn 3, modified residue 3, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDB	Title	Method	Resolution (Å)
2I5F	Crystal structure of the C-terminal PH domain of pleckstrin in complex with …	X-RAY DIFFRACTION	1.35
2I5C	Crystal structure of the C-terminal PH domain of pleckstrin in complex with …	X-RAY DIFFRACTION	1.75
1ZM0	Crystal Structure of the Carboxyl Terminal PH Domain of Pleckstrin To 2.1 Angstroms	X-RAY DIFFRACTION	2.1
1PLS	SOLUTION STRUCTURE OF A PLECKSTRIN HOMOLOGY DOMAIN	SOLUTION NMR
1W4M	Structure of the human pleckstrin DEP domain by multidimensional NMR	SOLUTION NMR
1X05	Solution structure of the C-terminal PH domain of human pleckstrin	SOLUTION NMR
1XX0	Structure of the C-terminal PH domain of human pleckstrin	SOLUTION NMR
2CSO	Solution structure of the DEP domain of human pleckstrin	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08567-F1	82.29	0.39

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoli

Antibody reliability (HPA): IH enhanced · IF approved

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 (3)

Type	Positions
N6-acetyllysine	64
Phosphoserine	113, 117

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-114608	Platelet degranulation	curated
R-HSA-109582	Hemostasis	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-76005	Response to elevated platelet cytosolic Ca2+	—

MSigDB gene sets: 443 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, MCLACHLAN_DENTAL_CARIES_UP, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, chr2p14, GOBP_PLATELET_ACTIVATION, MODULE_45, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_NEGATIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (24): hematopoietic progenitor cell differentiation (GO:0002244), platelet degranulation (GO:0002576), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), integrin-mediated signaling pathway (GO:0007229), positive regulation of platelet activation (GO:0010572), negative regulation of inositol phosphate biosynthetic process (GO:0010920), cell projection organization (GO:0030030), actin cytoskeleton organization (GO:0030036), positive regulation of actin filament depolymerization (GO:0030836), phospholipase C-inhibiting G protein-coupled receptor signaling pathway (GO:0030845), cortical actin cytoskeleton organization (GO:0030866), ruffle organization (GO:0031529), positive regulation of actin filament bundle assembly (GO:0032233), positive regulation of integrin activation (GO:0033625), intracellular signal transduction (GO:0035556), inositol phosphate metabolic process (GO:0043647), negative regulation of G protein-coupled receptor signaling pathway (GO:0045744), negative regulation of calcium-mediated signaling (GO:0050849), regulation of cell diameter (GO:0060305), thrombin-activated receptor signaling pathway (GO:0070493), negative regulation of thrombin-activated receptor signaling pathway (GO:0070495), platelet aggregation (GO:0070527), protein secretion by platelet (GO:0070560), positive regulation of cellular component biogenesis (GO:0044089)

GO Molecular Function (5): protein kinase C binding (GO:0005080), phosphatase activator activity (GO:0019211), protein homodimerization activity (GO:0042803), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), ruffle membrane (GO:0032587)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

58 GO namespaces:

Category	Terms
G protein-coupled receptor signaling pathway	4
cellular anatomical structure	4
positive regulation of cytoskeleton organization	2
positive regulation of supramolecular fiber organization	2
intracellular anatomical structure	2
hemopoiesis	1
cell differentiation	1
regulated exocytosis	1
establishment of localization in cell	1
phospholipase C activator activity	1
cell surface receptor signaling pathway	1
regulation of platelet activation	1
platelet activation	1
positive regulation of cell activation	1
negative regulation of phosphorus metabolic process	1
regulation of inositol phosphate biosynthetic process	1
inositol phosphate biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of alcohol biosynthetic process	1
cellular component organization	1
cytoskeleton organization	1
actin filament-based process	1
actin filament depolymerization	1
regulation of actin filament depolymerization	1
positive regulation of protein depolymerization	1
phospholipase C inhibitor activity	1
actin cytoskeleton organization	1
cortical cytoskeleton organization	1
plasma membrane bounded cell projection organization	1
regulation of actin filament bundle assembly	1
positive regulation of cellular component biogenesis	1
actin filament bundle assembly	1
positive regulation of protein-containing complex assembly	1
integrin activation	1
regulation of integrin activation	1
signal transduction	1
organophosphate metabolic process	1
polyol metabolic process	1
regulation of G protein-coupled receptor signaling pathway	1
negative regulation of signal transduction	1
calcium-mediated signaling	1
regulation of calcium-mediated signaling	1
negative regulation of intracellular signal transduction	1
regulation of cell size	1
protein kinase binding	1
enzyme activator activity	1
phosphatase activity	1
phosphatase regulator activity	1
identical protein binding	1
protein dimerization activity	1
phosphatidylinositol bisphosphate binding	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
ruffle	1
cell projection membrane	1
leading edge membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 23 of 36 annotations. The rest are phylogenetic / computational / electronic (IEA).

23 experimentally-supported GO terms:

GO term	NS	Evidence
actin cytoskeleton organization	BP	direct assay
cell projection organization	BP	direct assay
cortical actin cytoskeleton organization	BP	direct assay
hematopoietic progenitor cell differentiation	BP	expression pattern
inositol phosphate metabolic process	BP	direct assay
integrin-mediated signaling pathway	BP	direct assay
negative regulation of G protein-coupled receptor signaling pathway	BP	direct assay
negative regulation of inositol phosphate biosynthetic process	BP	direct assay
negative regulation of thrombin-activated receptor signaling pathway	BP	direct assay
phospholipase C-inhibiting G protein-coupled receptor signaling pathway	BP	direct assay
platelet degranulation	BP	direct assay
positive regulation of actin filament bundle assembly	BP	direct assay
positive regulation of actin filament depolymerization	BP	direct assay
regulation of cell diameter	BP	direct assay
ruffle organization	BP	direct assay
thrombin-activated receptor signaling pathway	BP	direct assay
cytoplasm	CC	direct assay
membrane	CC	high-throughput assay
ruffle membrane	CC	direct assay
phosphatase activator activity	MF	direct assay
phosphatidylinositol-3,4-bisphosphate binding	MF	direct assay
protein homodimerization activity	MF	direct assay
protein kinase C binding	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 3,820 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLEK	MCF2	P10911	974
PLEK	OSBP	P22059	901
PLEK	PLCD1	P51178	884
PLEK	SRC	P12931	868
PLEK	CYTH1	Q15438	858
PLEK	RABIF	P47224	848
PLEK	AKT1	P31749	842
PLEK	CDC42	P21181	838
PLEK	RHOA	P06749	828
PLEK	CYTH3	O43739	815
PLEK	SERPINA4	P29622	804
PLEK	PIK3CG	P48736	793
PLEK	RASA1	P20936	789
PLEK	BTK	Q06187	778
PLEK	ARF1	P10947	774
PLEK	PLEKHA3	Q9HB20	774

IntAct

Human interaction partners of PLEK in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

6 partners by confidence:

Partner	Interaction type	MIscore	Records
INPP5A	direct interaction	0.630	4
WDR75	physical association	0.590	2
CAVIN2	physical association	0.560	4
PF4	association	0.460	1
ARHGEF1	physical association	0.400	1
F13A1	association	0.350	1

BioGRID (11 interactions; top human partners by supporting records): WDR75 (Affinity Capture-MS; 2 records), ARHGEF1 (Affinity Capture-MS), ATG16L1 (Affinity Capture-MS), HPX (Cross-Linking-MS (XL-MS)), LNX1 (Affinity Capture-MS), NHLRC2 (Proximity Label-MS), PARP12 (Proximity Label-MS), RHOU (Reconstituted Complex), SARAF (Affinity Capture-MS), TIMP2 (Proximity Label-MS)

SIGNOR signaling

showing 1 of 3 signaling interactions:

A	Effect	B	Mechanism
PRKCA	up-regulates	PLEK	phosphorylation

Disease & clinical

Genetic variants

Variant evidence for PLEK: 50 ClinVar records (0 pathogenic / likely pathogenic); 20 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	40
Likely benign	0
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 753):

Position(s)	Effect	Δscore	Sites
2:68365394–68365395	donor_loss	1.0000	5
2:68380326–68380327	acceptor_loss	1.0000	6
2:68380484–68380485	donor_loss	1.0000	5
2:68380858	donor_gain	1.0000
2:68382531	acceptor_gain	1.0000
2:68386687–68386688	donor_loss	1.0000	4
2:68388385–68388386	acceptor_loss	1.0000	6
2:68388492–68388493	donor_loss	1.0000	5
2:68380721–68380722	acceptor_loss	0.9900	6
2:68386687	donor_loss	0.9900

AlphaMissense

790 missense substitutions predicted likely pathogenic (of 2,338 scored), across 220 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F156	8	0.946	0.995
F266	8	0.934	0.996
F315	8	0.888	0.995
F219	8	0.886	0.982
H256	8	0.880	0.972
H276	8	0.873	0.978
N260	8	0.837	0.982
D95	8	0.829	0.919
W338	7	0.991	0.999
W261	7	0.990	0.998
W21	7	0.989	0.999
R264	7	0.988	0.999
W92	7	0.977	0.999
K253	7	0.966	1.000
W25	7	0.965	0.994
W164	7	0.947	0.987
F109	7	0.919	0.985
R258	7	0.891	0.994
F241	7	0.866	0.953
C155	7	0.856	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:173570 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
autosomal dominant nonsyndromic hearing loss 58	Limited	Autosomal dominant

Mondo (1): autosomal dominant nonsyndromic hearing loss 58 (MONDO:0014293)

GWAS associations

20 associations:

Study	Trait	p-value
GCST90002388_133	Lymphocyte count	6e-28
GCST90002400_93	Plateletcrit	1e-27
GCST90002395_361	Mean platelet volume	2e-21
GCST90002401_8	Platelet distribution width	2e-21
GCST009597_142	Multiple sclerosis	5e-16
GCST90002393_615	Monocyte count	1e-14
GCST004607_141	Plateletcrit	2e-14
GCST005531_63	Multiple sclerosis	1e-13
GCST004627_165	Lymphocyte count	3e-13
GCST90002397_516	Mean spheric corpuscular volume	8e-13
GCST90002392_159	Mean corpuscular volume	2e-12
GCST90002407_19	White blood cell count	2e-12
GCST001198_70	Multiple sclerosis	5e-11
GCST90002399_309	Neutrophil percentage of white cells	7e-11
GCST009030_1	Venous thromboembolism	3e-10
GCST000274_1	Metabolite levels	2e-9
GCST90002379_123	Basophil count	4e-9
GCST000612_20	Celiac disease	8e-9
GCST001341_19	Multiple sclerosis	2e-7
GCST002324_1	Anger	4e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0003015	aggressive behavior
EFO:0007985	platelet crit
EFO:0004587	lymphocyte count
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523171 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression	3
tamibarotene	increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases reaction, increases phosphorylation	2
Air Pollutants	increases abundance, increases expression	2
Benzo(a)pyrene	increases expression, decreases expression	2
Smoke	increases abundance, increases expression, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
nickel sulfate	increases expression	1
dioleoylphosphatidic acid	increases phosphorylation, increases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
phosphatidylethanol	increases phosphorylation, increases reaction	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	increases expression, affects cotreatment	1
hexabrominated diphenyl ether 153	decreases expression	1
licochalcone B	increases expression	1
Pioglitazone	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Cisplatin	increases expression	1
Coal	increases abundance, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diuron	decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Nickel	increases expression	1
Ozone	increases abundance, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases reaction, increases phosphorylation	1
Tetradecanoylphorbol Acetate	decreases reaction, increases phosphorylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4419286	Binding	Binding affinity to PLEK PH-domain (unknown origin) at 0.01 to 50 uM by SPR spectroscopy	Methods and compositions for inhibiting cnksr1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.