CDK5R2

Summary

CDK5R2 (cyclin dependent kinase 5 regulatory subunit 2, HGNC:1776) is a protein-coding gene on chromosome 2q35, encoding Cyclin-dependent kinase 5 activator 2 (Q13319). Activator of CDK5/TPKII.

The protein encoded by this gene is a neuron-specific activator of CDK5 kinase. It associates with CDK5 to form an active kinase. This protein and neuron-specific CDK5 activator CDK5R1/p39NCK5A both share limited similarity to cyclins, and thus may define a distinct family of cyclin-dependent kinase activating proteins.

Source: NCBI Gene 8941 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_003936

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1776
Approved symbol	CDK5R2
Name	cyclin dependent kinase 5 regulatory subunit 2
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	p39nck5ai, P39, NCK5AI
Ensembl gene	ENSG00000171450
Ensembl biotype	protein_coding
OMIM	603764
Entrez	8941

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000302625

RefSeq mRNA: 1 — MANE Select: NM_003936 NM_003936

CCDS: CCDS2427

Canonical transcript exons

ENST00000302625 — 1 exons

Exon	Start	End
ENSE00001143471	218959666	218962155

Expression profiles

Bgee: expression breadth ubiquitous, 126 present calls, max score 91.71.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8989 / max 369.4029, expressed in 393 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25413	5.5283	390
25414	0.2469	87
25415	0.1237	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	91.71	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.10	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.76	gold quality
right frontal lobe	UBERON:0002810	90.68	gold quality
putamen	UBERON:0001874	89.71	gold quality
nucleus accumbens	UBERON:0001882	89.58	gold quality
cingulate cortex	UBERON:0003027	89.15	gold quality
anterior cingulate cortex	UBERON:0009835	88.92	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.78	gold quality
caudate nucleus	UBERON:0001873	88.42	gold quality
frontal cortex	UBERON:0001870	88.38	gold quality
neocortex	UBERON:0001950	87.83	gold quality
pituitary gland	UBERON:0000007	87.52	gold quality
substantia nigra pars compacta	UBERON:0001965	87.33	gold quality
adenohypophysis	UBERON:0002196	87.18	gold quality
cerebral cortex	UBERON:0000956	86.81	gold quality
telencephalon	UBERON:0001893	86.70	gold quality
forebrain	UBERON:0001890	86.58	gold quality
amygdala	UBERON:0001876	86.48	gold quality
brain	UBERON:0000955	85.48	gold quality
hypothalamus	UBERON:0001898	85.00	gold quality
central nervous system	UBERON:0001017	84.80	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.46	gold quality
islet of Langerhans	UBERON:0000006	83.65	gold quality
Ammon’s horn	UBERON:0001954	83.47	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.16	gold quality
temporal lobe	UBERON:0001871	83.05	gold quality
cerebellar cortex	UBERON:0002129	82.66	gold quality
cerebellar hemisphere	UBERON:0002245	82.65	gold quality
lateral globus pallidus	UBERON:0002476	82.48	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3

miRNA regulators (miRDB)

84 targeting CDK5R2, 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-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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-9851-3P	99.63	69.68	1110

Literature-anchored findings (GeneRIF, showing 8)

• Our data suggest that neurotoxic insults lead to calpain-mediated conversion of p39 to p29, which might contribute to deregulation of Cdk5 (PMID:11784720)
• role of the CDK5 molecular complex in the genetic etiology of early-onset Alzheimer disease; a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset Alzheimer disease (PMID:15917097)
• both proteasomal degradation and calpain cleavage of p35 and p39 are stimulated by membrane association, which is in turn mediated via myristoylation of their p10 regions. (PMID:20518484)
• Hepatocellular carcinoma patients with lower p39 expression had poorer overall survival rate than that with high expression. (PMID:20936377)
• Structural basis for the different stability and activity between the Cdk5 complexes with p35 and p39 activators. (PMID:24085300)
• p39 is essential for recruiting scaffolding protein muskelin to stress fibers. (PMID:25128817)
• a biomarker consisting of the phosphorylation of the retinoblastoma protein (Rb) on serine 249 combined with elevated p39 expression. This biomarker correlates with epithelial-to-mesenchymal transition traits in non-small cell lung carcinoma (NSCLC) cells. (PMID:30452490)
• S-Nitrosylation of p39 promotes its degradation and contributes to synaptic dysfunction induced by beta-amyloid peptide. (PMID:39256547)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdk5r2b	ENSDARG00000078671
mus_musculus	Cdk5r2	ENSMUSG00000090071
rattus_norvegicus	Cdk5r2	ENSRNOG00000037793
caenorhabditis_elegans		WBGENE00011955

Paralogs (1): CDK5R1 (ENSG00000176749)

Protein

Protein identifiers

Cyclin-dependent kinase 5 activator 2 — Q13319 (reviewed: Q13319)

Alternative names: Cyclin-dependent kinase 5 regulatory subunit 2, p39, p39I

All UniProt accessions (1): Q13319

UniProt curated annotations — full annotation on UniProt →

Function. Activator of CDK5/TPKII.

Subunit / interactions. Heterodimer of a catalytic subunit and a regulatory subunit.

Subcellular location. Cell membrane.

Tissue specificity. Brain and neuron specific.

Post-translational modifications. Myristoylated. The Gly-2-Ala mutant is absent of the cell periphery, suggesting that a proper myristoylation signal is essential for the proper distribution of CDK5R2 (p39).

Similarity. Belongs to the cyclin-dependent kinase 5 activator family.

RefSeq proteins (1): NP_003927* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004944	CDK5_activator	Family
IPR036915	Cyclin-like_sf	Homologous_superfamily

Pfam: PF03261

UniProt features (15 total): compositionally biased region 5, region of interest 4, initiator methionine 1, propeptide 1, modified residue 1, lipid moiety-binding region 1, mutagenesis site 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13319-F1	70.01	0.42

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): 84, 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
2	absent from the cell periphery.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-9031628	NGF-stimulated transcription
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 196 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GGGACCA_MIR133A_MIR133B, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_DEPENDENT_EXOCYTOSIS, GOBP_REGULATION_OF_PHOSPHORYLATION, GCANCTGNY_MYOD_Q6, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_LAYER_FORMATION_IN_CEREBRAL_CORTEX, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03

GO Biological Process (10): regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), neuron migration (GO:0001764), axon guidance (GO:0007411), brain development (GO:0007420), cerebellum development (GO:0021549), superior olivary nucleus maturation (GO:0021722), hippocampus development (GO:0021766), layer formation in cerebral cortex (GO:0021819), positive regulation of calcium ion-dependent exocytosis (GO:0045956), regulation of cytoskeleton organization (GO:0051493)

GO Molecular Function (4): actin binding (GO:0003779), lipid binding (GO:0008289), protein kinase binding (GO:0019901), cyclin-dependent protein serine/threonine kinase activator activity (GO:0061575)

GO Cellular Component (8): cyclin-dependent protein kinase holoenzyme complex (GO:0000307), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), protein kinase 5 complex (GO:0016533), growth cone (GO:0030426), neuron projection (GO:0043005), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Nuclear Events (kinase and transcription factor activation)	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cyclin-dependent protein serine/threonine kinase activity	2
anatomical structure development	2
serine/threonine protein kinase complex	2
regulation of protein serine/threonine kinase activity	1
cell migration	1
generation of neurons	1
axonogenesis	1
neuron projection guidance	1
central nervous system development	1
animal organ development	1
head development	1
metencephalon development	1
pons maturation	1
superior olivary nucleus development	1
anatomical structure maturation	1
pallium development	1
limbic system development	1
cerebral cortex radial glia-guided migration	1
anatomical structure formation involved in morphogenesis	1
calcium-ion regulated exocytosis	1
regulation of calcium ion-dependent exocytosis	1
positive regulation of regulated secretory pathway	1
cytoskeleton organization	1
regulation of organelle organization	1
cytoskeletal protein binding	1
binding	1
kinase binding	1
cyclin-dependent protein serine/threonine kinase regulator activity	1
protein serine/threonine kinase activator activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
site of polarized growth	1
distal axon	1
plasma membrane bounded cell projection	1
synapse	1

Protein interactions and networks

STRING

1712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDK5R2	CDK5	Q00535	966
CDK5R2	PDE4DIP	Q5VU43	450
CDK5R2	SET	Q01105	440
CDK5R2	PCDHB4	Q9Y5E5	434
CDK5R2	PCDHB7	Q9Y5E2	427
CDK5R2	PCDHB3	Q9Y5E6	425
CDK5R2	H2AC25	Q7L7L0	418
CDK5R2	NRARP	Q7Z6K4	406
CDK5R2	FZD10	Q9ULW2	398
CDK5R2	CRYBA2	P53672	398
CDK5R2	PCDHB10	Q9UN67	391
CDK5R2	NEURL1	O76050	325
CDK5R2	CTXN2	P0C2S0	323
CDK5R2	LRRCC1	Q9C099	317
CDK5R2	PCSK2	P16519	316

IntAct

2 interactions, top by confidence:

A	B	Type	Score
CDK5R2	CHN1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (21): CDK5R2 (Affinity Capture-MS), CDK5R2 (Two-hybrid), CDK5R2 (Reconstituted Complex), EEF1A1 (Cross-Linking-MS (XL-MS)), HIST3H2BB (Cross-Linking-MS (XL-MS)), HIST1H2BC (Cross-Linking-MS (XL-MS)), HIST1H2BK (Cross-Linking-MS (XL-MS)), HIST1H2BN (Cross-Linking-MS (XL-MS)), CDK5R2 (Cross-Linking-MS (XL-MS)), CDK5R2 (Cross-Linking-MS (XL-MS)), CDK5R2 (Cross-Linking-MS (XL-MS)), TEX35 (Cross-Linking-MS (XL-MS)), CDK5R2 (Cross-Linking-MS (XL-MS)), HIST1H2BL (Cross-Linking-MS (XL-MS)), HIST2H2BE (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2A699, A2WY46, A2XE76, A2YW03, A6NKL6, A8MVW0, B6SM63, O14492, O35615, O35926, O65001, O70143, P29353, P61809, P61810, Q0JGS5, Q13319, Q14003, Q15078, Q28199, Q2QXZ2, Q2RAQ5, Q3U0S6, Q40691, Q4ACU6, Q4KMP7, Q4KYY2, Q53LP3, Q5DU25, Q5JU85, Q5R7W7, Q5T442, Q5TJF3, Q5U651, Q61127, Q62925, Q63959, Q67UX6, Q6MWG9, Q6YPD0

Diamond homologs: O35926, P61809, P61810, Q13319, Q15078, Q22695, Q28199, Q4KYY2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

43 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218960691:G:GT	donor_gain	0.6800
2:218960637:AT:A	acceptor_gain	0.5300
2:218960189:GCC:G	donor_gain	0.4900
2:218960637:ATG:A	acceptor_gain	0.4900
2:218960692:A:T	donor_gain	0.4600
2:218960635:ACAT:A	acceptor_gain	0.3700
2:218960638:T:G	acceptor_gain	0.3500
2:218960635:ACATG:A	acceptor_gain	0.3400
2:218960638:T:TA	acceptor_gain	0.3400
2:218960779:A:AG	acceptor_gain	0.3300
2:218960780:G:GG	acceptor_gain	0.3300
2:218960496:C:T	donor_gain	0.3200
2:218960776:CGCA:C	acceptor_loss	0.3200
2:218960777:GCA:G	acceptor_loss	0.3200
2:218960778:CAGG:C	acceptor_loss	0.3200
2:218960779:A:AT	acceptor_loss	0.3200
2:218960780:G:GT	acceptor_loss	0.3200
2:218960805:G:GT	donor_gain	0.3100
2:218960753:C:CT	acceptor_gain	0.3000
2:218960427:GAGC:G	donor_gain	0.2600
2:218960768:C:G	acceptor_loss	0.2600
2:218960879:C:G	donor_gain	0.2600
2:218960070:A:AG	donor_gain	0.2500
2:218960775:ACGC:A	acceptor_loss	0.2500
2:218960776:C:CA	acceptor_gain	0.2500
2:218960430:C:G	donor_gain	0.2400
2:218960637:A:AG	acceptor_gain	0.2400
2:218960639:G:A	acceptor_gain	0.2400
2:218960690:G:GT	donor_gain	0.2400
2:218960636:C:G	acceptor_gain	0.2300

AlphaMissense

2313 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:218960365:C:T	S182F	1.000
2:218960368:C:T	T183I	1.000
2:218960377:T:C	L186P	1.000
2:218960380:T:C	L187P	1.000
2:218960397:T:C	F193L	1.000
2:218960398:T:C	F193S	1.000
2:218960399:C:A	F193L	1.000
2:218960399:C:G	F193L	1.000
2:218960454:T:A	W212R	1.000
2:218960454:T:C	W212R	1.000
2:218960458:T:C	F213S	1.000
2:218960469:G:C	D217H	1.000
2:218960469:G:T	D217Y	1.000
2:218960470:A:C	D217A	1.000
2:218960470:A:T	D217V	1.000
2:218960473:G:C	R218P	1.000
2:218960479:T:A	L220Q	1.000
2:218960479:T:C	L220P	1.000
2:218960482:T:C	L221P	1.000
2:218960490:G:C	G224R	1.000
2:218960490:G:T	G224C	1.000
2:218960491:G:A	G224D	1.000
2:218960491:G:T	G224V	1.000
2:218960493:T:A	W225R	1.000
2:218960493:T:C	W225R	1.000
2:218960494:G:C	W225S	1.000
2:218960495:G:C	W225C	1.000
2:218960495:G:T	W225C	1.000
2:218960497:A:C	Q226P	1.000
2:218960498:A:C	Q226H	1.000

dbSNP variants (sampled 300 via entrez): RS1001548062 (2:218958461 G>A), RS1001583364 (2:218958345 C>T), RS1001867213 (2:218958000 G>C), RS1002144360 (2:218959695 TC>T,TCC), RS1002241882 (2:218959838 T>A,C), RS1002838498 (2:218961664 G>A), RS1003552936 (2:218961261 C>T), RS1003571835 (2:218961331 C>G,T), RS1004180243 (2:218960297 T>C), RS1004970265 (2:218962262 G>A), RS1005083776 (2:218962570 C>A,G), RS1005979389 (2:218959099 C>G), RS1006727978 (2:218957983 T>G), RS1007535574 (2:218959789 C>T), RS1007695413 (2:218959150 G>A,C,T)

Disease associations

OMIM: gene MIM:603764 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001762_754	Obesity-related traits	7.000000e-06
GCST005171_34	QT interval	2.000000e-06
GCST006661_114	Male-pattern baldness	2.000000e-16
GCST010002_409	Refractive error	2.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
beta-lapachone	increases expression	1
cupric oxide	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
licochalcone B	decreases expression	1
Irinotecan	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Folic Acid	decreases expression	1
Lead	affects expression	1
Menthol	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Potassium Dichromate	increases expression	1
Smoke	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	decreases methylation	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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