KLK15

Summary

KLK15 (kallikrein related peptidase 15, HGNC:20453) is a protein-coding gene on chromosome 19q13.33, encoding Kallikrein-15 (Q9H2R5). Protease whose physiological substrate is not yet known.

Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. In prostate cancer, this gene has increased expression, which indicates its possible use as a diagnostic or prognostic marker for prostate cancer. The gene contains multiple polyadenylation sites and alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 55554 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 46 total
• MANE Select transcript: NM_017509

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20453
Approved symbol	KLK15
Name	kallikrein related peptidase 15
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	HSRNASPH, ACO, prostinogen
Ensembl gene	ENSG00000174562
Ensembl biotype	protein_coding
OMIM	610601
Entrez	55554

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000326856, ENST00000596531, ENST00000596931, ENST00000598239, ENST00000598673, ENST00000601680, ENST00000602114, ENST00000695963, ENST00000695964, ENST00000695965, ENST00000695998, ENST00000906215, ENST00000906216, ENST00000952480

RefSeq mRNA: 3 — MANE Select: NM_017509 NM_001277081, NM_001277082, NM_017509

CCDS: CCDS12805, CCDS12806, CCDS62766

Canonical transcript exons

ENST00000598239 — 6 exons

Exon	Start	End
ENSE00001188974	50826878	50827161
ENSE00001335780	50831450	50831523
ENSE00003094556	50825289	50825948
ENSE00003487314	50826621	50826757
ENSE00003549315	50827662	50827815
ENSE00003965641	50833527	50833574

Expression profiles

Bgee: expression breadth broad, 98 present calls, max score 91.17.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0190 / max 17.1412, expressed in 4 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182285	0.0190	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	91.17	silver quality
tendon of biceps brachii	UBERON:0008188	90.86	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.33	silver quality
cerebellar vermis	UBERON:0004720	88.65	silver quality
parotid gland	UBERON:0001831	88.16	silver quality
body of tongue	UBERON:0011876	86.60	silver quality
buccal mucosa cell	CL:0002336	84.89	gold quality
heart right ventricle	UBERON:0002080	84.35	silver quality
pons	UBERON:0000988	83.99	silver quality
pericardium	UBERON:0002407	83.33	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.99	silver quality
sperm	CL:0000019	82.47	gold quality
tongue	UBERON:0001723	81.69	silver quality
subthalamic nucleus	UBERON:0001906	81.66	silver quality
saphenous vein	UBERON:0007318	81.65	silver quality
lateral globus pallidus	UBERON:0002476	81.04	silver quality
superior surface of tongue	UBERON:0007371	80.34	silver quality
substantia nigra pars compacta	UBERON:0001965	80.02	silver quality
superior vestibular nucleus	UBERON:0007227	79.93	silver quality
dorsal plus ventral thalamus	UBERON:0001897	79.82	silver quality
male germ cell	CL:0000015	79.75	gold quality
superficial temporal artery	UBERON:0001614	79.54	gold quality
trachea	UBERON:0003126	79.41	silver quality
globus pallidus	UBERON:0001875	79.07	silver quality
substantia nigra pars reticulata	UBERON:0001966	78.56	silver quality
trigeminal ganglion	UBERON:0001675	78.35	silver quality
synovial joint	UBERON:0002217	78.34	silver quality
medial globus pallidus	UBERON:0002477	77.97	silver quality
oocyte	CL:0000023	77.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR2F1, PPARA, PPARG, RXRA

miRNA regulators (miRDB)

11 targeting KLK15, 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-6748-5P	100.00	65.81	1057
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-212-5P	96.83	67.43	950
HSA-MIR-6856-3P	96.47	66.27	781
HSA-MIR-1293	96.16	64.69	916

Literature-anchored findings (GeneRIF, showing 14)

• Kallikrein 15 expression is an independent prognostic factors of progression-free and overall survival in breast cancer patients (PMID:12439720)
• KLK15 expression, as assessed by quantitative RT-PCR, is an independent marker of unfavorable prognosis for ovarian cancer. (PMID:12915603)
• Data show six non-synonymous amino acid or frame shift changes in the KLK3 gene and three changes in each of the neighboring genes, KLK15 and KLK2. (PMID:19823874)
• KLK15 expression analysis could be employed as a valuable tool for the discrimination between benign prostatic hyperplasia and prostate cancer tissue specimens and as an unfavorable prognostic marker for prostate cancer. (PMID:20067463)
• Multivariate analysis identified dichotomised KLK15 expression, corrected for patient parameters age, preoperative prostate-specific antigen level, pathological tumour stage, Gleason score and surgical margins, as an prognostic factor for poor outcome. (PMID:20473923)
• association with ovarian cancer survival (PMID:21457553)
• These findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry. (PMID:22132073)
• Advanced pathologic stage was associated with significantly higher expression of KLK15 and PCA3 mRNAs. (PMID:23391636)
• KLK15 mRNA expression levels are a novel marker for the differential diagnosis of prostate cancer. (PMID:23620432)
• Variations in KLK15, but not KLK11 expression were significantly associated with prognosis in gastric cancer (PMID:26224476)
• Pronounced correlations between KLK10/KLK11 (rs = 0.647) and between KLK9/KLK15 (rs = 0.716) mRNA, but not between other combinations, indicate coordinate expression of distinct pairs of peptidases (PMID:29095848)
• KLK15 may be able to cleave many ECM components, similar to several members of the KLK family. Thus the protease could potentially be linked to tumorigenesis by promoting metastasis via this mechanism. (PMID:29928903)
• Data provide insights into the localization and possible role of KLK15 in human physiology. (PMID:29958881)
• Identification and characterization of novel KLK15 alternative splice variants and their expression patterns in a wide panel of human cancer and normal cell lines (PMID:32334022)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:100868	ENSDARG00000004748
danio_rerio	zgc:123217	ENSDARG00000059026
danio_rerio	si:dkeyp-93a5.3	ENSDARG00000096975
danio_rerio	si:ch73-182e20.3	ENSDARG00000100953
danio_rerio	si:ch73-182e20.4	ENSDARG00000102727
mus_musculus	Klk15	ENSMUSG00000055193
rattus_norvegicus	Klk15	ENSRNOG00000049445

Paralogs (14): PRSS33 (ENSG00000103355), PLAT (ENSG00000104368), PLG (ENSG00000122194), PLGLB2 (ENSG00000125551), PRSS37 (ENSG00000165076), PRSS27 (ENSG00000172382), PLGLB1 (ENSG00000183281), PRSS57 (ENSG00000185198), TMPRSS12 (ENSG00000186452), OVCH1 (ENSG00000187950), PRSS48 (ENSG00000189099), GZMM (ENSG00000197540), KLK9 (ENSG00000213022), PRSS50 (ENSG00000283706)

Protein

Protein identifiers

Kallikrein-15 — Q9H2R5 (reviewed: Q9H2R5)

Alternative names: ACO protease

All UniProt accessions (5): Q9H2R5, A0A6B7HBY5, M0QX22, M0R0D7, M0R2F7

UniProt curated annotations — full annotation on UniProt →

Function. Protease whose physiological substrate is not yet known.

Subcellular location. Secreted.

Tissue specificity. Highest expression in the thyroid gland. Also expressed in the prostate, salivary, and adrenal glands and in the colon testis and kidney.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the peptidase S1 family. Kallikrein subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9H2R5-1	1	yes
Q9H2R5-2	2
Q9H2R5-3	3
Q9H2R5-4	4
Q9H2R5-5	5

RefSeq proteins (3): NP_001264010, NP_001264011, NP_059979* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.35 — tissue kallikrein (BRENDA: 12 organisms, 294 substrates, 207 inhibitors, 205 Km, 182 kcat entries)

Substrate kinetics (BRENDA)

161 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DL-VAL-LEU-ARG-P-NITROANILIDE	0.12–58.8	6
PRO-PHE-ARG-4-METHYLCOUMARIN 7-AMIDE	0.07–0.114	5
N-ALPHA-BENZOYL-L-ARGININE ETHYL ESTER	0.08–0.333	4
N-ALPHA-TOSYL-L-ARGININE METHYL ESTER	0.022–0.117	4
SUCCINYL-VAL-PRO-PHE-THIOBENZYL ESTER	0.516–0.842	4
D-PRO-PHE-ARG-4-METHYLCOUMARIN-7-AMIDE	0.0002–0.0031	3
D-PRO-PHE-PHE-4-METHYLCOUMARIN-7-AMIDE	0.001–0.07	3
D-VAL-LEU-ARG-P-NITROANILIDE	0.0183–28.4	3
O-AMINOBENZOYL-GFSPFRSVTVQ-ETHYLENEDIAMINE 2,4-D	0.0002–0.0025	3
O-AMINOBENZOYL-MTEMARRPQ-ETHYLENEDIAMINE 2,4-DIN	0.003–0.0073	3
ABZ-KLRSSQ-EDDNP	0.0006	2
ACETYL-ALA-ARG METHYL ESTER	0.6–1.14	2
ACETYL-PHE-ARG METHYL ESTER	0.0244–0.0311	2
O-AMINOBENZOYL-FRSSR-N-(2,4-DINITROPHENYL)ETHYLE	0.0002–0.0006	2
O-AMINOBENZOYL-FRSVQ-N-(2,4-DINITROPHENYL)ETHYLE	0.0009–0.0073	2

UniProt features (21 total): splice variant 5, disulfide bond 4, active site 3, sequence variant 2, glycosylation site 2, signal peptide 1, propeptide 1, chain 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2R5-F1	86.51	0.72

Functional residue map

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

Catalytic / active sites (3): 62 (charge relay system); 106 (charge relay system); 209 (charge relay system)

Disulfide bonds (4): 138–215, 180–194, 205–230, 47–63

Glycosylation sites (2): 171, 232

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 45 (showing top): GOCC_SECRETORY_GRANULE, PEREZ_TP63_TARGETS, TGACCTY_ERR1_Q2, GGGCATT_MIR365, GOBP_PROTEIN_MATURATION, CCTGTGA_MIR513, GTGACTT_MIR224, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, TGACCTTG_SF1_Q6, GOCC_SECRETORY_VESICLE, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, PR_Q2, ERR1_Q2, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY

GO Biological Process (2): proteolysis (GO:0006508), protein maturation (GO:0051604)

GO Molecular Function (5): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), secretory granule (GO:0030141), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
gene expression	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
endomembrane system	1
secretory vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLK15	ACO2	Q99798	818
KLK15	ACO1	P21399	715
KLK15	IDH2	P48735	659
KLK15	IDH1	O75874	658
KLK15	IREB2	P48200	594
KLK15	ACOX3	O15254	581
KLK15	HBS1L	Q9Y450	573
KLK15	PPARA	Q07869	570
KLK15	CS	O75390	544
KLK15	FH	P07954	544
KLK15	ACOX1	Q15067	540
KLK15	OGDH	Q02218	507
KLK15	ACSL5	Q9ULC5	479
KLK15	ACSL6	Q9UKU0	474
KLK15	ACSL1	P33121	448

IntAct

17 interactions, top by confidence:

A	B	Type	Score
	KLK15	psi-mi:“MI:0915”(physical association)	0.560
KLK15	TRIP6	psi-mi:“MI:0915”(physical association)	0.560
TRIP6	KLK15	psi-mi:“MI:0915”(physical association)	0.560
DYNLT1	KLK15	psi-mi:“MI:0915”(physical association)	0.560
HOOK2	KLK15	psi-mi:“MI:0915”(physical association)	0.370
KLK15	SLC25A20	psi-mi:“MI:0914”(association)	0.350
KLK15	SPINT1	psi-mi:“MI:0914”(association)	0.350
KLK15	DENND11	psi-mi:“MI:0914”(association)	0.350
KLK15	APAF1	psi-mi:“MI:0914”(association)	0.350
FCER1A	RCCD1	psi-mi:“MI:0914”(association)	0.350
KLK15	GLA	psi-mi:“MI:0914”(association)	0.350
KLK15	DYNLT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (156): KLK15 (Two-hybrid), KRTAP10-3 (Two-hybrid), SEC16A (Affinity Capture-MS), CBWD1 (Affinity Capture-MS), HOXD13 (Affinity Capture-MS), ABHD3 (Affinity Capture-MS), SMG7 (Affinity Capture-MS), SLC25A20 (Affinity Capture-MS), KLK15 (Two-hybrid), SMG7 (Affinity Capture-MS), SLC25A20 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), CBWD1 (Affinity Capture-MS), KLK15 (Two-hybrid), KIAA1244 (Affinity Capture-MS)

ESM2 similar proteins: A1L453, A6NIE9, O43240, P07288, P15944, P20151, P20231, P33619, P49862, P51124, P51779, P83748, Q03238, Q14B24, Q15661, Q16651, Q2L4Q9, Q2UVH8, Q571E5, Q5K2P8, Q5K2P9, Q61096, Q6BEA2, Q6DT45, Q6IE59, Q6IE62, Q6UWY2, Q76B45, Q7JIG6, Q7RTY9, Q7Z5A4, Q80WM7, Q8K4I7, Q920S2, Q92876, Q9BQR3, Q9BZJ3, Q9ER04, Q9ES87, Q9ESD1

Diamond homologs: A0A1S4GMJ4, A6NIE9, A8JUP7, G3V801, O08762, O42207, O60235, P00741, P00745, P00762, P00765, P03951, P05049, P07477, P07478, P0CW18, P15120, P16292, P16295, P19799, P29786, P29787, P35030, P35039, P69525, P79953, Q14B25, Q14BX2, Q14C59, Q1JRP2, Q27081, Q28278, Q28315, Q28412, Q29463, Q2KJ63, Q2VG86, Q5G265, Q5U405, Q6BEA2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	40
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

627 predictions. Top by Δscore:

Variant	Effect	Δscore
19:50827187:C:CT	acceptor_gain	1.0000
19:50827188:A:T	acceptor_gain	1.0000
19:50827203:A:T	acceptor_gain	1.0000
19:50827208:T:TC	acceptor_gain	1.0000
19:50827215:C:CT	acceptor_gain	1.0000
19:50827216:A:T	acceptor_gain	1.0000
19:50827218:G:C	acceptor_gain	1.0000
19:50827218:G:GC	acceptor_gain	1.0000
19:50827661:CCGG:C	donor_gain	1.0000
19:50825945:CACC:C	acceptor_gain	0.9900
19:50825947:CC:C	acceptor_gain	0.9900
19:50825948:CC:C	acceptor_gain	0.9900
19:50825949:C:CA	acceptor_loss	0.9900
19:50825950:T:A	acceptor_loss	0.9900
19:50826754:CTCA:C	acceptor_gain	0.9900
19:50827184:C:CT	acceptor_gain	0.9900
19:50827201:CCAG:C	acceptor_gain	0.9900
19:50827202:CAG:C	acceptor_gain	0.9900
19:50827204:G:GC	acceptor_gain	0.9900
19:50827208:T:C	acceptor_gain	0.9900
19:50827213:C:CT	acceptor_gain	0.9900
19:50827213:C:T	acceptor_gain	0.9900
19:50827652:G:A	donor_gain	0.9900
19:50827656:TCATA:T	donor_loss	0.9900
19:50827657:CATAC:C	donor_loss	0.9900
19:50827658:ATAC:A	donor_loss	0.9900
19:50827661:C:CG	donor_loss	0.9900
19:50827813:CTG:C	acceptor_gain	0.9900
19:50827816:C:CC	acceptor_gain	0.9900
19:50825944:TCACC:T	acceptor_gain	0.9800

AlphaMissense

1653 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:50826930:C:A	W143C	0.999
19:50826930:C:G	W143C	0.999
19:50825823:C:A	W248C	0.998
19:50825823:C:G	W248C	0.998
19:50827042:T:A	D106V	0.997
19:50827042:T:G	D106A	0.996
19:50825892:C:A	W225C	0.994
19:50825892:C:G	W225C	0.994
19:50827041:G:C	D106E	0.994
19:50827041:G:T	D106E	0.994
19:50827043:C:G	D106H	0.994
19:50826658:C:G	C194S	0.992
19:50826659:A:T	C194S	0.992
19:50827033:A:G	L109S	0.992
19:50827042:T:C	D106G	0.992
19:50827671:C:G	C63S	0.992
19:50827672:A:T	C63S	0.992
19:50825825:A:G	W248R	0.991
19:50825825:A:T	W248R	0.991
19:50826700:C:G	C180S	0.991
19:50826701:A:T	C180S	0.991
19:50827691:C:A	W56C	0.991
19:50827691:C:G	W56C	0.991
19:50825906:C:A	G221C	0.990
19:50825938:C:A	G210V	0.990
19:50827043:C:A	D106Y	0.990
19:50827719:C:G	C47S	0.990
19:50827720:A:T	C47S	0.990
19:50827754:C:A	W35C	0.990
19:50827754:C:G	W35C	0.990

dbSNP variants (sampled 300 via entrez): RS1000290070 (19:50831936 C>T), RS1000426976 (19:50831595 A>T), RS1000549668 (19:50825501 C>T), RS1000704134 (19:50831246 GC>G), RS1000854107 (19:50825721 C>A,G), RS1001604429 (19:50832524 T>C,G), RS1001741766 (19:50832329 T>C), RS1001979045 (19:50832275 C>T), RS1002227163 (19:50826396 T>C,G), RS1002548727 (19:50828192 C>T), RS1002613496 (19:50833584 A>G), RS1002747901 (19:50833350 G>T), RS1002832075 (19:50827645 A>C,G), RS1002927678 (19:50827936 CT>C), RS1003398133 (19:50833711 G>A)

Disease associations

OMIM: gene MIM:610601 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002112_14	Celiac disease	6.000000e-06
GCST002703_4	Prostate-specific antigen levels	9.000000e-21
GCST008476_3	Emphysema annual change measurement in smokers (percent low attenuation area)	9.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement

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
terbufos	increases methylation	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cisplatin	affects response to substance	1
Diazinon	decreases methylation	1
Fonofos	increases methylation	1
Fluorouracil	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methotrexate	decreases expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Dihydrotestosterone	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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