SPINK6

Summary

SPINK6 (serine peptidase inhibitor Kazal type 6, HGNC:29486) is a protein-coding gene on chromosome 5q32, encoding Serine protease inhibitor Kazal-type 6 (Q6UWN8). Serine protease inhibitor selective for kallikreins.

The protein encoded by this gene is a Kazal-type serine protease inhibitor that acts on kallikrein-related peptidases in the skin. Two transcript variants the same protein have been found for this gene.

Source: NCBI Gene 404203 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 17 total
• MANE Select transcript: NM_205841

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29486
Approved symbol	SPINK6
Name	serine peptidase inhibitor Kazal type 6
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	MGC21394, UNQ844, BUSI2
Ensembl gene	ENSG00000178172
Ensembl biotype	protein_coding
OMIM	615868
Entrez	404203

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000325630, ENST00000514389, ENST00000621437

RefSeq mRNA: 2 — MANE Select: NM_205841 NM_001195290, NM_205841

CCDS: CCDS34268

Canonical transcript exons

ENST00000325630 — 4 exons

Exon	Start	End
ENSE00001228948	148213910	148214025
ENSE00001228955	148206036	148206058
ENSE00001228965	148214905	148215137
ENSE00001228970	148203042	148203154

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 78.35.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9603 / max 690.2523, expressed in 77 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59290	1.3933	68
59282	0.1082	25
59287	0.0934	22
59283	0.0826	23
59286	0.0775	17
59288	0.0722	16
59284	0.0509	23
59289	0.0466	20
59285	0.0357	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.35	silver quality
right hemisphere of cerebellum	UBERON:0014890	77.65	gold quality
cerebellar cortex	UBERON:0002129	73.05	gold quality
cerebellar hemisphere	UBERON:0002245	73.00	gold quality
cerebellum	UBERON:0002037	72.52	gold quality
minor salivary gland	UBERON:0001830	71.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.09	gold quality
mouth mucosa	UBERON:0003729	68.15	gold quality
saliva-secreting gland	UBERON:0001044	66.34	gold quality
lower esophagus mucosa	UBERON:0035834	65.25	gold quality
vagina	UBERON:0000996	60.58	gold quality
corpus callosum	UBERON:0002336	59.97	gold quality
right adrenal gland cortex	UBERON:0035827	53.69	gold quality
skin of hip	UBERON:0001554	52.90	silver quality
esophagus mucosa	UBERON:0002469	52.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	51.95	gold quality
right adrenal gland	UBERON:0001233	51.71	gold quality
skin of leg	UBERON:0001511	50.03	gold quality
buccal mucosa cell	CL:0002336	49.93	gold quality
tendon of biceps brachii	UBERON:0008188	49.48	gold quality
left coronary artery	UBERON:0001626	49.23	gold quality
coronary artery	UBERON:0001621	47.87	gold quality
mucosa of stomach	UBERON:0001199	47.80	gold quality
zone of skin	UBERON:0000014	47.00	gold quality
left adrenal gland	UBERON:0001234	46.90	gold quality
upper leg skin	UBERON:0004262	46.83	silver quality
omental fat pad	UBERON:0010414	46.21	gold quality
peritoneum	UBERON:0002358	46.19	gold quality
adipose tissue of abdominal region	UBERON:0007808	45.90	gold quality
skin of abdomen	UBERON:0001416	45.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting SPINK6, 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-4692	100.00	67.32	2066
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-634	97.74	67.11	818
HSA-MIR-9851-5P	97.57	67.49	1067

Literature-anchored findings (GeneRIF, showing 10)

• Data suggest that SPINK6 plays a role in modulating the activity of kallikreins in human skin. (PMID:20667819)
• Serine protease of Kazal-type (SPINK6) expressed in normal human skin is a potent natural inhibitor of Kallikrein-related peptidases, KLK12 and KLK13. (PMID:21439340)
• Cross-linked SPINK6 might protect specific substrates such as fibronectin from kallikrein-related peptidases cleavage and contribute to the regulation of proteases in the epidermis. (PMID:23303447)
• Our study indicates that Spink6 is a potent inhibitor of kallikrein related peptidases and involved in skin barrier function. (PMID:24352040)
• KLKs. Thereby, beside the conserved binding mode, we identified an alternate binding mode which has so far not been observed for SPINK inhibitors. (PMID:26828269)
• a significant fraction of SPINK6-sensitive proteases in healthy saliva and confirmed the ability of gingipains to inactivate SPINK6 under ex vivo conditions (PMID:27354280)
• our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis (PMID:27671677)
• Study showed that the expression of SPINK6 is specifically suppressed in liver tumor tissues. The suppression could be even detected in the early stage tumors. As SPINK6 is a secretory protein, the extracellular protein level may be decreased because of tumor development. These results support that SPINK6 is an important tumor suppressor in liver. (PMID:27999203)
• Single-cell RNA sequencing of human nail unit defines RSPO4 onychofibroblasts and SPINK6 nail epithelium. (PMID:34099859)
• SPINK6 inhibits human airway serine proteases and restricts influenza virus activation. (PMID:34826211)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spink6	ENSMUSG00000055095
rattus_norvegicus	Spink6	ENSRNOG00000013073

Paralogs (6): FSTL4 (ENSG00000053108), FSTL3 (ENSG00000070404), SPINK5 (ENSG00000133710), FST (ENSG00000134363), FSTL1 (ENSG00000163430), FSTL5 (ENSG00000168843)

Protein

Protein identifiers

Serine protease inhibitor Kazal-type 6 — Q6UWN8 (reviewed: Q6UWN8)

Alternative names: Kallikrein inhibitor

All UniProt accessions (2): Q6UWN8, D6RGX9

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease inhibitor selective for kallikreins. Efficiently inhibits KLK4, KLK5, KLK6, KLK7, KLK12, KLK13 and KLK14. Doesn’t inhibit KLK8.

Subcellular location. Secreted.

RefSeq proteins (2): NP_001182219, NP_995313* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002350	Kazal_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR050159	Kazal-type_SerProtInhib	Family

Pfam: PF00050

UniProt features (16 total): strand 5, disulfide bond 3, signal peptide 1, chain 1, helix 1, turn 1, domain 1, site 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2N52	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UWN8-F1	87.51	0.56

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 (1): 42–43 (reactive bond)

Post-translational modifications (1): 24

Disulfide bonds (3): 30–62, 40–59, 48–80

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 36 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, NKX25_02, RACCACAR_AML_Q6, TGANTCA_AP1_C, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, AFP1_Q6, GOBP_REGULATION_OF_PROTEOLYSIS, RICKMAN_HEAD_AND_NECK_CANCER_C, chr5q32, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, GOMF_SERINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GSE13522_WT_VS_IFNG_KO_SKIN_DN

GO Biological Process (0):

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

348 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPINK6	KLK4	Q9Y5K2	706
SPINK6	SPINK5	Q9NQ38	632
SPINK6	EGFR	P00533	616
SPINK6	KLK14	Q9P0G3	616
SPINK6	SPINK14	Q6IE38	599
SPINK6	SPINK7	P58062	588
SPINK6	KLK13	Q9UKR3	586
SPINK6	D6RI10	D6RI10	518
SPINK6	FOXL2NB	Q6ZUU3	512
SPINK6	ING1	Q9UK53	509
SPINK6	SPINK13	Q1W4C9	504
SPINK6	KLK12	Q9UKR0	491
SPINK6	SPINK4	O60575	483
SPINK6	KLK6	Q92876	477
SPINK6	KLK1	P06870	443

IntAct

0 interactions, top by confidence:

BioGRID (3): SPINK6 (Positive Genetic), SPINK6 (Proximity Label-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0A6B9L1F0, A0A8K1YTT9, A3FM53, A8N285, B3EWF8, C1IBZ2, C6JUP2, C8YJB3, C8YJB4, L0GCJ1, P00995, P00996, P01001, P09036, P09655, P09656, P0DKM7, P0DKT1, P0DKT2, P0DKT3, P0DKT4, P0DKT5, P0DQC9, P0DQD0, P0DQG9, P0DQP2, P0DXW5, P17696, P19959, P84843, Q00222, Q09TK7, Q2VBN4, Q2VBN5, Q2VBN7, Q45Z11, Q53B46, Q5DT21, Q69CK0, Q6IE32

Diamond homologs: D0MVC9, D0NJ41, G4V4G1, O96790, P00995, P00996, P00997, P00998, P01001, P01002, P01003, P01005, P05585, P05596, P05599, P05600, P05601, P08479, P08480, P08481, P09036, P09656, P09865, P0DKM7, P0DKM8, P0DKM9, P0DKT1, P0DKT2, P0DKT3, P0DKT4, P0DKT5, P16895, P34953, P37109, P52245, P52261, P58062, P67944, P67945, P67946

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

286 predictions. Top by Δscore:

Variant	Effect	Δscore
5:148214021:ATAGT:A	donor_gain	0.9900
5:148214022:TAGT:T	donor_gain	0.9900
5:148214024:GT:G	donor_gain	0.9900
5:148214026:G:GG	donor_gain	0.9900
5:148205340:T:G	donor_gain	0.9800
5:148214023:AGT:A	donor_gain	0.9800
5:148214023:AGTGT:A	donor_loss	0.9800
5:148214024:GTG:G	donor_gain	0.9800
5:148214024:GTGT:G	donor_loss	0.9800
5:148214025:TGT:T	donor_gain	0.9800
5:148214025:TGTAA:T	donor_loss	0.9800
5:148214026:GT:G	donor_loss	0.9800
5:148214027:TA:T	donor_loss	0.9800
5:148214028:AAGT:A	donor_loss	0.9800
5:148214029:A:AC	donor_loss	0.9800
5:148214030:G:T	donor_loss	0.9800
5:148214899:TTGTA:T	acceptor_loss	0.9800
5:148214900:TGTA:T	acceptor_loss	0.9800
5:148214901:GTA:G	acceptor_loss	0.9800
5:148214902:TAG:T	acceptor_loss	0.9800
5:148214903:A:AG	acceptor_gain	0.9800
5:148214903:A:G	acceptor_loss	0.9800
5:148214904:G:A	acceptor_loss	0.9800
5:148214904:G:GG	acceptor_gain	0.9800
5:148213904:TGGTA:T	acceptor_loss	0.9700
5:148213905:GGTA:G	acceptor_loss	0.9700
5:148213906:GTAG:G	acceptor_loss	0.9700
5:148213907:TA:T	acceptor_loss	0.9700
5:148213908:AGGT:A	acceptor_loss	0.9700
5:148213909:G:GA	acceptor_loss	0.9700

AlphaMissense

520 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:148213970:T:A	C48S	0.993
5:148213971:G:C	C48S	0.993
5:148214003:T:A	C59S	0.992
5:148214004:G:C	C59S	0.992
5:148213999:T:A	N57K	0.991
5:148213999:T:G	N57K	0.991
5:148213946:T:A	C40S	0.990
5:148213947:G:C	C40S	0.990
5:148214010:T:C	F61S	0.989
5:148214945:T:A	C80S	0.988
5:148214946:G:C	C80S	0.988
5:148214012:T:A	C62S	0.987
5:148214013:G:C	C62S	0.987
5:148214010:T:G	F61C	0.986
5:148214945:T:C	C80R	0.985
5:148213998:A:T	N57I	0.984
5:148214947:C:G	C80W	0.984
5:148214003:T:C	C59R	0.981
5:148213970:T:C	C48R	0.980
5:148214018:G:C	A64P	0.979
5:148213946:T:C	C40R	0.977
5:148213971:G:A	C48Y	0.977
5:148213979:G:C	D51H	0.977
5:148213947:G:A	C40Y	0.976
5:148214012:T:C	C62R	0.976
5:148214013:G:A	C62Y	0.976
5:148213972:T:G	C48W	0.975
5:148213971:G:T	C48F	0.972
5:148213973:G:T	G49C	0.972
5:148213981:T:A	D51E	0.972

dbSNP variants (sampled 300 via entrez): RS1000139253 (5:148202539 T>G), RS1000543585 (5:148215030 A>G), RS1000703649 (5:148208841 A>C,G), RS1001158285 (5:148209238 A>G), RS1001193791 (5:148209867 G>A,T), RS1001193891 (5:148212510 TTATA>T,TTA,TTATATA,TTATATATA,TTATATATATA,TTATATATATATA), RS1001246344 (5:148212854 A>C), RS1002212886 (5:148213672 G>C), RS1002263548 (5:148214097 G>A), RS1002345456 (5:148203544 G>A,T), RS1002783768 (5:148207358 T>C), RS1003024555 (5:148206604 T>G), RS1003075010 (5:148204670 T>C), RS1003361777 (5:148205141 T>C), RS1003432507 (5:148204422 T>A,C)

Disease associations

OMIM: gene MIM:615868 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1125	Blood protein levels	2.000000e-210

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, increases expression	3
sodium arsenate	increases abundance, decreases expression	1
butyraldehyde	increases expression	1
hydroquinone	decreases expression	1
avobenzone	increases expression	1
CGP 52608	increases reaction, affects binding	1
abrine	increases expression	1
Arsenic	increases abundance, decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Citrulline	increases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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