TAC4

Summary

TAC4 (tachykinin precursor 4, HGNC:16641) is a protein-coding gene on chromosome 17q21.33, encoding Tachykinin-4 (Q86UU9). Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles.

This gene is a member of the tachykinin family of neurotransmitter-encoding genes. Tachykinin proteins are cleaved into small, secreted peptides that activate members of a family of receptor proteins. The products of this gene preferentially activate tachykinin receptor 1, and are thought to regulate peripheral endocrine and paracrine functions including blood pressure, the immune system, and endocrine gland secretion. The products of this gene lack a dibasic cleavage site found in other tachykinin proteins. Consequently, the nature of the cleavage products generated in vivo remains to be determined. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 255061 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 16 total
• MANE Select transcript: NM_001077506

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16641
Approved symbol	TAC4
Name	tachykinin precursor 4
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	HK-1, Pptc, PPT-C
Ensembl gene	ENSG00000176358
Ensembl biotype	protein_coding
OMIM	607833
Entrez	255061

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 retained_intron

ENST00000326219, ENST00000334568, ENST00000352793, ENST00000398154, ENST00000436235, ENST00000503603, ENST00000608380, ENST00000608861

RefSeq mRNA: 5 — MANE Select: NM_001077506 NM_001077503, NM_001077504, NM_001077505, NM_001077506, NM_170685

CCDS: CCDS42357, CCDS42358, CCDS42359, CCDS42360, CCDS45727

Canonical transcript exons

ENST00000436235 — 5 exons

Exon	Start	End
ENSE00001288317	49844064	49844157
ENSE00001332699	49841552	49841584
ENSE00001376294	49839850	49839909
ENSE00003932122	49838300	49838673
ENSE00003937786	49847913	49848069

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 86.85.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	86.85	gold quality
buccal mucosa cell	CL:0002336	85.04	silver quality
myocardium	UBERON:0002349	82.54	silver quality
granulocyte	CL:0000094	77.41	gold quality
sperm	CL:0000019	77.38	gold quality
vena cava	UBERON:0004087	76.86	silver quality
cerebellar vermis	UBERON:0004720	75.46	silver quality
adenohypophysis	UBERON:0002196	74.53	gold quality
pituitary gland	UBERON:0000007	74.03	gold quality
right lobe of thyroid gland	UBERON:0001119	73.80	gold quality
blood	UBERON:0000178	73.66	gold quality
lower esophagus mucosa	UBERON:0035834	72.70	gold quality
left lobe of thyroid gland	UBERON:0001120	72.01	gold quality
thyroid gland	UBERON:0002046	71.70	gold quality
leukocyte	CL:0000738	70.74	gold quality
nipple	UBERON:0002030	70.73	silver quality
monocyte	CL:0000576	70.66	gold quality
pharyngeal mucosa	UBERON:0000355	70.47	gold quality
gingival epithelium	UBERON:0001949	70.36	gold quality
spleen	UBERON:0002106	69.86	gold quality
corpus callosum	UBERON:0002336	69.80	gold quality
oocyte	CL:0000023	69.64	gold quality
amniotic fluid	UBERON:0000173	69.47	silver quality
right lobe of liver	UBERON:0001114	69.40	gold quality
gingiva	UBERON:0001828	69.28	gold quality
mucosa of stomach	UBERON:0001199	69.04	gold quality
descending thoracic aorta	UBERON:0002345	68.97	gold quality
tendon	UBERON:0000043	68.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	68.79	gold quality
cartilage tissue	UBERON:0002418	68.74	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	402.54
E-ANND-3	no	0.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EBF1, NFKB

miRNA regulators (miRDB)

12 targeting TAC4, 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-574-5P	100.00	66.01	989
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-1909-5P	98.94	64.01	484
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-3944-5P	98.50	67.55	997
HSA-MIR-6818-5P	97.50	67.10	1167
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-24-1-5P	95.57	65.85	492
HSA-MIR-24-2-5P	95.57	66.16	484

Literature-anchored findings (GeneRIF, showing 12)

• Results suggest that Hemokinin-1 is regulated by a unique transcription regulation system that likely governs its differential expression pattern and suggests a role for Hemokinin-1 distinct from Substance P. (PMID:19081134)
• A possible association is found between a tachykinin-4 single nucleotide polymorphism and susceptibility to asthma. (PMID:20580442)
• Endogenous expression of hemokinin-1 is demonstrated in bronchi and is involved in contraction of airway explants. (PMID:20929541)
• hHK-1 and its C-terminal fragments are human NK1 receptor agonists with different functional selectivity properties and that such functional selectivity leads to differential activation of downstream signaling and receptor trafficking. (PMID:21168392)
• Data provide evidence for the first time that hemokinin-1, like substance P, may be involved in the pathophysiology of inflammatory bowel disease. (PMID:21342363)
• HK-1 and substance P are novel T helper (Th)17 cell-inducing factors that may act locally on memory T cells to amplify inflammatory responses. (PMID:21368235)
• HKs emerge as pivotal endogenous regulators of angiogenesis through neurokinin-1 receptor (PMID:22554585)
• expressed in mural granulosa and cumulus cells (PMID:27146034)
• Expression substance P/neurokinin A/hemokinin-1 and their preferred neurokinin 1/neurokinin 2 receptors are dysregulated in uterine leiomyomata. (PMID:27456549)
• Kinase activation led to increased MMP-2 and MT1-MMP expression and melanoma cell migration induced by hHK-1. Thus, hHK-1 and the NK1 receptor are critical to melanoma cell migration and each may be a promising chemotherapeutic target (PMID:27458061)
• Hemokinin-1 and substance P stimulate production of inflammatory cytokines and chemokines in human colonic mucosa via both NK1 and NK2 tachykinin receptors. (PMID:32600668)
• Serum level of hemokinin-1 is significantly lower in patients with chronic spontaneous urticaria than in healthy subjects. (PMID:34090787)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tac4	ENSMUSG00000020872
rattus_norvegicus	Tac4	ENSRNOG00000004404

Protein

Protein identifiers

Tachykinin-4 — Q86UU9 (reviewed: Q86UU9)

Alternative names: Preprotachykinin-C

All UniProt accessions (1): Q86UU9

UniProt curated annotations — full annotation on UniProt →

Function. Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles. Endokinin-A induces thermal hyperalgesia and pain-related behavior such as scratching following intrathecal administration in rats. These effects are suppressed by treatment with endokinin-C. Endokinin-A/B reduces arterial blood pressure and increases sperm motility.

Subcellular location. Secreted.

Tissue specificity. Expressed at low levels in the uterus of both pregnant and non-pregnant women. Isoform 1 is found only in the adrenal gland and fetal liver. Isoform 2 is found in heart, liver, bone marrow, prostate, adrenal gland and testis. Isoform 3 and isoform 4 are expressed predominantly in adrenal gland and placenta.

Similarity. Belongs to the tachykinin family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q86UU9-1	1, Alpha	yes
Q86UU9-2	2, Beta
Q86UU9-3	3, Gamma
Q86UU9-4	4, Delta
Q86UU9-5	5

RefSeq proteins (5): NP_001070971, NP_001070972, NP_001070973, NP_001070974, NP_733786 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013055	Tachy_Neuro_lke_CS	Conserved_site

UniProt features (14 total): splice variant 4, peptide 3, helix 2, propeptide 2, modified residue 2, signal peptide 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2MOC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UU9-F1	56.47	0.00

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): 67, 95

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 68 (showing top): GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_SENSORY_PERCEPTION_OF_PAIN, GOBP_DETECTION_OF_TEMPERATURE_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_CILIUM_MOVEMENT

GO Biological Process (9): negative regulation of systemic arterial blood pressure (GO:0003085), inflammatory response (GO:0006954), positive regulation of cytosolic calcium ion concentration (GO:0007204), tachykinin receptor signaling pathway (GO:0007217), regulation of blood pressure (GO:0008217), detection of temperature stimulus involved in sensory perception of pain (GO:0050965), regulation of sensory perception of pain (GO:0051930), positive regulation of flagellated sperm motility (GO:1902093), negative regulation of sensory perception of pain (GO:1904057)

GO Molecular Function (3): substance P receptor binding (GO:0031835), substance K receptor binding (GO:0031837), receptor ligand activity (GO:0048018)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of pain	3
regulation of biological quality	2
neurokinin receptor binding	2
regulation of systemic arterial blood pressure	1
negative regulation of blood pressure	1
defense response	1
G protein-coupled receptor signaling pathway	1
blood circulation	1
detection of temperature stimulus involved in sensory perception	1
regulation of sensory perception	1
positive regulation of cilium movement	1
flagellated sperm motility	1
regulation of flagellated sperm motility	1
positive regulation of cilium-dependent cell motility	1
positive regulation of reproductive process	1
negative regulation of nervous system process	1
regulation of sensory perception of pain	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

386 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TAC4	TACR1	P25103	941
TAC4	CHKB	Q9Y259	927
TAC4	TAC3	Q9UHF0	908
TAC4	TACR2	P21452	906
TAC4	TAC1	P20366	898
TAC4	TACR3	P29371	896
TAC4	RLN1	P04808	495
TAC4	OR7C2	O60412	445
TAC4	NPW	Q8N729	443
TAC4	PLEKHA4	Q9H4M7	435
TAC4	IAPP	P10997	432
TAC4	RLN3	Q8WXF3	431
TAC4	OR5C1	Q8NGR4	428
TAC4	NMU	P48645	418
TAC4	TMEM65	Q6PI78	417

IntAct

0 interactions, top by confidence:

BioGRID (2): TACR2 (Reconstituted Complex), TACR1 (Reconstituted Complex)

ESM2 similar proteins: A0A0F7YZQ7, D3Z752, F1QQI2, I7C2V3, M0R8L2, O35417, O62647, O93448, P01146, P01213, P01214, P01258, P01261, P01301, P06300, P08435, P08858, P0DP56, P0DQY8, P0DQY9, P13241, P25308, P48756, P49188, P55099, P57774, P63152, P67934, Q06145, Q0VBW8, Q0VC44, Q13519, Q1HA20, Q4QXT8, Q5H8A1, Q5H8A2, Q5H8A3, Q60478, Q62923, Q64387

Diamond homologs: Q6ECK6, Q86UU9, Q8CH01, Q99N14

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

882 predictions. Top by Δscore:

Variant	Effect	Δscore
17:49844102:G:A	donor_gain	0.9800
17:49844154:CTTC:C	acceptor_gain	0.9700
17:49839908:TG:T	acceptor_gain	0.9500
17:49844157:CCTGA:C	acceptor_loss	0.9500
17:49844158:CTGAA:C	acceptor_loss	0.9500
17:49847909:TTA:T	donor_loss	0.9500
17:49847910:T:TG	donor_loss	0.9500
17:49847911:A:AT	donor_loss	0.9500
17:49847912:CCCA:C	donor_loss	0.9500
17:49839910:C:CC	acceptor_gain	0.9400
17:49839916:G:C	acceptor_gain	0.9400
17:49841585:C:CC	acceptor_gain	0.9400
17:49847911:AC:A	donor_gain	0.9400
17:49847912:CC:C	donor_gain	0.9400
17:49844058:ACTC:A	donor_loss	0.9300
17:49844060:T:TA	donor_loss	0.9300
17:49844062:AC:A	donor_loss	0.9300
17:49844062:ACCTC:A	donor_gain	0.9300
17:49844063:C:CA	donor_loss	0.9300
17:49844063:CCTCC:C	donor_gain	0.9300
17:49844107:G:A	donor_gain	0.9300
17:49844158:C:CC	acceptor_gain	0.9300
17:49847906:CAATT:C	donor_loss	0.9300
17:49839118:T:TA	donor_gain	0.9200
17:49839913:G:GC	acceptor_gain	0.9200
17:49839916:G:GC	acceptor_gain	0.9200
17:49841547:CTTA:C	donor_loss	0.9200
17:49841548:TTAC:T	donor_loss	0.9200
17:49841549:TACC:T	donor_loss	0.9200
17:49841550:A:AG	donor_loss	0.9200

AlphaMissense

680 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:49844092:G:C	F63L	0.967
17:49844092:G:T	F63L	0.967
17:49844094:A:G	F63L	0.967
17:49844089:A:C	F64L	0.942
17:49844089:A:T	F64L	0.942
17:49844091:A:G	F64L	0.942
17:49844080:C:A	M67I	0.914
17:49844080:C:G	M67I	0.914
17:49844080:C:T	M67I	0.914
17:49844074:C:A	K69N	0.876
17:49844074:C:G	K69N	0.876
17:49844093:A:G	F63S	0.868
17:49844079:C:A	G68W	0.844
17:49844075:T:G	K69T	0.839
17:49844093:A:C	F63C	0.835
17:49844079:C:G	G68R	0.830
17:49844079:C:T	G68R	0.830
17:49844078:C:A	G68V	0.826
17:49844104:C:A	K59N	0.812
17:49844104:C:G	K59N	0.812
17:49844113:C:A	K56N	0.812
17:49844113:C:G	K56N	0.812
17:49844078:C:T	G68E	0.762
17:49844084:A:G	L66P	0.758
17:49844075:T:A	K69M	0.753
17:49844091:A:T	F64I	0.744
17:49844090:A:C	F64C	0.742
17:49844081:A:G	M67T	0.710
17:49844091:A:C	F64V	0.703
17:49844076:T:C	K69E	0.693

dbSNP variants (sampled 300 via entrez): RS1000363890 (17:49841025 A>C), RS1000580865 (17:49840563 C>T), RS1000778850 (17:49846990 T>A,C), RS1001020421 (17:49842842 T>C), RS1001034785 (17:49840379 G>A), RS1001470393 (17:49841303 C>T), RS1002022214 (17:49846045 C>A), RS1002185613 (17:49842452 C>A,T), RS1002363060 (17:49846252 C>G,T), RS1002424685 (17:49840075 T>C), RS1002543728 (17:49840546 A>G), RS1002618275 (17:49842189 C>G), RS1002721783 (17:49846877 C>T), RS1002816076 (17:49838833 C>G,T), RS1002816845 (17:49847120 C>T)

Disease associations

OMIM: gene MIM:607833 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST012490_233	Femur bone mineral density x serum urate levels interaction	5.000000e-10
GCST90011900_150	Serum alkaline phosphatase levels	7.000000e-25

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Lead	increases expression	1
Quercetin	increases expression	1
Valproic Acid	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Lactic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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