PCSK6 (proprotein convertase subtilisin/kexin type 6)

2014-11-01 Majid Khatib , Béatrice Demoures Affiliation

University Bordeaux 1, INSERM U1029, Avenue des Facultes, Batiment B2, Talence 33405, France

Identity

HGNC

PCSK6

LOCATION

15q26.3

LOCUSID

5046

ALIAS

PACE4,SPC4

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

This gene can be found on chromosome 15 at location: 101844134-102029873.

Transcription

The DNA sequence contains 23 exons and the transcript length: 4236 bps translated to a 968 residues protein.

Proteins

Description

PCSK6 is a member of the family of subtilisin-like proprotein convertases (PCs) that process precursor proteins at their paired basic amino acid processing sites (RXR). This protease undergoes an initial autocatalytic processing event in the endoplasmic reticulum (ER) to generate a heterodimer which exits the ER and sorts to the trans-Golgi network (TGN). In the TGN a second autocatalytic cleavage takes place in order to release an active PCSK6.

Expression

PCSK6 is expressed in many tissues and encoded by different alternatively spliced mRNAs: the PACE4A-I form is secreted and expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, but at comparatively higher levels in the liver. Isoform PACE4A-II is secreted and at least expressed in placenta. Isoform PACE4B is secreted and was only found in the embryonic kidney cell line from which it was isolated. Isoforms PACE4C and PACE4D are located in ER (not secreted, remain probably inactive unprocessed form in endoplasmic reticulum) and expressed in placenta too. Isoforms PACE4E-I and PACE4E-II are probably retained intracellularly through a hydrophobic cluster in their C-terminus, and expressed in cerebellum (E-I and -II), placenta and pituitary (only E-I). The PACE4CS was also found to probably lack enzymatic activity.

Localisation

PCSK6 is activated predominantly at the cell surface and able to process its substrates within the extracellular matrix and cell surface.

Function

PCSK6 induce protein precursors cleavage at the R-X-(K/R)-R motif to release mature proteins. PCSK6 substrates include enzymes (ADAMTS-4 and ADAMTS-5), HIV accessory protein Vpr, NODAL, TGF-beta related proteins, proalbumin and von Willebrand factor. This protein is thought to play a role in tumor progression and left-right patterning.

Homology

The PCSK6 catalytic domain has a high percentage of homology with those of the other PCs: 42% between PCSK6 and Furin.

Implicated in

Entity name

Breast cancer

Note

Higher expression of PCSK6 has been detected in human breast cancer. There was a correlation between the amount of PACE4 gene product and estrogen receptor content.

Entity name

Prostate cancer

Note

A recent study demonstrated that PSCK6 was highly overexpressed in prostate cancer tissues.

Entity name

Skin cancer

Note

Transgenic expression of PACE4 in keratinocytes of the epidermal basal layer was more susceptible to chemical carcinogenesis, evidenced by increased tumor multiplicity, tumor volume, and metastasis.

Entity name

Association with degree of handedness

Note

There is a significant association with a VNTR polymorphism in PCSK6 and handedness.

Bibliography

Pubmed ID	Last Year	Title	Authors

Other Information

Locus ID:

NCBI: 5046
MIM: 167405
HGNC: 8569
Ensembl: ENSG00000140479

Variants:

dbSNP: 5046
ClinVar: 5046
TCGA: ENSG00000140479
COSMIC: PCSK6

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000140479	ENST00000331826	H7BXT3
ENSG00000140479	ENST00000398185	H0Y3Q0
ENSG00000140479	ENST00000558864	H0YKK2
ENSG00000140479	ENST00000558951	H0YMW5
ENSG00000140479	ENST00000559417	H0YKZ4
ENSG00000140479	ENST00000559605	H0YLC8
ENSG00000140479	ENST00000611716	P29122
ENSG00000140479	ENST00000611967	P29122
ENSG00000140479	ENST00000615296	P29122
ENSG00000140479	ENST00000618548	P29122
ENSG00000140479	ENST00000619160	A0A087WZR0
ENSG00000140479	ENST00000621185	A0A087X025
ENSG00000140479	ENST00000622483	A0A087WY68
ENSG00000140479	ENST00000632686	A0A0J9YW51

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Signal Transduction	REACTOME	R-HSA-162582
Signalling by NGF	REACTOME	R-HSA-166520
NGF processing	REACTOME	R-HSA-167060
Metabolism	REACTOME	R-HSA-1430728
Metabolism of lipids and lipoproteins	REACTOME	R-HSA-556833
Lipid digestion, mobilization, and transport	REACTOME	R-HSA-73923
Lipoprotein metabolism	REACTOME	R-HSA-174824
Chylomicron-mediated lipid transport	REACTOME	R-HSA-174800
Developmental Biology	REACTOME	R-HSA-1266738
Signaling by NODAL	REACTOME	R-HSA-1181150
Keratinization	REACTOME	R-HSA-6805567
Formation of the cornified envelope	REACTOME	R-HSA-6809371

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
20379614	2010	Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.	62
21051773	2011	PCSK6 is associated with handedness in individuals with dyslexia.	40
21051773	2011	PCSK6 is associated with handedness in individuals with dyslexia.	40
18671934	2008	Proprotein convertase activation of aggrecanases in cartilage in situ.	34
26259032	2015	PCSK6-mediated corin activation is essential for normal blood pressure.	33
18772886	2008	Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation.	30
23908247	2013	Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis.	27
17909005	2007	Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1.	26
22440827	2012	A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.	23

Citation

Majid Khatib ; Béatrice Demoures

PCSK6 (proprotein convertase subtilisin/kexin type 6)

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

Online version: http://atlasgeneticsoncology.org/gene/41630/welcome