PCSK6 (proprotein convertase subtilisin/kexin type 6)

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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

LOCATION

15q26.3

LOCUSID

ALIAS

PACE4,SPC4

FUSION GENES

Show Gene Fusions

DNA/RNA

Atlas Image

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

Atlas Image

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
19013448	2009	Inhibition and transcriptional silencing of a subtilisin-like proprotein convertase, PACE4/SPC4, reduces the branching morphogenesis of and AQP5 expression in rat embryonic submandibular gland.	Akamatsu T et al
23826248	2013	PCSK6 VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness.	Arning L et al
22204726	2011	Proprotein convertases in health and disease.	Artenstein AW et al
24845697	2015	Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6).	Bassi DE et al
16103082	2005	PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression.	Bassi DE et al
10900462	2000	The proprotein convertases furin and PACE4 play a significant role in tumor progression.	Bassi DE et al
20651981	2010	Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis.	Bassi DE et al
12447384	2002	Extraembryonic proteases regulate Nodal signalling during gastrulation.	Beck S et al
18772886	2008	Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation.	Blanchet MH et al
20447377	2010	Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions.	Byun S et al
23226097	2012	Role of proprotein convertases in prostate cancer progression.	Couture F et al
18508561	2008	Knock-out mouse models of proprotein convertases: unique functions or redundancy?	Creemers JW et al
8940009	1996	Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(+) cell lines.	Decroly E et al
21722156	2012	Identification and functional validation of CDH11, PCSK6 and SH3GL3 as novel glioma invasion-associated candidate genes.	Delic S et al
23409034	2013	Alterations in gene expression of proprotein convertases in human lung cancer have a limited number of scenarios.	Demidyuk IV et al
17914070	2008	Regulation of Pcsk6 expression during the preantral to antral follicle transition in mice: opposing roles of FSH and oocytes.	Diaz FJ et al
23441131	2013	Enhanced UV-induced skin carcinogenesis in transgenic mice overexpressing proprotein convertases.	Fu J et al
21805246	2011	Analysis of epigenetic alterations to proprotein convertase genes in disease.	Fu Y et al
8995442	1997	Endoprotease activities other than furin and PACE4 with a role in processing of HIV-I gp160 glycoproteins in CHO-K1 cells.	Inocencio NM et al
24913567	2014	miR-124 exhibits antiproliferative and antiaggressive effects on prostate cancer cells through PACE4 pathway.	Kang S et al
20625388	2010	Zebrafish ProVEGF-C expression, proteolytic processing and inhibitory effect of unprocessed ProVEGF-C during fin regeneration.	Khatib AM et al
11402025	2001	Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions.	Khatib AM et al
19780834	2009	Membrane type-1 matrix metalloprotease-independent activation of pro-matrix metalloprotease-2 by proprotein convertases.	Koo BH et al
24350995	2014	Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor.	Kwiatkowska A et al
19149690	2009	The potential anti-tumorigenic and anti-metastatic side of the proprotein convertases inhibitors.	Lahlil R et al
17909005	2007	Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1.	Lapierre M et al
23126600	2012	The Multi-Leu peptide inhibitor discriminates between PACE4 and furin and exhibits antiproliferative effects on prostate cancer cells.	Levesque C et al
10657249	2000	Endoproteolytic processing of integrin pro-alpha subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7.	Lissitzky JC et al
11960907	2002	Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4.	Mahloogi H et al
22440827	2012	A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.	Malfait AM et al
21896659	2011	The microenvironment patterns the pluripotent mouse epiblast through paracrine Furin and Pace4 proteolytic activities.	Mesnard D et al
10050053	1999	Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells.	Mori K et al
9192737	1997	A novel human PACE4 isoform, PACE4E is an active processing protease containing a hydrophobic cluster at the carboxy terminus.	Mori K et al
9521771	1998	Retroviral envelope glycoprotein processing: structural investigation of the cleavage site.	Moulard M et al
11063880	2000	Maturation of HIV envelope glycoprotein precursors by cellular endoproteases.	Moulard M et al
21183657	2011	Pcsk6 mutant mice exhibit progressive loss of ovarian function, altered gene expression, and formation of ovarian pathology.	Mujoomdar ML et al
9738469	1998	Biosynthetic processing and quaternary interactions of proprotein convertase SPC4 (PACE4).	Nagahama M et al
23908247	2013	Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis.	Perisic L et al
18664504	2008	Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7.	Scamuffa N et al
21051773	2011	PCSK6 is associated with handedness in individuals with dyslexia.	Scerri TS et al
16913836	2006	The proprotein convertases and their implication in sterol and/or lipid metabolism.	Seidah NG et al
22679642	2012	The biology and therapeutic targeting of the proprotein convertases.	Seidah NG et al
23775089	2013	The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions.	Seidah NG et al
21388412	2011	What lies ahead for the proprotein convertases?	Seidah NG et al
24961901	2014	Repression of liver colorectal metastasis by the serpin Spn4A a naturally occurring inhibitor of the constitutive secretory proprotein convertases.	Sfaxi F et al
16007151	2005	Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases.	Siegfried G et al
10215603	1999	Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain.	Sucic JF et al
11785985	2002	A critical role for the carboxy terminal region of the proprotein convertase, PACE4A, in the regulation of its autocatalytic activation coupled with secretion.	Taniguchi T et al
8179631	1994	Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms.	Tsuji A et al
9378725	1997	Genomic organization and alternative splicing of human PACE4 (SPC4), kexin-like processing endoprotease.	Tsuji A et al
17351018	2007	Engineering of alpha1-antitrypsin variants selective for subtilisin-like proprotein convertases PACE4 and PC6: importance of the P2' residue in stable complex formation of the serpin with proprotein convertase.	Tsuji A et al
12535616	2003	Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix.	Tsuji A et al
10467164	1999	Human subtilisin-like proprotein convertase, PACE4 (SPC4) gene expression is highly regulated through E-box elements in HepG2 and GH4C1 cells.	Tsuji A et al
12762230	2003	[Extracellular processing protease PACE4: significance of diversity of SPC family proteases].	Tsuji A et al
10037747	1999	Cellular localization and role of prohormone convertases in the processing of pro-melanin concentrating hormone in mammals.	Viale A et al
8670066	1996	Comparative cellular processing of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases.	Vollenweider F et al
24860148	2014	PCSK6 regulated by LH inhibits the apoptosis of human granulosa cells via activin A and TGFβ2.	Wang Y et al
10888676	2000	Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases.	Yana I et al
11736660	2001	Proprotein convertase PACE4 is down-regulated by the basic helix-loop-helix transcription factor hASH-1 and MASH-1.	Yoshida I et al
22925071	2012	Subtilisin-like proprotein convertase paired basic amino acid-cleaving enzyme 4 is required for chondrogenic differentiation in ATDC5 cells.	Yuasa K et al
19520771	2009	Subtilisin-like proprotein convertase PACE4 is required for skeletal muscle differentiation.	Yuasa K et al
17825503	2007	Transcriptional regulation of subtilisin-like proprotein convertase PACE4 by E2F: possible role of E2F-mediated upregulation of PACE4 in tumor progression.	Yuasa K et al
8906861	1996	Functional analysis of human PACE4-A and PACE4-C isoforms: identification of a new PACE4-CS isoform.	Zhong M et al

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)

0

5

10

15

20

25

30

35

40

45

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
38216110	2024	PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.	0
38216110	2024	PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.	0
36780644	2023	PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.	9
36780644	2023	PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.	9
35410344	2022	PACE4-altCT isoform of proprotein convertase PACE4 as tissue and plasmatic biomarker for prostate cancer.	3
35410344	2022	PACE4-altCT isoform of proprotein convertase PACE4 as tissue and plasmatic biomarker for prostate cancer.	3
33359561	2021	Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis.	8
34301174	2021	Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome.	13
33359561	2021	Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis.	8
34301174	2021	Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome.	13
31893970	2020	PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling.	24
32119574	2020	Upregulation of PACE4 in prostate cancer is not dependent on E2F transcription factors.	3
32449780	2020	Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma.	5
31893970	2020	PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling.	24
32119574	2020	Upregulation of PACE4 in prostate cancer is not dependent on E2F transcription factors.	3

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/gene-fusions/js/lib/jquery-3.5.1.min.js