PCSK6 (proprotein convertase subtilisin/kexin type 6)

2014-11-01   Majid Khatib , Béatrice Demoures 

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




Atlas Image


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


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


Atlas Image


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.


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.


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


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.


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
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.
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Prostate cancer
A recent study demonstrated that PSCK6 was highly overexpressed in prostate cancer tissues.
Entity name
Skin cancer
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.
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Association with degree of handedness
There is a significant association with a VNTR polymorphism in PCSK6 and handedness.


Pubmed IDLast YearTitleAuthors
190134482009Inhibition 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
238262482013PCSK6 VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness.Arning L et al
222047262011Proprotein convertases in health and disease.Artenstein AW et al
248456972015Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6).Bassi DE et al
161030822005PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression.Bassi DE et al
109004622000The proprotein convertases furin and PACE4 play a significant role in tumor progression.Bassi DE et al
206519812010Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis.Bassi DE et al
124473842002Extraembryonic proteases regulate Nodal signalling during gastrulation.Beck S et al
187728862008Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation.Blanchet MH et al
204473772010Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions.Byun S et al
232260972012Role of proprotein convertases in prostate cancer progression.Couture F et al
185085612008Knock-out mouse models of proprotein convertases: unique functions or redundancy?Creemers JW et al
89400091996Identification 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
217221562012Identification and functional validation of CDH11, PCSK6 and SH3GL3 as novel glioma invasion-associated candidate genes.Delic S et al
234090342013Alterations in gene expression of proprotein convertases in human lung cancer have a limited number of scenarios.Demidyuk IV et al
179140702008Regulation of Pcsk6 expression during the preantral to antral follicle transition in mice: opposing roles of FSH and oocytes.Diaz FJ et al
234411312013Enhanced UV-induced skin carcinogenesis in transgenic mice overexpressing proprotein convertases.Fu J et al
218052462011Analysis of epigenetic alterations to proprotein convertase genes in disease.Fu Y et al
89954421997Endoprotease activities other than furin and PACE4 with a role in processing of HIV-I gp160 glycoproteins in CHO-K1 cells.Inocencio NM et al
249135672014miR-124 exhibits antiproliferative and antiaggressive effects on prostate cancer cells through PACE4 pathway.Kang S et al
206253882010Zebrafish ProVEGF-C expression, proteolytic processing and inhibitory effect of unprocessed ProVEGF-C during fin regeneration.Khatib AM et al
114020252001Inhibition 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
197808342009Membrane type-1 matrix metalloprotease-independent activation of pro-matrix metalloprotease-2 by proprotein convertases.Koo BH et al
243509952014Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor.Kwiatkowska A et al
191496902009The potential anti-tumorigenic and anti-metastatic side of the proprotein convertases inhibitors.Lahlil R et al
179090052007Opposing 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
231266002012The Multi-Leu peptide inhibitor discriminates between PACE4 and furin and exhibits antiproliferative effects on prostate cancer cells.Levesque C et al
106572492000Endoproteolytic 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
119609072002Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4.Mahloogi H et al
224408272012A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.Malfait AM et al
218966592011The microenvironment patterns the pluripotent mouse epiblast through paracrine Furin and Pace4 proteolytic activities.Mesnard D et al
100500531999Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells.Mori K et al
91927371997A novel human PACE4 isoform, PACE4E is an active processing protease containing a hydrophobic cluster at the carboxy terminus.Mori K et al
95217711998Retroviral envelope glycoprotein processing: structural investigation of the cleavage site.Moulard M et al
110638802000Maturation of HIV envelope glycoprotein precursors by cellular endoproteases.Moulard M et al
211836572011Pcsk6 mutant mice exhibit progressive loss of ovarian function, altered gene expression, and formation of ovarian pathology.Mujoomdar ML et al
97384691998Biosynthetic processing and quaternary interactions of proprotein convertase SPC4 (PACE4).Nagahama M et al
239082472013Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis.Perisic L et al
186645042008Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7.Scamuffa N et al
210517732011PCSK6 is associated with handedness in individuals with dyslexia.Scerri TS et al
169138362006The proprotein convertases and their implication in sterol and/or lipid metabolism.Seidah NG et al
226796422012The biology and therapeutic targeting of the proprotein convertases.Seidah NG et al
237750892013The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions.Seidah NG et al
213884122011What lies ahead for the proprotein convertases?Seidah NG et al
249619012014Repression of liver colorectal metastasis by the serpin Spn4A a naturally occurring inhibitor of the constitutive secretory proprotein convertases.Sfaxi F et al
160071512005Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases.Siegfried G et al
102156031999Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain.Sucic JF et al
117859852002A 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
81796311994Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms.Tsuji A et al
93787251997Genomic organization and alternative splicing of human PACE4 (SPC4), kexin-like processing endoprotease.Tsuji A et al
173510182007Engineering 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
125356162003Secretory 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
104671641999Human subtilisin-like proprotein convertase, PACE4 (SPC4) gene expression is highly regulated through E-box elements in HepG2 and GH4C1 cells.Tsuji A et al
127622302003[Extracellular processing protease PACE4: significance of diversity of SPC family proteases].Tsuji A et al
100377471999Cellular localization and role of prohormone convertases in the processing of pro-melanin concentrating hormone in mammals.Viale A et al
86700661996Comparative cellular processing of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases.Vollenweider F et al
248601482014PCSK6 regulated by LH inhibits the apoptosis of human granulosa cells via activin A and TGFβ2.Wang Y et al
108886762000Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases.Yana I et al
117366602001Proprotein convertase PACE4 is down-regulated by the basic helix-loop-helix transcription factor hASH-1 and MASH-1.Yoshida I et al
229250712012Subtilisin-like proprotein convertase paired basic amino acid-cleaving enzyme 4 is required for chondrogenic differentiation in ATDC5 cells.Yuasa K et al
195207712009Subtilisin-like proprotein convertase PACE4 is required for skeletal muscle differentiation.Yuasa K et al
178255032007Transcriptional regulation of subtilisin-like proprotein convertase PACE4 by E2F: possible role of E2F-mediated upregulation of PACE4 in tumor progression.Yuasa K et al
89068611996Functional 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


dbSNP: 5046
ClinVar: 5046
TCGA: ENSG00000140479


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF processingREACTOMER-HSA-167060
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Lipid digestion, mobilization, and transportREACTOMER-HSA-73923
Lipoprotein metabolismREACTOMER-HSA-174824
Chylomicron-mediated lipid transportREACTOMER-HSA-174800
Developmental BiologyREACTOMER-HSA-1266738
Signaling by NODALREACTOMER-HSA-1181150
Formation of the cornified envelopeREACTOMER-HSA-6809371

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
210517732011PCSK6 is associated with handedness in individuals with dyslexia.40
210517732011PCSK6 is associated with handedness in individuals with dyslexia.40
186719342008Proprotein convertase activation of aggrecanases in cartilage in situ.34
262590322015PCSK6-mediated corin activation is essential for normal blood pressure.33
187728862008Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation.30
239082472013Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis.27
179090052007Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1.26
224408272012A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.23


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/pcsk6