PCSK6 (proprotein convertase subtilisin/kexin type 6)
2014-11-01 Majid Khatib , Béatrice Demoures AffiliationUniversity Bordeaux 1, INSERM U1029, Avenue des Facultes, Batiment B2, Talence 33405, France
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.
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
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
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/tumors-explorer/submit-meetings/
