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

Identity

HGNC
LOCATION
15q26.3
LOCUSID
ALIAS
PACE4,SPC4
FUSION GENES

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 IDLast YearTitleAuthors

Other Information

Locus ID:

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

Variants:

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

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000140479ENST00000331826H7BXT3
ENSG00000140479ENST00000398185H0Y3Q0
ENSG00000140479ENST00000558864H0YKK2
ENSG00000140479ENST00000558951H0YMW5
ENSG00000140479ENST00000559417H0YKZ4
ENSG00000140479ENST00000559605H0YLC8
ENSG00000140479ENST00000611716P29122
ENSG00000140479ENST00000611967P29122
ENSG00000140479ENST00000615296P29122
ENSG00000140479ENST00000618548P29122
ENSG00000140479ENST00000619160A0A087WZR0
ENSG00000140479ENST00000621185A0A087X025
ENSG00000140479ENST00000622483A0A087WY68
ENSG00000140479ENST00000632686A0A0J9YW51

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF processingREACTOMER-HSA-167060
MetabolismREACTOMER-HSA-1430728
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
KeratinizationREACTOMER-HSA-6805567
Formation of the cornified envelopeREACTOMER-HSA-6809371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
382161102024PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.0
382161102024PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.0
367806442023PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.9
367806442023PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.9
354103442022PACE4-altCT isoform of proprotein convertase PACE4 as tissue and plasmatic biomarker for prostate cancer.3
354103442022PACE4-altCT isoform of proprotein convertase PACE4 as tissue and plasmatic biomarker for prostate cancer.3
333595612021Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis.8
343011742021Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome.13
333595612021Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis.8
343011742021Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome.13
318939702020PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling.24
321195742020Upregulation of PACE4 in prostate cancer is not dependent on E2F transcription factors.3
324497802020Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma.5
318939702020PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling.24
321195742020Upregulation 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/teaching-explorer/