PCSK6

PCSK6
Identifiers
AliasesPCSK6, PACE4, SPC4, proprotein convertase subtilisin/kexin type 6
External IDsOMIM: 167405; MGI: 102897; HomoloGene: 20569; GeneCards: PCSK6; OMA:PCSK6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5046

18553

Ensembl

ENSG00000140479

ENSMUSG00000030513

UniProt

P29122

n/a

RefSeq (mRNA)

NM_001291184
NM_011048

RefSeq (protein)

n/a

Location (UCSC)Chr 15: 101.29 – 101.53 MbChr 7: 65.51 – 65.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Proprotein convertase subtilisin/kexin type 6 is an protease that in humans is encoded by the PCSK6 gene which is located in chromosome 15.[5][6] Pcsk6 is a calcium-dependent serine endoprotease that catalyzes the post-translational modification of precursor proteins from its 'latent' form to the cleaved 'active' form.[5] Active Pcsk6 has been reported to process substrates such as transforming growth factor β,[7] pro-albumin,[8] von Willebrand factor,[9] and corin.[10] Clinically, Pcsk6 is suggested to play a role in left/right asymmetry,[11] structural asymmetry of the brain,[12] handedness,[13][14][15] tumor progression,[16] hemostasis,[9][8][7] and cardiovascular diseases.[10][17]

Function

The protein encoded by this gene belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can cleave precursor protein at their paired basic amino acid processing sites. Some of its substrates are - transforming growth factor beta related proteins,[7] pro-albumin,[8] von Willebrand factor,[9] and corin.[10] Alternatively spliced transcript variants encoding different isoforms have been identified.[6]

Clinical significance

During development

Throughout development, the spatial and temporal expression of pcsk6 regulates embryogenesis by activating TGFβ related differentiation factors, which include BMP and Nodal.[7][18] Elevated levels of Pcsk6 was detected in maternal decidual cells of the implantation site and the extraembryonic ectoderm.[19] The regulation of proper gradient of Nodal and BMPs is crucial for gastrulation,[20] proximal-distal axis,[21] and establishment of left-right axis patterning.[22]

Developmental Pcsk6 knockout studies found that mice embryos that lack Pcsk6 develop heterotaxia, left pulmonary isomerism, and/or craniofacial malformations due to disruption in specification of anterior-posterior and left-right axis that resulted from the dysregulation of Nodal and BMP signaling.[11]

In humans, Pcsk6 VNTR polymorphism is associated with the structural asymmetry of the frontal and temporal lobe,[12] and degree of handedness.[13][14]

Cardiovascular disease

Pcsk6 is increasing interest as indicator and factor of cardiovascular disease. Pcsk6 KO mice was shown to develop salt-sensitive hypertension due to failure of pro-corin activation crucial to atrial natriuretic peptide regulation of blood pressure.[10] A hypertensive patient was found to have a G/A mutation on the PCSK6 gene that resulted in an Asp282Asn (D282N) substitution at the Pcsk6 catalytic domain, which in turn, hinders corin processing.[10] In vascular remodeling, Pcsk6 was found to induce smooth muscle cell migration in response to PDGFB by activating MMP14.[17] When Pcsk6 was knocked out, the intimal hyperplasia response to in vivo carotid ligation was lowered.[17]

Cancer

This gene is thought to play a role in tumor progression.[6][16]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000140479 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030513 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ (December 1991). "Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15". DNA and Cell Biology. 10 (10): 757–769. doi:10.1089/dna.1991.10.757. PMID 1741956.
  6. ^ a b c "Entrez Gene: PCSK6 proprotein convertase subtilisin/kexin type 6".
  7. ^ a b c d Constam DB (August 2014). "Regulation of TGFβ and related signals by precursor processing". Seminars in Cell & Developmental Biology. 32: 85–97. doi:10.1016/j.semcdb.2014.01.008. PMID 24508081.
  8. ^ a b c Mori K, Imamaki A, Nagata K, Yonetomi Y, Kiyokage-Yoshimoto R, Martin TJ, et al. (March 1999). "Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells". Journal of Biochemistry. 125 (3): 627–633. doi:10.1093/oxfordjournals.jbchem.a022329. PMID 10050053.
  9. ^ a b c Rehemtulla A, Barr PJ, Rhodes CJ, Kaufman RJ (November 1993). "PACE4 is a member of the mammalian propeptidase family that has overlapping but not identical substrate specificity to PACE". Biochemistry. 32 (43): 11586–11590. doi:10.1021/bi00094a015. PMID 8218226.
  10. ^ a b c d e Chen S, Cao P, Dong N, Peng J, Zhang C, Wang H, et al. (September 2015). "PCSK6-mediated corin activation is essential for normal blood pressure". Nature Medicine. 21 (9): 1048–1053. doi:10.1038/nm.3920. PMC 4710517. PMID 26259032.
  11. ^ a b Constam DB, Robertson EJ (May 2000). "SPC4/PACE4 regulates a TGFbeta signaling network during axis formation". Genes & Development. 14 (9): 1146–1155. doi:10.1101/gad.14.9.1146. PMC 316583. PMID 10809672.
  12. ^ a b Berretz G, Arning L, Gerding WM, Friedrich P, Fraenz C, Schlüter C, et al. (November 2019). "Structural Asymmetry in the Frontal and Temporal Lobes Is Associated with PCSK6 VNTR Polymorphism". Molecular Neurobiology. 56 (11): 7765–7773. doi:10.1007/s12035-019-01646-1. PMID 31115778. S2CID 160009569.
  13. ^ a b Robinson KJ, Hurd PL, Read S, Crespi BJ (April 2016). "The PCSK6 gene is associated with handedness, the autism spectrum, and magical ideation in a non-clinical population". Neuropsychologia. 84: 205–212. doi:10.1016/j.neuropsychologia.2016.02.020. PMID 26921480. S2CID 6142024.
  14. ^ a b Arning L, Ocklenburg S, Schulz S, Ness V, Gerding WM, Hengstler JG, et al. (2013-06-27). "PCSK6 VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness". PLOS ONE. 8 (6) e67251. Bibcode:2013PLoSO...867251A. doi:10.1371/journal.pone.0067251. PMC 3695088. PMID 23826248.
  15. ^ Scerri TS, Brandler WM, Paracchini S, Morris AP, Ring SM, Richardson AJ, et al. (February 2011). "PCSK6 is associated with handedness in individuals with dyslexia". Human Molecular Genetics. 20 (3): 608–614. doi:10.1093/hmg/ddq475. PMC 3016905. PMID 21051773.
  16. ^ a b Bassi DE, Mahloogi H, Klein-Szanto AJ (June 2000). "The proprotein convertases furin and PACE4 play a significant role in tumor progression". Molecular Carcinogenesis. 28 (2): 63–69. doi:10.1002/1098-2744(200006)28:2<63::aid-mc1>3.0.co;2-c. PMID 10900462. S2CID 22849623.
  17. ^ a b c Rykaczewska U, Suur BE, Röhl S, Razuvaev A, Lengquist M, Sabater-Lleal M, et al. (February 2020). "PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling". Circulation Research. 126 (5): 571–585. doi:10.1161/circresaha.119.316063. hdl:1887/3185300. PMID 31893970. S2CID 209539709.
  18. ^ Constam DB, Robertson EJ (January 1999). "Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases". The Journal of Cell Biology. 144 (1): 139–149. doi:10.1083/jcb.144.1.139. PMC 2148113. PMID 9885250.
  19. ^ Constam DB, Calfon M, Robertson EJ (July 1996). "SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis". The Journal of Cell Biology. 134 (1): 181–191. doi:10.1083/jcb.134.1.181. PMC 2120924. PMID 8698813.
  20. ^ Mesnard D, Guzman-Ayala M, Constam DB (July 2006). "Nodal specifies embryonic visceral endoderm and sustains pluripotent cells in the epiblast before overt axial patterning". Development. 133 (13): 2497–2505. doi:10.1242/dev.02413. PMID 16728477.
  21. ^ Arnold SJ, Robertson EJ (February 2009). "Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo". Nature Reviews. Molecular Cell Biology. 10 (2): 91–103. doi:10.1038/nrm2618. PMID 19129791. S2CID 94174.
  22. ^ Brennan J, Norris DP, Robertson EJ (September 2002). "Nodal activity in the node governs left-right asymmetry". Genes & Development. 16 (18): 2339–2344. doi:10.1101/gad.1016202. PMC 187443. PMID 12231623.

Further reading

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