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]

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PCSK6
Identifiers
Aliases	PCSK6, PACE4, SPC4, proprotein convertase subtilisin/kexin type 6
External IDs	OMIM: 167405 MGI: 102897 HomoloGene: 20569 GeneCards: PCSK6
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q26.3 Start 101,289,784 bp[1] End 101,525,202 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 C|7 35.36 cM Start 65,511,482 bp[2] End 65,700,134 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in liver right lobe of liver middle frontal gyrus corpus callosum spleen inferior ganglion of vagus nerve inferior olivary nucleus synovial joint subthalamic nucleus pons Top expressed in ankle calvaria stria vascularis lip esophagus left lobe of liver membranous bone body of femur cerebellar vermis maxilla More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding nerve growth factor binding peptidase activity serine-type peptidase activity serine-type endopeptidase activity hydrolase activity endopeptidase activity protein binding Cellular component membrane extracellular matrix cell surface endoplasmic reticulum Golgi lumen endomembrane system extracellular region extracellular space plasma membrane collagen-containing extracellular matrix Biological process glycoprotein metabolic process secretion by cell protein processing proteolysis regulation of BMP signaling pathway determination of left/right symmetry peptide hormone processing zygotic determination of anterior/posterior axis, embryo nerve growth factor production cornification regulation of lipoprotein lipase activity nerve growth factor processing Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5046 18553 Ensembl ENSG00000140479 ENSMUSG00000030513 UniProt P29122 n/a RefSeq (mRNA) NM_138325 NM_001291309 NM_002570 NM_138319 NM_138320 NM_138321 NM_138322 NM_138323 NM_138324 NM_001291184 NM_011048 RefSeq (protein) NP_001278238 NP_002561 NP_612192 NP_612195 NP_612196 NP_612197 NP_612198 n/a Location (UCSC) Chr 15: 101.29 – 101.53 Mb Chr 7: 65.51 – 65.7 Mb PubMed search [3] [4]
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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]

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]

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