Alternative titles; symbols
HGNC Approved Gene Symbol: PCSK5
Cytogenetic location: 9q21.13 Genomic coordinates (GRCh38): 9:75,889,809-76,362,975 (from NCBI)
PCSK5 mediates posttranslational endoproteolytic processing for several integrin alpha subunits (Cao et al., 2001). For background information on proprotein convertases, see PC4 (PCSK4; 600487).
De Bie et al. (1996) noted that 2 splice variants of mouse Pcsk5 encode isoforms with different C termini. The 915-amino acid isoform, Pcsk5a, which was cloned by Lusson et al. (1993) and Nakagawa et al. (1993), contains an N-terminal signal peptide, followed by a prosegment, a catalytic domain, 2 tandem P domains (also called homo B domains), a cysteine-rich domain, and 38 C-terminal amino acids unique to Pcsk5a. In comparison, the 1,877-amino acid isoform, Pcsk5b, which was cloned by Nakagawa et al. (1993), contains an extended cysteine-rich domain, followed by a C-terminal transmembrane region and a short cytoplasmic tail. Pcsk5a is widely expressed, with highest abundance in intestine and adrenal gland, but Pcsk5b is expressed only in intestine, adrenal gland, and lung. De Bie et al. (1996) found that the soluble Pcsk5a protein was sorted to secretory granules via its unique C-terminal sequence, whereas the membrane-bound Pcsk5b protein was located in the Golgi. Immunogold electron microscopy localized Pcsk5 in glucagon-containing granules of mouse pancreatic cells.
Using pharmacologic inhibitors and PC5-specific antisense oligonucleotides, Stawowy et al. (2004) found that PC5 was involved in adhesion of rat vascular smooth muscle cells to vitronectin (VTN; 193190), an integrin alpha-V (ITGAV; 193210)/beta-3 (ITGB3; 173470)/beta-5 (ITGB5; 147561) ligand. Inhibition of PC5 also inhibited migration of vascular smooth muscle cells on vitronectin-coated wells. Stawowy et al. (2004) found that PC5 colocalized with alpha-V integrin in human vascular smooth muscle cells in atherosclerotic plaques. They concluded that vascular smooth muscle cell PC5 is necessary for endoproteolytic activation of integrin alpha-V, which leads to integrin-mediated cell adhesion, migration, and signaling.
PCSK5 cleaves and activates GDF11 (603936), a growth and differentiation factor that controls anterior/posterior patterning during embryonic development. Tsuda et al. (2011) found that teratogenic doses of all-trans retinoic acid (ATRA), when administered to pregnant mice via gavage at embryonic day 9 (E9), inhibited Pcsk5 and Gdf11 expression in the hindgut at E12 and E18. ATRA treatment resulted in anorectal malformations, with either rectourethral or rectocloacal fistula, and short tail. Furthermore, most ATRA-treated embryos exhibited sacral malformations, tethered spinal cords, and presacral masses resembling the malformations found in caudal regression syndrome (600145).
Cao et al. (2001) determined that the PCSK5 gene at least contains 12 exons.
Mbikay et al. (1995) mapped the Pcsk5 locus to mouse chromosome 19 close to the lipocortin-1 (Lpc1) locus (LPC1; 151690) by RFLP analysis of a DNA panel from an interspecific backcross. The human homolog was localized to chromosome 9 by Southern blot analysis of a DNA panel from human/rodent somatic cell hybrids, most of which contained a single human chromosome.
Using analysis of somatic cell hybrids and YAC clones, as well as fluorescence in situ hybridization, van de Loo et al. (1996) mapped the PCSK5 gene to 9q21.3 near markers D9S175 and D9S276.
Cao et al. (2001) identified 2 silent SNPs in PCSK5 and found that they varied in frequency among ethnic groups. They suggested that SNPs provide tools to investigate PCSK5 for association with inflammatory or vascular phenotypes.
Szumska et al. (2008) identified an N-ethyl-N-nitrosourea (ENU)-induced recessive mouse mutation that resulted in a pleiotropic phenotype including cardiac, tracheoesophageal, anorectal, and anteroposterior patterning defects, exomphalos, hindlimb hypoplasia, presacral mass, renal and palatal agenesis, and pulmonary hypoplasia. They called the mutation Vcc, because the phenotype resembled many aspects of human VACTERL association (192350), caudal regression syndrome (600145), and Currarino syndrome (176450). Szumska et al. (2008) identified the Vcc mutation as a cys470-to-arg (C470R) substitution in Pcsk5 that ablated a disulfide bond in the P domain, blocking export from the ER and rendering the enzyme inactive. Wildtype Pcsk5a, but not Pcsk5a with the Vcc mutation, cleaved and activated Gdf11, and Gdf11-deficient embryos partially phenocopied Vcc mutants, including anteroposterior patterning defects, renal and palatal agenesis, a presacral mass, anorectal malformation, and exomphalos. The C470R Pcsk5 mutation resulted in abnormal expression of several Hox genes (see HOXA1; 142955) and Mnx1 (HLXB9; 142994), and these included Gdf11 targets and genes necessary for caudal development. Szumska et al. (2008) proposed that PCSK5, at least in part via GDF11, regulates caudal HOX genes to control anteroposterior patterning, nephrogenesis, and skeletal and anorectal development.
Cao, H., Mok, A., Miskie, B., Hegele, R. A. Single-nucleotide polymorphisms of the proprotein convertase subtilisin/kexin type 5 (PCSK5) gene. J. Hum. Genet. 46: 730-732, 2001. [PubMed: 11776387] [Full Text: https://doi.org/10.1007/s100380170008]
De Bie, I., Marcinkiewicz, M., Malide, D., Lazure, C., Nakayama, K., Bendayan, M., Seidah, N. G. The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments. J. Cell Biol. 135: 1261-1275, 1996. [PubMed: 8947550] [Full Text: https://doi.org/10.1083/jcb.135.5.1261]
Lusson, J., Vieau, D., Hamelin, J., Day, R., Chretien, M., Seidah, N. G. cDNA structure of the mouse and rat subtilisin/kexin-like PC5: a candidate proprotein convertase expressed in endocrine and nonendocrine cells. Proc. Nat. Acad. Sci. 90: 6691-6695, 1993. [PubMed: 8341687] [Full Text: https://doi.org/10.1073/pnas.90.14.6691]
Mbikay, M., Seidah, N. G., Chretien, M., Simpson, E. M. Chromosomal assignment of the genes for proprotein convertases PC4, PC5, and PACE 4 in mouse and human. Genomics 26: 123-129, 1995. [PubMed: 7782070] [Full Text: https://doi.org/10.1016/0888-7543(95)80090-9]
Nakagawa, T., Hosaka, M., Torii, S., Watanabe, T., Murakami, K., Nakayama, K. Identification and functional expression of a new member of the mammalian Kex2-like processing endoprotease family: its striking structural similarity to PACE4. J. Biochem. 113: 132-135, 1993. [PubMed: 8468318] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a124015]
Nakagawa, T., Murakami, K., Nakayama, K. Identification of an isoform with an extremely large Cys-rich region of PC6, a Kex2-like processing endoprotease. FEBS Lett. 327: 165-171, 1993. [PubMed: 8335106] [Full Text: https://doi.org/10.1016/0014-5793(93)80163-o]
Stawowy, P., Kallisch, H., Veinot, J. P., Kilimnik, A., Prichett, W., Goetze, S., Seidah, N. G., Chretien, M., Fleck, E., Graf, K. Endoproteolytic activation of alpha(V) integrin by proprotein convertase PC5 is required for vascular smooth muscle cell adhesion to vitronectin and integrin-dependent signaling. Circulation 109: 770-776, 2004. [PubMed: 14970114] [Full Text: https://doi.org/10.1161/01.CIR.0000112583.50762.DE]
Szumska, D., Pieles, G., Essalmani, R., Bilski, M., Mesnard, D., Kaur, K., Franklyn, A., El Omari, K., Jefferis, J., Bentham, J., Taylor, J. M., Schneider, J. E., and 16 others. VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev. 22: 1465-1477, 2008. [PubMed: 18519639] [Full Text: https://doi.org/10.1101/gad.479408]
Tsuda, T., Iwai, N., Deguchi, E., Kimura, O., Ono, S., Furukawa, T., Sasaki, Y., Fumino, S., Kubota, Y. PCSK5 and GDF11 expression in the hindgut region of mouse embryos with anorectal malformations. Europ. J. Pediat. Surg. 21: 238-241, 2011. [PubMed: 21480163] [Full Text: https://doi.org/10.1055/s-0031-1273691]
van de Loo, J.-W. H. P., Creemers, J. W. M., Kas, K., Roebroek, A. J. M., Van de Ven, W. J. M. Assignment of the human proprotein convertase gene PCSK5 to chromosome 9q21.3 Cytogenet. Cell Genet. 75: 227-229, 1996. [PubMed: 9067430] [Full Text: https://doi.org/10.1159/000134489]