Alternative titles; symbols
HGNC Approved Gene Symbol: PCSK4
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1,481,428-1,490,876 (from NCBI)
Proprotein convertases, including PCSK4, are calcium-dependent serine proteases related to bacterial subtilisins and to yeast kexin. These enzymes process precursor proteins to their active forms by selective cleavage of the polypeptide at sites following paired basic amino acids. In mammals, this family comprises PC1 (162150), PC2 (162151), PC4, PC5 (600488), furin (FUR; 136950), and PACE4 (167405). Substrates for these enzymes range from prohormones to precursors for growth factors to cell surface receptors and viral surface glycoproteins (Cao et al., 2001).
By Western blot analysis of a human invasive extravillous trophoblast cell line and placental tissue extracts, Qiu et al. (2005) found that pro-PC4 and mature PC4 have apparent molecular masses of 72 and 54 kD, respectively. In situ hybridization revealed that PC4 mRNA localized predominantly in the cytotrophoblast layer during the first trimester and in syncytiotrophoblasts, stroma cells, and to a lesser extent cytotrophoblasts during the third trimester. Immunostaining detected PC4 in villous cytotrophoblasts and syncytiotrophoblasts in both first and third trimester placental tissues.
Intrauterine growth restriction (IUGR) is a leading cause of perinatal mortality. Qiu et al. (2005) found that aberrant processing of pro-IGF2 (147470) by PC4 may be a cause of IUGR. PC4 cleaved pro-IGF2 to generate the intermediate processed form, IGF2 (1-102). Mature IGF2 (1-67), likely resulting from further processing by carboxypeptidases (see CPE; 114855), is capable of activating invasive trophoblast cells through AKT (see AKT1; 164730) phosphorylation. Inhibition of PC4 by a PC4-specific inhibitor blocked pro-IGF2 processing and reduced trophoblast cell migration. Serum samples of women carrying IUGR fetuses displayed elevated levels of pro-IGF2 compared to normal pregnant women. Qiu et al. (2005) suggested that abnormal processing of IGF2 by PC4 may be a mechanism involved in the pathophysiology of fetoplacental growth restriction.
Mbikay et al. (1995) mapped PC4, PC5, and PACE4 in the mouse by RFLP analysis of a DNA panel from an interspecific backcross. The chromosomal locations of the human homologs were determined by Southern blot analysis of a DNA panel from human/rodent somatic cell hybrids, most of which contained a single human chromosome. The gene for PC4 (Pcsk4 locus) was mapped to mouse chromosome 10, close to the adipsin locus (Adn; see 134350) and near the gene encoding anti-mullerian hormone (Amh; see 600957); in the human, the gene was localized to chromosome 19.
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]
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]
Qiu, Q., Basak, A., Mbikay, M., Tsang, B. K., Gruslin, A. Role of pro-IGF-II processing by proprotein convertase 4 in human placental development. Proc. Nat. Acad. Sci. 102: 11047-11052, 2005. [PubMed: 16040806] [Full Text: https://doi.org/10.1073/pnas.0502357102]