Disease relevance of Pcsk6

• Because PACE4 is overexpressed in skin carcinomas and in vitro overexpression of PACE4 resulted in enhanced invasiveness, we investigated whether or not in vivo PACE4 expression leads to the acquisition of invasiveness and increased tumorigenesis [1].

High impact information on Pcsk6

• Gene expression analysis during early somite stages indicates that spc4 is genetically upstream of nodal, pitx2, lefty1, and lefty2 and perhaps maintains the balance between Nodal and BMP signaling in the lateral plate that is critical for L/R axis formation [2].
• SPC4/PACE4 regulates a TGFbeta signaling network during axis formation [2].
• A lack of Spc1 and Spc4 affects both pathways because these proteases also stimulate induction of Bmp4 [3].
• In contrast, SPC4 and SPC6 exhibit dynamic expression patterns [4].
• Shortly after implantation, SPC4 transcripts are localized to extraembryonic cell populations, and at later stages are detected in discrete tissues including the primitive gut, heart, neural tube, and limb buds [4].

Biological context of Pcsk6

• Pcsk3 and Pcsk6 mapped to a region of mouse chromosome 7 that has been associated cytogenetically with postnatal lethality in maternal disomy, suggesting that these genes might be candidates for imprinting [5].
• The genes for three subtilisin/kexin-like proprotein convertases, PC4, PC5, and PACE4, were mapped in the mouse by RFLP analysis of a DNA panel from a (C57BL/6JEi x SPRET/Ei)F1 x SPRET/Ei backcross [5].
• The rat PACE4 sequence has the Asp-His-Ser catalytic site triad, an Arg-Gly-Asp potential integrin binding site, and three potential sites for N-linked glycosylation [6].
• Thus, although furin and PACE4 mRNA (4.4 kb each) exhibit a widespread tissue distribution only furin is ubiquitously expressed [7].
• It exhibited striking sequence similarity to PACE4 and contained similar protein domains, such as the COOH-terminal Cys-rich region [8].

Anatomical context of Pcsk6

• PACE4 mRNA levels in anterior pituitary are strikingly regulated by thyroid status, with more than a 10-fold increase seen from hypothyroid to hyperthyroid animals [6].
• PACE4 mRNA is prevalent in Buffalo rat liver and GH3 cells and present at low levels in AtT-20 cells, whereas it is undetectable in several other cell lines [6].
• The unique signal sequence of rat PACE4 mediates translocation across microsomal membranes during in vitro translation and secretion of PACE4 from stably transfected fibroblast cells [6].
• Within the limb buds, SPC4 mRNA is most abundant in the apical ectodermal ridge (AER) [4].
• SPC4 transcripts were initially detected in the granulosa cells of secondary follicles [4].

Associations of Pcsk6 with chemical compounds

• Rat PACE4 has a long COOH-terminal region, which is very rich in Cys residues (15%) [6].

Other interactions of Pcsk6

• The K(i) values for the related convertases PACE4 and prohormone convertase-1 (PC1) were 110 nm and 2.5 microm, respectively [9].
• Overexpression of PACE4 led to a significant increase in the processing of stromelysin-3, a well-characterized substrate of this PC [10].
• Some processing of chromogranin B and formation of free PE-11 were also observed with PC2 and PACE4 [11].

Analytical, diagnostic and therapeutic context of Pcsk6

• In situ hybridization coupled with immunocytochemistry revealed that PACE4 is produced by somatotropes, mammotropes, and corticotropes, whereas less PACE4 mRNA was detected in thyrotropes [6].
• Northern blot analysis revealed that PC6 mRNA, as with furin and PACE4 mRNAs, was expressed in various tissues and cell lines, with the highest level in the intestine [8].
• Understanding the functions of the widely expressed PCs (prohormone/proprotein convertases), including PC5/6, furin and PACE4 (paired basic amino acid cleaving enzyme 4), in animal models is difficult since individual knockouts of these PCs in mice exhibit early embryonic lethality [12].

References