Extended interaction network of procollagen C-proteinase enhancer-1 in the extracellular matrix

Abstract

PCPE-1 (procollagen C-proteinase enhancer-1) is an extracellular matrix glycoprotein that can stimulate procollagen processing by procollagen C-proteinases such as BMP-1 (bone morphogenetic protein 1). PCPE-1 interacts with several proteins in addition to procollagens and BMP-1, suggesting that it could be involved in biological processes other than collagen maturation. We thus searched for additional partners of PCPE-1 in the extracellular matrix, which could provide new insights into its biological roles. We identified 17 new partners of PCPE-1 by SPR (surface plasmon resonance) imaging. PCPE-1 forms a transient complex with the β-amyloid peptide, whereas it forms high or very high affinity complexes with laminin-111 (KD=58.8 pM), collagen VI (KD=9.5 nM), TSP-1 (thrombospondin-1) (KD1=19.9 pM, KD2=14.5 nM), collagen IV (KD=49.4 nM) and endostatin, a fragment of collagen XVIII (KD1=0.30 nM, KD2=1.1 nM). Endostatin binds to the NTR (netrin-like) domain of PCPE-1 and decreases the degree of superstimulation of PCPE-1 enhancing activity by heparin. The analysis of the PCPE-1 interaction network based on Gene Ontology terms suggests that, besides its role in collagen deposition, PCPE-1 might be involved in tumour growth, neurodegenerative diseases and angiogenesis. In vitro assays have indeed shown that the CUB1CUB2 (where CUB is complement protein subcomponents C1r/C1s, urchin embryonic growth factor and BMP-1) fragment of PCPE-1 inhibits angiogenesis.

The NTR domain of procollagen C-proteinase enhancer-1 (PCPE-1) mediates PCPE-1 binding to syndecans-1, -2 and -4 as well as fibronectin

“…Seventeen additional binding partners of PCPE-1, including laminin 111, collagen VI, thrombospondin 1, collagen IV and endostatin (a fragment of collagen XVIII) were identified recently by SPR (surface plasmon resonance) imaging (Salza et al, 2014). Surprisingly, neither recombinant syndecans-1, -2 or -4 nor fibronectin bound to PCPE-1 in the SPR binding assays.…”

“…The NTR domain also interacts with BMP-1 (Beckhouche et al, 2010) and mediates PCPE-1 binding to ␤2-microglobulin (Morimoto et al, 2008). Additional interaction targets of PCPE-1 in the ECM include laminin 111, collagens VI and IV, thrombospondin-1 and endostatin (Salza et al, 2014).…”

“…The NTR domain of PCPE-1 shares homology with TIMP (Bányai and Patthy, 1999) and is preceded by an un-structured linker that is sensitive to proteolysis (Salza et al, 2014;Kronenberg et al, 2009;Williamson et al, 2008). Although naturally occurring NTR fragmens were reported to inhibit the activity of matrix metalloproteinases (MMPs) (Mott et al, 2000), no inhibitory activity was detected by other investigators against a range of metalloproteinases, including MMPs and BMP-1 (Beckhouche et al, 2010).…”

Procollagen C-proteinase enhancer 1 (PCPE-1) functions as an anti-angiogenic factor and enhances epithelial recovery in injured cornea

“…Thus, because of recent in vitro evidence that PCPE-1 can bind the anti-angiogenic factor endostatin, and can itself inhibit angiogenesis in an in vitro assay (Salza, et al, 2014), corneas of WT and Pcolce −/− mice were examined for degree of neovascularization 5 days post alkali burn. Interestingly, a striking difference in neovascularization following the alkali burn was found between Pcolce −/− and WT corneas, with a marked increase in intracorneal hemangiogenesis in Pcolce −/− cornea compared with WT, as detected by light microscopy (Fig.…”

“…Differences in PCPE-1 expression levels in quiescent versus proliferating smooth muscle cells (Kanaki, et al, 2000), and the induced anchorage-independent growth of cultured fibroblasts in which the PCPE-1 gene has been disrupted (Masuda, et al, 1998), have also suggested a possible role for PCPE-1 in cell proliferation control. It was also recently reported that PCPE-1 can bind the anti-angiogenic factor endostatin and can itself inhibit angiogenesis in an in vitro assay (Salza, et al, 2014). In addition, PCPE-1 may be necessary for lumen formation in a model of in vitro angiogenesis, although the latter effect may be secondary to PCPE-1’s role in collagen biosynthesis and consequent effects on extracellular matrix (ECM) stiffness (Newman, et al, 2011).…”