Post-translational Proteolytic Processing of Procollagen C-terminal Proteinase Enhancer Releases a Metalloproteinase Inhibitor

Mott, Joni D.; Thomas, Christina L.; Rosenbach, Morgan T.; Takahara, Kazuhiko; Greenspan, Daniel S.; Banda, Michael J.

doi:10.1074/jbc.275.2.1384

Cited by 119 publications

(100 citation statements)

References 42 publications

(29 reference statements)

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“…Because the NTR domains of TIMPs are responsible for their metalloprotease inhibitory activity, we have suggested that NTR modules might be involved in controlling the activity of zinc metalloproteases (1). Our prediction that the NTR module of PCOLCE may be a metalloprotease inhibitor has been confirmed by recent experiments (2).…”

supporting

confidence: 70%

A human protein containing multiple types of protease-inhibitory modules

Trexler

Bányai

Patthy

2001

Proc. Natl. Acad. Sci. U.S.A.

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By using sensitive homology-search and gene-finding programs, we have found that a genomic region from the tip of the short arm of human chromosome 16 (16p13.3) encodes a putative secreted protein consisting of a domain related to the whey acidic protein (WAP) domain, a domain homologous with follistatin modules of the Kazaldomain family (FS module), an immunoglobulin-related domain (Ig domain), two tandem domains related to Kunitz-type protease inhibitor modules (KU domains), and a domain belonging to the recently defined NTR-module family (NTR domain). The gene encoding these WAP, FS, Ig, KU, and NTR modules (hereafter referred to as the WFIKKN gene) is intron-depleted-its single 1,157-bp intron splits the WAP module. The validity of our gene prediction was confirmed by sequencing a WFIKKN cDNA cloned from a lung cDNA library. Studies on the tissue-expression pattern of the WFIKKN gene have shown that the gene is expressed primarily in pancreas, kidney, liver, placenta, and lung. As to the function of the WFIKKN protein, it is noteworthy that it contains FS, WAP, and KU modules, i.e., three different module types homologous with domains frequently involved in inhibition of serine proteases. The protein also contains an NTR module, a domain type implicated in inhibition of zinc metalloproteinases of the metzincin family. On the basis of its intriguing homologies, we suggest that the WFIKKN protein is a multivalent protease inhibitor that may control the action of multiple types of serine proteases as well as metalloproteinase(s).multidomain protease inhibitors ͉ zinc metalloproteinases ͉ serine and cysteine proteinases ͉ NTR modules ͉ netrins T he NTR module has been defined recently as a domain type(1) present in netrins; complement proteins C3, C4, C5; secreted frizzled-related proteins; type I procollagen Cproteinase enhancer proteins (PCOLCE); and tissue inhibitors of metalloproteinases (TIMPs). Because the NTR domains of TIMPs are responsible for their metalloprotease inhibitory activity, we have suggested that NTR modules might be involved in controlling the activity of zinc metalloproteases (1). Our prediction that the NTR module of PCOLCE may be a metalloprotease inhibitor has been confirmed by recent experiments (2).Studies on the netrin-netrin receptor system also have provided evidence that netrins may serve to inhibit metalloprotease activity. The axonal chemoattractant netrin-1 guides spinal commissural axons by activating the netrin receptor deleted in colorectal cancer (DCC). Galko and Tessier-Lavigne (3) have found that chemical inhibitors of metalloproteases potentiate netrin-mediated axon outgrowth in vitro. Their experiments suggest that potentiation of netrin activity by metalloprotease inhibitors results from stabilization of DCC on the axons against proteolysis. The synergistic action of chemical metalloprotease inhibitors and netrins raises the possibility that netrins may protect DCC from metalloproteases via NTR module-mediated inhibition of the metalloprotease (4). Consistent with this...

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supporting

confidence: 70%

A human protein containing multiple types of protease-inhibitory modules

Trexler

Bányai

Patthy

2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Sfrps, TIMPs and PCOLCEs share similarities in the NTR domain which, in TIMP and POLCE is thought to interfere with protease activity 44 . The structure of ADAM10 comprises, adjacent to the catalytic and disintegrin domains, a cysteine-rich motif, which is thought to mediate interaction with other molecules 42 .…”

Section: Discussionmentioning

confidence: 99%

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

et al. 2011

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It is well established that embryonic mouse retinal neurogenesis requiresNotch and Wnt signaling are also required for the development of vertebrate neural retina.This structure develops from a neuroepithelium composed of multipotent progenitors, which undergo a series of competence states to give rise to six neuronal and one glial cell types 2 . As progenitor cells produce the various cell types, Notch through lateral inhibition, maintains neighboring cells in a multipotent, proliferative state, ensuring that sufficient numbers of progenitors are retained for consecutive waves of neurogenesis. Thus, downregulation of Notch is a prerequisite for retinal neuronal differentiation 2 .Wnt/βcatenin signaling has also been implicated in the proliferation of vertebrate retinal precursors. However, in the mouse embryonic neural retina this function is limited to progenitor cells located in the periphery 3, 4 . In contrast, Wnt/βcatenin signaling is not active in the central retina and cell proliferation and differentiation proceed normally in mice with conditional deletion of βcatenin in the neural retina, although retinal lamination is altered 5 .Similarly, retinal specific inactivation of Fzd5, a non-canonical Wnt receptor mostly impacts on retinal vasculature formation but has no effect on neurogenesis 6 By analyzing the functional consequences of Sfrp1 and Sfrp2 compound inactivation during mouse retinal neurogenesis, we demonstrate here a novel and Wnt-independent role of Sfrps in the regulation of Notch signaling. We explain this finding by demonstrating that Sfrps can bind and downregulate the activity of ADAM10, a metalloprotease with multiple substrates including Notch, N-cadherin and APP. 4 RESULTS Sfrp1 and Sfrp2 are essential for proper eye developmentSfrp1 and Sfrp2 are expressed during murine eye development with a complementary pattern that includes all eye structures 7 . Sfrp1 transcripts are localized to the optic cup periphery and the retina pigmented epithelium from E10.5, while Sfrp2 is predominant in the neural retina (Fig. S1). Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9, 11, 12 .Accordingly, the eye of Sfrp1 and Sfrp2 single null embryos appeared histologically normal.In contrast at E16.5, the latest viable stage, the eyes of Sfrp1 -/-;Sfrp2 -/-compound mutants (n=20) were smaller than those of control littermates (n=30) with morphological visible alterations, including dorsal peripheral defects, reduction of the lens size, abnormal cornea and eye lid formation, increased thickness of the neural retina and abnormal vitreal accumulation of mesenchyme-derived angioblasts that normally form the hyaloid artery, the major vascular structure of the embryonic eye (Fig. S2). Inactivation of Sfrp1/2 alters retinal neurogenesisMultipotent progenitors in the neural retina generates neuronal and one glial cells wi...

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“…Thus, PCOLCEs may act via forming a ternary complex between the most carboxyl-terminal domains of BMP1/TLD-like proteinases and their procollagen substrates. The PCOLCE1 NTR domain possesses inhibitory activity against MMPs, and perhaps other proteinases (Mott et al, 2000), and thus may play some role as an inhibitor of collagen catabolism. PCOLCE1-null mice have profoundly abnormal collagen fibrils in both bone and soft tissues, suggesting that PCOLCE1 may play additional in vivo roles beyond enhancement of pCP acitivity .…”

Section: Procollagen C-proteinase Enhancersmentioning

confidence: 99%

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

2007

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A decade ago, bone morphogenetic protein 1 (BMP1) was shown to provide the activity necessary for proteolytic removal of the C-propeptides of procollagens I-III: precursors of the major fibrillar collagens. Subsequent studies have shown BMP1 to be the prototype of a small group of extracellular metalloproteinases that play manifold roles in regulating formation of the extracellular matrix (ECM). Soon after initial cloning of BMP1, genetic studies showed the related Drosophila proteinase Tolloid (TLD) to be necessary for formation of the dorsal-ventral axis in early embryogenesis. It is now clear that the BMP1/TLD-like proteinases, conserved in species ranging from Drosophila to humans, act in dorsal-ventral patterning via activation of transforming growth factor β (TGFβ)-like proteins BMP2, BMP4 (vertebrates) and decapentaplegic (arthropods). More recently, it has become apparent that the BMP1/TLD-like proteinases are key activators of a broader subset of the TGFβ superfamily of proteins, with implications that these proteinases may be key in orchestrating formation of ECM with growth factor activation and BMP signaling in morphogenetic processes.

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Post-translational Proteolytic Processing of Procollagen C-terminal Proteinase Enhancer Releases a Metalloproteinase Inhibitor

Cited by 119 publications

References 42 publications

A human protein containing multiple types of protease-inhibitory modules

A human protein containing multiple types of protease-inhibitory modules

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

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