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PMID:19079247

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Citation

Kobayashi, K, Luo, M, Zhang, Y, Wilkes, DC, Ge, G, Grieskamp, T, Yamada, C, Liu, TC, Huang, G, Basson, CT, Kispert, A, Greenspan, DS and Sato, TN (2009) Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nat. Cell Biol. 11:46-55

Abstract

Secreted Frizzled-related proteins (sFRPs) have emerged as key regulators of a wide range of developmental and disease processes. Most of the known functions of mammalian sFRPs have been attributed to their ability to antagonize Wnt signalling. Recently however, Xenopus laevis and zebrafish sFRP, Sizzled, was shown to function as an antagonist of Chordin processing by Tolloid-like metalloproteinases. This has led to the proposal that sFRPs may function as evolutionarily conserved antagonists of chordinase activities of this class of proteinases. In contrast to this proposal, we show here that the mammalian sFRP, sFRP2, does not affect Chordin processing, but instead, can serve as a direct enhancer of procollagen C proteinase activity of Tolloid-like metalloproteinases. We also show that the level of fibrosis, in which procollagen processing by Tolloid-like proteinases has a rate-limiting role, is markedly reduced in Sfrp2-null mice subjected to myocardial infarction. Importantly, this reduced level of fibrosis is accompanied by significantly improved cardiac function. This study thus uncovers a function for sFRP2 and a potential therapeutic application for sFRP2 antagonism in controlling fibrosis in the infarcted heart.

Links

PubMed PMC2722759 Online version:10.1038/ncb1811

Keywords

Animals; Bone Morphogenetic Protein 1/metabolism; Cells, Cultured; Collagen/biosynthesis; Collagen/genetics; Disease Models, Animal; Down-Regulation/genetics; Fibrosis/etiology; Fibrosis/metabolism; Fibrosis/physiopathology; Male; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mice, Knockout; Muscle Contraction/genetics; Myocardial Infarction/complications; Myocardial Infarction/metabolism; Myocardial Infarction/physiopathology; Myocardium/metabolism; Myocardium/pathology; Myocytes, Cardiac/metabolism; Recovery of Function/physiology; Tolloid-Like Metalloproteinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SFRP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P98063

F

Seeded From UniProt

complete

MOUSE:SFRP2

enables

GO:0008047: enzyme activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:88176)

Seeded From UniProt

complete

MOUSE:SFRP2

acts_upstream_of_or_within

GO:0010950: positive regulation of endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_has_input:(MGI:MGI:88176)

Seeded From UniProt

complete

MOUSE:SFRP2

enables

GO:0061133: endopeptidase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:88176)

Seeded From UniProt

complete

MOUSE:BMP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P97299

F

Seeded From UniProt

complete

MOUSE:BMP1

enables

GO:0004222: metalloendopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SFRP2

enables

GO:0061133: endopeptidase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_regulation_target:(MGI:MGI:88176)

Seeded From UniProt

complete

MOUSE:SFRP2

acts_upstream_of_or_within

GO:0030199: collagen fibril organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3664776

P

Seeded From UniProt

complete

MOUSE:SFRP2

acts_upstream_of_or_within

GO:0010950: positive regulation of endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(MGI:MGI:88176)

Seeded From UniProt

complete

MOUSE:SFRP2

enables

GO:0008047: enzyme activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_regulation_target:(MGI:MGI:88176)

Seeded From UniProt

complete


See also

References

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