Abstract
HtrA1, a member of the mammalian HtrA serine protease family, has a highly conserved protease domain followed by a PDZ domain. Because HtrA1 is a secretory protein and has another functional domain with homology to follistatin, we examined whether HtrA1 functions as an antagonist of Tgfbeta family proteins. During embryo development, mouse HtrA1 was expressed in specific areas where signaling by Tgfbeta family proteins plays important regulatory roles. The GST-pulldown assay showed that HtrA1 binds to a broad range of Tgfbeta family proteins, including Bmp4, Gdf5, Tgfbetas and activin. HtrA1 inhibited signaling by Bmp4, Bmp2, and Tgfbeta1 in C2C12 cells, presumably by preventing receptor activation. Experiments using a series of deletion mutants indicated that the binding activity of HtrA1 required the protease domain and a small linker region preceding it, and that inhibition of Tgfbeta signaling is dependent on the proteolytic activity of HtrA1. Misexpression of HtrA1 near the developing chick eye led to suppression of eye development that was indistinguishable from the effects of noggin. Taken together, these data indicate that HtrA1 protease is a novel inhibitor of Tgfbeta family members.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Avian Proteins / genetics
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Base Sequence
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Bone Development / genetics
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Proteins / antagonists & inhibitors
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Bone Morphogenetic Proteins / metabolism
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Cell Line
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Chick Embryo
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DNA, Complementary / genetics
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Eye / embryology
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Gene Expression Regulation, Developmental
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Heat-Shock Proteins / chemistry
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Homeodomain Proteins / genetics
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Mice
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Periplasmic Proteins / chemistry
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Periplasmic Proteins / genetics
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Periplasmic Proteins / metabolism*
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Protein Binding
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Protein Structure, Tertiary
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Sequence Deletion
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Serine Endopeptidases / chemistry
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
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Signal Transduction
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism*
Substances
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Avian Proteins
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Bmp4 protein, mouse
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Proteins
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DNA, Complementary
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Heat-Shock Proteins
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Homeodomain Proteins
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Periplasmic Proteins
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RNA, Messenger
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Transforming Growth Factor beta
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Vax protein, chicken
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DegP protease
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Serine Endopeptidases