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Development 131 (5): 1041-1053

HtrA1 serine protease inhibits signaling mediated by Tgfß family proteins

Chio Oka1, Rumi Tsujimoto1, Miwa Kajikawa1, Kazuko Koshiba-Takeuchi2, Junko Ina1, Masato Yano1, Akiho Tsuchiya1, Yoshihumi Ueta1, Akinobu Soma1, Hidenobu Kanda1, Michio Matsumoto1, and Masashi Kawaichi1,*

1 Division of Gene Function in Animals, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan
2 Division of Metabolic Regulation of Animal Cells, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan

* Author for correspondence (e-mail: mkawaich{at}

Accepted for publication 21 November 2003.

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 Tgfß family proteins. During embryo development, mouse HtrA1 was expressed in specific areas where signaling by Tgfß family proteins plays important regulatory roles. The GST-pulldown assay showed that HtrA1 binds to a broad range of Tgfß family proteins, including Bmp4, Gdf5, Tgfßs and activin. HtrA1 inhibited signaling by Bmp4, Bmp2, and Tgfß1 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 Tgfß 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 Tgfß family members.

Key Words: HtrA1 • Tgfß • Bmp • Serine protease • Noggin • Follistatin

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