Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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}bs.aist-nara.ac.jp)

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Expression of TGF-beta superfamily growth factors, their receptors, the associated SMADs and antagonists in five isolated size-matched populations of pre-antral follicles from normal human ovaries.
S. G. Kristensen, K. Andersen, C. A. Clement, S. Franks, K. Hardy, and C. Y. Andersen (2014)
Mol. Hum. Reprod. 20, 293-308
   Abstract »    Full Text »    PDF »
A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
Y. Chen, Z. He, S. Meng, L. Li, H. Yang, and X. Zhang (2013)
Journal of International Medical Research 41, 1445-1455
   Abstract »    Full Text »    PDF »
Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1.
S. M. P. Jacobo, M. M. DeAngelis, I. K. Kim, and A. Kazlauskas (2013)
Mol. Cell. Biol. 33, 1976-1990
   Abstract »    Full Text »    PDF »
HtrA1 Is a Novel Antagonist Controlling Fibroblast Growth Factor (FGF) Signaling via Cleavage of FGF8.
G.-Y. Kim, H.-Y. Kim, H.-T. Kim, J.-M. Moon, C.-H. Kim, S. Kang, and H. Rhim (2012)
Mol. Cell. Biol. 32, 4482-4492
   Abstract »    Full Text »    PDF »
High Temperature Requirement Factor A1 (HTRA1) Gene Regulates Angiogenesis through Transforming Growth Factor-{beta} Family Member Growth Differentiation Factor 6.
L. Zhang, S. L. Lim, H. Du, M. Zhang, I. Kozak, G. Hannum, X. Wang, H. Ouyang, G. Hughes, L. Zhao, et al. (2012)
J. Biol. Chem. 287, 1520-1526
   Abstract »    Full Text »    PDF »
Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers.
S. L. Neuhausen, S. Brummel, Y. C. Ding, L. Steele, K. L. Nathanson, S. Domchek, T. R. Rebbeck, C. F. Singer, G. Pfeiler, H. T. Lynch, et al. (2011)
Cancer Epidemiol. Biomarkers Prev. 20, 1690-1702
   Abstract »    Full Text »    PDF »
Interactive Expressions of HtrA1 and VEGF in Human Vitreous Humors and Fetal RPE Cells.
T. K. Ng, G. H. F. Yam, W. Q. Chen, V. Y. W. Lee, H. Chen, L. J. Chen, K. W. Choy, Z. Yang, and C. P. Pang (2011)
Invest. Ophthalmol. Vis. Sci. 52, 3706-3712
   Abstract »    Full Text »    PDF »
Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-{beta}1 via cleavage of proTGF-{beta}1.
A. Shiga, H. Nozaki, A. Yokoseki, M. Nihonmatsu, H. Kawata, T. Kato, A. Koyama, K. Arima, M. Ikeda, S. Katada, et al. (2011)
Hum. Mol. Genet. 20, 1800-1810
   Abstract »    Full Text »    PDF »
A novel mutation in the HTRA1 gene causes CARASIL without alopecia.
Y. Nishimoto, M. Shibata, M. Nihonmatsu, H. Nozaki, A. Shiga, A. Shirata, K. Yamane, A. Kosakai, K. Takahashi, M. Nishizawa, et al. (2011)
Neurology 76, 1353-1355
   Full Text »    PDF »
The Serine Protease HtrA1 Specifically Interacts and Degrades the Tuberous Sclerosis Complex 2 Protein.
M. Campioni, A. Severino, L. Manente, I. L. Tuduce, S. Toldo, M. Caraglia, S. Crispi, M. Ehrmann, X. He, J. Maguire, et al. (2010)
Mol. Cancer Res. 8, 1248-1260
   Abstract »    Full Text »    PDF »
Polymorphisms in CFH, HTRA1 and CX3CR1 confer risk to exudative age-related macular degeneration in Han Chinese.
X. Yang, J. Hu, J. Zhang, and H. Guan (2010)
Br J Ophthalmol 94, 1211-1214
   Abstract »    Full Text »    PDF »
REVIEW PAPER: Animals as Models of Age-Related Macular Degeneration: An Imperfect Measure of the Truth.
C. J. Zeiss (2010)
Veterinary Pathology 47, 396-413
   Abstract »    Full Text »    PDF »
Analysis of Six Genetic Risk Factors Highly Associated with AMD in the Region Surrounding ARMS2 and HTRA1 on Chromosome 10, Region q26.
D. Hadley, A. Orlin, G. Brown, A. J. Brucker, A. C. Ho, C. D. Regillo, L. A. Donoso, L. Tian, B. Kaderli, and D. Stambolian (2010)
Invest. Ophthalmol. Vis. Sci. 51, 2191-2196
   Abstract »    Full Text »    PDF »
Identification of a Novel HtrA1-susceptible Cleavage Site in Human Aggrecan: EVIDENCE FOR THE INVOLVEMENT OF HtrA1 IN AGGRECAN PROTEOLYSIS IN VIVO.
A. Chamberland, E. Wang, A. R. Jones, L. A. Collins-Racie, E. R. LaVallie, Y. Huang, L. Liu, E. A. Morris, C. R. Flannery, and Z. Yang (2009)
J. Biol. Chem. 284, 27352-27359
   Abstract »    Full Text »    PDF »
Enhanced HtrA2/Omi Expression in Oxidative Injury to Retinal Pigment Epithelial Cells and Murine Models of Neurodegeneration.
X. Ding, M. Patel, D. Shen, A. A. Herzlich, X. Cao, R. Villasmil, K. Klupsch, J. Tuo, J. Downward, and C.-C. Chan (2009)
Invest. Ophthalmol. Vis. Sci. 50, 4957-4966
   Abstract »    Full Text »    PDF »
Regulation of tumor necrosis factor receptor-1 and the IKK-NF-{kappa}B pathway by LDL receptor-related protein explains the antiinflammatory activity of this receptor.
A. Gaultier, S. Arandjelovic, S. Niessen, C. D. Overton, M. F. Linton, S. Fazio, W. M. Campana, B. F. Cravatt III, and S. L. Gonias (2008)
Blood 111, 5316-5325
   Abstract »    Full Text »    PDF »
HtrA1 Inhibits Mineral Deposition by Osteoblasts: REQUIREMENT FOR THE PROTEASE AND PDZ DOMAINS.
K. D. Hadfield, C. F. Rock, C. A. Inkson, S. L. Dallas, L. Sudre, G. A. Wallis, R. P. Boot-Handford, and A. E. Canfield (2008)
J. Biol. Chem. 283, 5928-5938
   Abstract »    Full Text »    PDF »
Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle.
K. Mitko, S. E Ulbrich, H. Wenigerkind, F. Sinowatz, H. Blum, E. Wolf, and S. Bauersachs (2008)
Reproduction 135, 225-240
   Abstract »    Full Text »    PDF »
Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation.
H. Watanabe, M. Shionyu, T. Kimura, K. Kimata, and H. Watanabe (2007)
J. Biol. Chem. 282, 20728-20738
   Abstract »    Full Text »    PDF »
A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration.
Z. Yang, N. J. Camp, H. Sun, Z. Tong, D. Gibbs, D. J. Cameron, H. Chen, Y. Zhao, E. Pearson, X. Li, et al. (2006)
Science 314, 992-993
   Abstract »    Full Text »    PDF »
Negative and Positive Regulation of Gene Expression by Mouse Histone Deacetylase 1.
G. Zupkovitz, J. Tischler, M. Posch, I. Sadzak, K. Ramsauer, G. Egger, R. Grausenburger, N. Schweifer, S. Chiocca, T. Decker, et al. (2006)
Mol. Cell. Biol. 26, 7913-7928
   Abstract »    Full Text »    PDF »
Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: Role of the BMP-4 gene.
R. R. Bowers, J. W. Kim, T. C. Otto, and M. D. Lane (2006)
PNAS 103, 13022-13027
   Abstract »    Full Text »    PDF »
Serine Peptidase HTRA3 Is Closely Associated with Human Placental Development and Is Elevated in Pregnancy Serum.
G. Nie, Y. Li, K. Hale, H. Okada, U. Manuelpillai, E. M. Wallace, and L. A. Salamonsen (2006)
Biol Reprod 74, 366-374
   Abstract »    Full Text »    PDF »
Pattern of Expression of HtrA1 During Mouse Development.
A. De Luca, M. De Falco, L. De Luca, R. Penta, V. Shridhar, F. Baldi, M. Campioni, M. G. Paggi, and A. Baldi (2004)
Journal of Histochemistry & Cytochemistry 52, 1609-1617
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882