Abstract

The transforming growth factor-beta (TGF-beta) family of morphogenic peptides (which includes bone morphogenic proteins-BMPs-Xnrs, Xolloids, etc.) must be proteolytically cleaved in order to be activated. The proproteins of these peptides are cleaved by a small group of serine proteases. Once cleaved, the peptides either diffuse extracellularly or are kept close to the secreting cell by being bound to membrane-associated proteins. The mature peptides signal by binding to specific receptors (I and II) in target cells, which results in the Ser/Thr phosphorylation of Smad proteins. These in turn enter the nucleus to act as transcription activators. This application proposes to characterize proprotein convertases (PCs): (1) by determining the sequence of in vivo cleavages in the proprotein BMPs; (2) by identifying the specific PCs responsible for processing Xolloid; (3) by examining the localization of specific PCs in the developing Xenopus embryo; and (4) by determining the functions of specific PCs during early embryogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037976-05
Application #
6637019
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (01))
Program Officer
Klein, Steven
Project Start
1999-09-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2006-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$264,214
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Neugebauer, Judith M; Kwon, Sunjong; Kim, Hyung-Seok et al. (2015) The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo. Proc Natl Acad Sci U S A 112:E2307-16
Tilak, Anup; Nelsen, Sylvia M; Kim, Hyung-Seok et al. (2014) Simultaneous rather than ordered cleavage of two sites within the BMP4 prodomain leads to loss of ligand in mice. Development 141:3062-71
Christian, Jan L (2012) Morphogen gradients in development: from form to function. Wiley Interdiscip Rev Dev Biol 1:3-15
Pratt, Emily B; Wentzell, Jill S; Maxson, Julia E et al. (2011) The cell giveth and the cell taketh away: an overview of Notch pathway activation by endocytic trafficking of ligands and receptors. Acta Histochem 113:248-55
Mimoto, Mizuho S; Christian, Jan L (2011) Manipulation of gene function in Xenopus laevis. Methods Mol Biol 770:55-75
Kwon, Sunjong; Christian, Jan L (2011) Sortilin associates with transforming growth factor-beta family proteins to enhance lysosome-mediated degradation. J Biol Chem 286:21876-85
Sopory, Shailaja; Kwon, Sunjong; Wehrli, Marcel et al. (2010) Regulation of Dpp activity by tissue-specific cleavage of an upstream site within the prodomain. Dev Biol 346:102-12
Nelsen, Sylvia M; Christian, Jan L (2009) Site-specific cleavage of BMP4 by furin, PC6, and PC7. J Biol Chem 284:27157-66
Goldman, Devorah C; Donley, Nathan; Christian, Jan L (2009) Genetic interaction between Bmp2 and Bmp4 reveals shared functions during multiple aspects of mouse organogenesis. Mech Dev 126:117-27
Goldman, Devorah C; Hackenmiller, Renee; Nakayama, Takuya et al. (2006) Mutation of an upstream cleavage site in the BMP4 prodomain leads to tissue-specific loss of activity. Development 133:1933-42

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