Abstract

HB-EGF is synthesized as a membrane-anchored juxtacrine growth factor that is shred to released mature HB-EGF, a potent mitogen and chemotactic factor for smooth muscle cells (SMC). HB-EGF activity is mediated by two receptors, ErbB1 and ErbB4. For the most part HB-EGF function in vivo is not well characterized. In the first aim the role of SMC-derived HB-EGF in mediating SMC-EC interactions in blood vessels will be examined in vivo and in vitro. In addition, potential differences in the roles of transmembrane and mature HB-EGF will be analyzed in vivo in transgenic mice.
The second aim i nvolves characterization of novel HB-EGF receptors. One is a 140 kDa protein that has been recently purified and cloned, binds HB-EGF specifically and as a soluble receptor is a specific HB-EGF antagonist. In addition, two novel ErbB4 isoforms, one with an alteration in the juxtamembrane domain that can not be shed and one that lacks the PI3-kinase binding site and can not activate PI3-kinase activity will be further characterized. These proposed studies on HB-EGF function and receptors are significant since HB-EGF has been suggested to contribute to normal physiological responses such as wound healing and pathological processes such as atherosclerosis and pulmonary hypertension.
The Specific Aims of the proposal are: 1. To Investigate the Role of HB-EGF in Blood Vessels including: a) analysis of temporal and spatial HB-EGF promoter-lacZ reporter gene expression in blood vessels of transgenic mice; b) analysis of the effects of HB-EGF on EC-SMC interactions in vitro; c) over- expression of mature, transmembrane and non-cleavable transmembrane forms in the blood vessels of transgenic mice; d) generation of transgenic mice expressing mature HB-EGF only, by deleting the transmembrane and cytoplasmic domains. 2. To Characterize Novel HB-EGF Receptors including: a) Structure and functional analysis of a novel specific 140 kDa HB-EGF receptor; b) characterization of novel alternatively spliced ErbB4 isoforms differing in the juxtamembrane domain and the PI-3K binding domains.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047397-10
Application #
6386296
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Ikeda, Richard A
Project Start
1992-05-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
10
Fiscal Year
2001
Total Cost
$283,143
Indirect Cost

  Institution

Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Thorsness, Mary K; White, Karen H; Thorsness, Peter E (2002) Migration of mtDNA into the nucleus. Methods Mol Biol 197:177-86
Nishi, E; Prat, A; Hospital, V et al. (2001) N-arginine dibasic convertase is a specific receptor for heparin-binding EGF-like growth factor that mediates cell migration. EMBO J 20:3342-50
Kainulainen, V; Sundvall, M; Maatta, J A et al. (2000) A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis. J Biol Chem 275:8641-9
Gechtman, Z; Alonso, J L; Raab, G et al. (1999) The shedding of membrane-anchored heparin-binding epidermal-like growth factor is regulated by the Raf/mitogen-activated protein kinase cascade and by cell adhesion and spreading. J Biol Chem 274:28828-35
Arbiser, J L; Raab, G; Rohan, R M et al. (1999) Isolation of mouse stromal cells associated with a human tumor using differential diphtheria toxin sensitivity. Am J Pathol 155:723-9
Elenius, K; Choi, C J; Paul, S et al. (1999) Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase. Oncogene 18:2607-15
Campbell, C L; Thorsness, P E (1998) Escape of mitochondrial DNA to the nucleus in yme1 yeast is mediated by vacuolar-dependent turnover of abnormal mitochondrial compartments. J Cell Sci 111 ( Pt 16):2455-64
Suzuki, M; Raab, G; Moses, M A et al. (1997) Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J Biol Chem 272:31730-7
Elenius, K; Corfas, G; Paul, S et al. (1997) A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem 272:26761-8
Soker, S; Gollamudi-Payne, S; Fidder, H et al. (1997) Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165. J Biol Chem 272:31582-8

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