| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
1)HB-EGF is a member of the EGF family of growth factors that has a high affinity for heparin and heparan sulfate (HS). While interactions with heparin are thought to modulate the biological activity of HB-EGF, the precise role of the heparin-binding domain (HBD) has remained unclear. We analyzed the activity of wild-type HB-EGF and a mutant form lacking HBD (ΔHB) in the presence or absence of heparin. The activity of the EGF-like domain of HB-EGF was determined by measuring binding to diphtheria toxin (DT) as well as the growth factor activity in EGF receptor (EGFR)-expressing cells. Our results indicate that the HBD suppresses of the activity of the EGF-like domain of HB-EGF and that association of heparin with HB-EGF via HBD removes the suppressive effect. Thus, we conclude that HBD serves as a negative regulator of this growth factor.
(JBC 2004,279,47335-47343)
2)HB-EGF transduces mitogenic signals through EGFR. While interactions with heparin or HS up-regulate the mitogenic activity
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of HB-EGF, the effect of the interaction with HS in a form of HS-proteoglycans (HSPGs) on the biological activity of HB-EGF has remained unclear. We studied the biological activity of HB-EGF that binds to HSPGs by using a model in which EGFR-expressing target cells were co-cultured with the HSPG-expressing effecter cells that bind HB-EGF via HSPGs. Our results indicate that HSPG-bound HB-EGF induces sustained activation of EGFR-MAPK signaling pathway, followed by growth inhibition of the EGFR-expressing effecter cells.
(Manuscript in preparation)
3)HB-EGF is a member of the EGF family of growth factors that has a high affinity for heparin and heparan sulfate (HS). While interactions with heparin are thought to modulate the biological activity of HB-EGF, the physiological role of the heparin-binding activity of HB-EGF has remained unclear. To examine the physiological significance of the heparin-binding activity of HB-EGF in vivo, we generated mutant mice by targeted gene replacement, expressing HBD-truncated form (HB^<Δhb>) of the molecule. HB^<Δhb/Δhb> mice were normally born and fertile. However, these mice developed enlarged cardiac valves with abnormal hyperproliferation of the mesenchymal cells during the process of cardiac valve remodeling, that phenocopy HB-EGF null mice. Our results indicate that the heparin-binding activity of HB-EGF is essential for physiological function of HB-EGF during cardiac valve development, and that the interaction of HB-EGF with HSPGs promotes growth inhibition of the mesenchymal cells in the developing cardiac valves.
(Manuscript in preparation) Less
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