Importance of the major extracellular domain of CD9 and the epidermal growth factor (EGF)-like domain of heparin-binding EGF-like growth factor for up-regulation of binding and activity.
Heparin-binding epidermal growth factor (EGF)-like growth factor ( HB-EGF) is a member of the EGF family of growth factors. The membrane-anchored form of HB-EGF (proHB- EGF) is mitogenically active to neighboring cells as well as being a precursor of the soluble form. In addition to its mitogenic activity, proHB- EGF has the property of binding to diphtheria toxin (DT), serving as the specific receptor for DT. Tetramembrane-spanning protein CD9, a member of the TM4 superfamily, is physically associated with proHB- EGF at the cell surface and up-regulates both mitogenic and DT binding activities of proHB- EGF. To understand this up-regulation mechanism, we studied essential regions of both CD9 and proHB- EGF for up-regulation. Immunoprecipitation experiments revealed that not only CD9 but also other TM4 proteins including CD63, CD81, and CD82 associate with proHB- EGF on the cell surface. However, these TM4 proteins did not up-regulate DT binding activity of proHB- EGF. Transfection of a series of chimeric constructs comprising CD9 and CD81 showed that the major extracellular domain of CD9 is essential for up-regulation. Assays of DT binding activity and juxtacrine mitogenic activity of the deletion mutants of proHB- EGF and chimeric molecules, derived from proHB- EGF and TGF-alpha, showed that the essential domain of proHB- EGF for up-regulation is the EGF-like domain. These results indicate that the interaction of the extracellular domains of both molecules is important for up-regulation.[1]References
- Importance of the major extracellular domain of CD9 and the epidermal growth factor (EGF)-like domain of heparin-binding EGF-like growth factor for up-regulation of binding and activity. Nakamura, K., Mitamura, T., Takahashi, T., Kobayashi, T., Mekada, E. J. Biol. Chem. (2000) [Pubmed]
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