Juxtacrine stimulation of cellular communication by HB-EGF.

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We have found that the membrane-anchored form of heparin-binding EGF-like growth factor (proHB-EGF) has a juxtacrine mitogenic activity. ProHB-EGF associates with tetramembrane-spanning protein CD9. CD9 was found to enhance the juxtacrine mitogenic activity of proHB-EGF.Furthermore, proHB-EGF forms a complex with integrin alpha3beta1. The aim of this study is to understand the physiological role of this complex. We have done sevaral experiments and obtained the following results.(1) Localization of the complexVero cell, derived from monkey kidney, was studied by immunofluorescence using specific antibodies to proHB-EGF,CD9, integrin alpha3, and integrin beta1. The results revealed that proHB-EGF,CD9 and integrin alpha3b1 localized at cell-cell junction region.(2) The role of heparin-binding domain (KBD)To analyze the role of HBD domain of proHB-EGF,the deletion mutants of HBD of proHB-EGF were produced. The results showed that HBD is not essential for the mitogenic activity and diphtheria toxin binding activity. Heparansulfate proteoglycans may modulate the mitogenic activity of proHB-EGF by interacting with the HBD domain of proHB-EGF.These results indicate that proHB-EGF may play the role of cell-cell interaction in a large complex.