ACTIVATION OF HER4 BY HEPARIN-BINDING EGF-LIKE GROWTH-FACTOR STIMULATES CHEMOTAXIS BUT NOT PROLIFERATION

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a potent mitogen and chemotactic factor for fibroblasts, smooth muscl e cells and keratinocytes. It is demonstrated that HB-EGF is not only a ligand for HER1, as previously reported, but for HER4 as well, HB-EG F binds to NIH 3T3 cells overexpressing either HER1 or HER4 alone, but not HER2 or HER3 alone, Binding to HER4 is independent of HER1, The a bility of HB-EGF to bind to two different receptors is in contrast to EGF which binds to HER1, but not to HER4, and heregulin-beta 1 which b inds to HER4, but not to HER1. Besides binding, HB-EGF activates HER4, For example (i) it induces tyrosine phosphorylation of HER4 in cells overexpressing this receptor and of endogenous HER4 in MDA-MB-453 cell s and astrocytes; (ii) it induces association of phosphatidylinositol 3-kinase (PI3-K) activity with HER4; and (iii) it is a potent chemotac tic factor for cells overexpressing HER4, Chemotaxis is inhibited by w ortmannin, a PI3-K inhibitor, suggesting a possible role for PI3-K in mediating HB-EGF-stimulated chemotaxis, On the other hand, HB-EGF is n ot a mitogen for cells expressing HER4, in contrast to its ability to stimulate both chemotaxis and proliferation in cells expressing HER1, It was concluded that HER4 is a newly described receptor for HB-EGF an d that HB-EGF can activate two EGF receptor subtypes, HER1 and HER4, b ut with different biological responses.