Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation

Abstract

Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is a potent mitogen and chemotactic factor for fibroblasts, smooth muscle 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‐EGF binds to NIH 3T3 cells over‐expressing either HER1 or HER4 alone, but not HER2 or HER3 alone. Binding to HER4 is independent of HER1. The ability of HB‐EGF to bind to two different receptors is in contrast to EGF which binds to HER1, but not to HER4, and heregulin‐β1 which binds 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 cells and astrocytes; (ii) it induces association of phosphatidylinositol 3‐kinase (PI3‐K) activity with HER4; and (iii) it is a potent chemotactic factor for cells overexpressing HER4. Chemotaxis is inhibited by wortmannin, a PI3‐K inhibitor, suggesting a possible role for PI3‐K in mediating HB‐EGF‐stimulated chemotaxis. On the other hand, HB‐EGF is not 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 and that HB‐EGF can activate two EGF receptor subtypes, HER1 and HER4, but with different biological responses.