A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis

ErbB4 is a member of the epidermal growth factor receptor (ErbB) family tha t mediates cellular responses activated by neuregulins (NRG) and other epid ermal growth factor-like growth factors. TWO naturally occurring ErbB4 isof orms, ErbB4 CYT-1 and ErbB4 CYT-2, have previously been identified. Unlike ErbB4 CYT-1, ErbB4 CYT-2 lacks a phosphoinositide 3-kinase (PIS-K)binding s ite and is incapable of activating PI3-K. We have now examined the conseque nces of the inability of this isoform to activate PI3-K on cell proliferati on, survival, and chemotaxis in response to NRG-1 beta: (i) NRG-1 beta stim ulated proliferation of cells expressing either ErbB4 CYT-1 or ErbB4 CYT-S, Consistent with the mitogenic responsiveness, analysis of downstream signa ling showed that Shc and MAPK were phosphorylated after stimulating either isoform with NRG-1 beta. (ii) NRG-1 beta protected cells expressing ErbB4 C YT-1 but not cells expressing ErbB4 CYT-Q from starvation-induced apoptosis as measured by effects on cell number and 4',6-diamidino-2-phenylindole st aining. Furthermore, in cells expressing ErbB4 CYT-2, Akt, a protein kinase that mediates cell survival, was not phosphorylated. (iii) NRG-1 beta stim ulated chemotaxis and membrane ruffling in cells expressing ErbB4 CYT-1 but not in cells expressing ErbB4 CYT-8, In summary, ErbB4 CYT-8 can mediate p roliferation but not chemotaxis or survival. These results suggest a novel mechanism by which cellular responses such as chemotaxis and survival may b e regulated by the expression of alternative receptor-tyrosine kinase isofo rms that differ in their coupling to PI3-K signaling.