HER4 expression correlates with cytotoxicity directed by a heregulin-toxin fusion protein.

The Journal of Biological Chemistry
C B SiegallI Hellström

Abstract

We have constructed, expressed, and purified a fusion protein, HAR-TX beta 2, consisting of heregulin-beta 2 fused to a binding-defective form of Pseudomonas exotoxin A, PE40. The fusion protein was found to induce receptor tyrosine phosphorylation in CEM cells transfected with HER4 alone or in combination with HER2 but not in cells transfected with HER2 or HER1 alone. The phosphorylation of receptor tyrosines was both dose-dependent and saturable in amounts similar to those shown to be active for native heregulin. HAR-TX beta 2 was specifically cytotoxic toward a variety of carcinoma cell lines in the ng/ml range. However, some tumor cell lines were found to be insensitive to the cytotoxic action of the fusion protein even at > 2 micrograms/ml. Relative amounts of HER4, HER3, and HER2 were determined on seven cell lines sensitive and four cell lines insensitive to HAR-TX beta 2. All lines that express HER4 were killed by HAR-TX beta 2, while none lacking HER4 were affected. HAR-TX beta 2 was able to bind to and signal via tyrosine phosphorylation in cell lines that co-express HER2 and HER3 in the absence of HER4 without inducing cytotoxicity. Thus HAR-TX beta 2 may prove to be a useful reagent for the targeting and elimination...Continue Reading

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Citations

Mar 17, 1997·International Journal of Cancer. Journal International Du Cancer·B GronerE Stöcklin
Mar 8, 2000·The Journal of Steroid Biochemistry and Molecular Biology·R B LichtnerM R Schneider
Jul 27, 2002·Journal of Immunotherapy·Cinzia RicciPier-Luigi Lollini
Dec 10, 1999·Protein Engineering·R LandgrafD Eisenberg
Mar 1, 1996·The Journal of Biological Chemistry·J BaulidaG Carpenter
Apr 10, 1997·Experimental Cell Research·J Baulida, G Carpenter

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