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Mol. Biol. Cell 21 (23): 4275-4286

Copyright © 2010 by The American Society for Cell Biology.


Cell Death or Survival Promoted by Alternative Isoforms of ErbB4

Maria Sundvall*,{dagger},{ddagger}, Ville Veikkolainen*,{ddagger},§, Kari Kurppa*, Zaidoun Salah||, Denis Tvorogov*, E. Joop van Zoelen, Rami Aqeilan||, and Klaus Elenius*,{dagger}

*Department of Medical Biochemistry and Genetics, and Medicity Research Laboratory, University of Turku, Turku, Finland; {dagger}Department of Oncology, Turku University Hospital, FIN-20520 Turku, Finland; §Turku Graduate School of Biomedical Sciences, FIN-20520 Turku, Finland; ||The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University, Hadassah Medical School, 91120 Jerusalem, Israel; and Department of Cell Biology, University of Nijmegen, 6525 Nijmegen, The Netherlands

Received for publication April 21, 2010. Revision received September 30, 2010. Accepted for publication September 30, 2010.

Monitoring Editor: Jonathan Chernoff

Abstract: The significance of ErbB4 in tumor biology is poorly understood. The ERBB4 gene is alternatively spliced producing juxtamembrane (JM-a and JM-b) and cytoplasmic (CYT-1 and CYT-2) isoforms. Here, signaling via the two alternative ErbB4 JM isoforms (JM-a CYT-2 and JM-b CYT-2) was compared. Fibroblasts expressing ErbB4 JM-a demonstrated enhanced ErbB4 autophosphorylation, growth, and survival. In contrast, cells overexpressing ErbB4 JM-b underwent starvation-induced death. Both pro- and antisurvival responses to the two ErbB4 isoforms were sensitive to an ErbB kinase inhibitor. Platelet-derived growth factor receptor-alpha (PDGFRA) was identified as an ErbB4 target gene that was differentially regulated by the two ErbB4 isoforms. The soluble intracellular domain of ErbB4, released from the JM-a but not from the JM-b isoform, associated with the transcription factor AP-2 and promoted its potential to enhance PDGFRA transcription. Survival of cells expressing JM-a was suppressed by targeting either PDGFR-{alpha} or AP-2, whereas cells expressing JM-b were rescued from cell death by the PDGFR-{alpha} agonist, PDGF-BB. These findings indicate that two alternative ErbB4 isoforms may promote antagonistic cellular responses and suggest that pharmacological inhibition of ErbB4 kinase activity may lead to either suppression or promotion of cellular growth.

This article was published online ahead of print in MBoC in Press ( on October 13, 2010.

{ddagger} These authors contributed equally to this work.

Address correspondence to: Dr. Klaus Elenius (klaus.elenius{at}

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C. Kiel, E. Verschueren, J.-S. Yang, and L. Serrano (2013)
Science Signaling 6, ra109
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Protein Inhibitor of Activated STAT3 (PIAS3) Protein Promotes SUMOylation and Nuclear Sequestration of the Intracellular Domain of ErbB4 Protein.
M. Sundvall, A. Korhonen, K. Vaparanta, J. Anckar, K. Halkilahti, Z. Salah, R. I. Aqeilan, J. J. Palvimo, L. Sistonen, and K. Elenius (2012)
J. Biol. Chem. 287, 23216-23226
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