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Originally published as MBC in Press, 10.1091/mbc.E05-05-0402 on October 26, 2005

Vol. 17, Issue 1, 67-79, January 2006

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Proteolytic Cleavage and Phosphorylation of a Tumor-associated ErbB4 Isoform Promote Ligand-independent Survival and Cancer Cell GrowthFormula

Jorma A. Määttä * {dagger}, Maria Sundvall * {dagger} {ddagger}, Teemu T. Junttila * {dagger} {ddagger}, Liisa Peri *, V. Jukka O. Laine §, Jorma Isola ||, Mikala Egeblad ¶, and Klaus Elenius * #

* Medicity Research Laboratory and Department of Medical Biochemistry and Molecular Biology, University of Turku, FIN-20520 Turku, Finland; {ddagger} Turku Postgraduate School of Biomedical Sciences, University of Turku, FIN-20520 Turku, Finland; § Department of Pathology, University of Turku, FIN-20520 Turku, Finland; || Laboratory of Cancer Biology, Institute of Medical Technology, Tampere University and Tampere University Hospital, FIN-33101 Tampere, Finland; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143; and # Department of Oncology, Turku University Central Hospital, FIN-20520 Turku, Finland

Submitted May 6, 2005; Revised October 11, 2005; Accepted October 14, 2005
Monitoring Editor: Carl-Henrik Heldin

The ErbB1 and ErbB2 receptors are oncogenes with therapeutic significance in human cancer, whereas the transforming potential of the related ErbB4 receptor has remained controversial. Here, we have addressed whether four alternatively spliced ErbB4 isoforms differ in regulating cellular responses relevant for tumor growth. We show that the two tumor necrosis factor-{alpha} converting enzyme (TACE)-cleavable ErbB4 isoforms (the juxtamembrane [JM]-a isoforms) were overexpressed in a subset of primary human breast cancers together with TACE. The overexpression of the JM-a cytoplasmic (CYT)-2 ErbB4 isoform promoted ErbB4 phosphorylation, survival of interleukin-3-dependent cells, and proliferation of breast cancer cells even in the absence of ligand stimulation, whereas activation of the other three ErbB4 isoforms required ligand stimulation. Ligand-independent cellular responses to ErbB4 JM-a CYT-2 overexpression were regulated by both tyrosine kinase activity and a two-step proteolytic generation of an intracellular receptor fragment involving first a TACE-like proteinase, followed by {gamma}-secretase activity. These data suggest a novel transforming mechanism for the ErbB4 receptor in human breast cancer that is 1) specific for a single receptor isoform and 2) depends on proteinase cleavage and kinase activity but not ligand activation of the receptor.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05–05–0402) on October 26, 2005.

Formula The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

{dagger} These authors have contributed equally to this work.

Address correspondence to: Klaus Elenius (klaus.elenius{at}utu.fi).




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