Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth

Määttä, J. A., Sundvall, M., Junttila, T. T., Peri, L., Laine, V. J. O., Isola, J., Egeblad, M., Elenius, K. (2006) Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth. Molecular Biology of the Cell, 17 (1). pp. 67-79. ISSN 10591524 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/16251361
DOI: 10.1091/mbc.E05-05-0402

Abstract

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-α 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 γ-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. © 2005 by The American Society for Cell Biology.

Item Type: Paper
Uncontrolled Keywords: epidermal growth factor receptor epidermal growth factor receptor 2 epidermal growth factor receptor 4 gamma secretase interleukin 3 isoprotein protein tyrosine kinase proteinase tumor necrosis factor alpha converting enzyme alternative RNA splicing article breast cancer cancer growth cell growth cell proliferation cell survival controlled study gene overexpression human human cell human tissue ligand binding malignant transformation priority journal promoter region protein degradation protein phosphorylation receptor binding receptor upregulation ADAM Proteins Adult Aged Aged, 80 and over Amyloid Precursor Protein Secretases Aspartic Endopeptidases Cell Line, Tumor Cell Membrane Dimerization Endopeptidases Gene Expression Regulation, Neoplastic Humans Ligands Middle Aged Neoplasms Phosphorylation Phosphotyrosine Protein Isoforms Protein Processing, Post-Translational Receptor, Epidermal Growth Factor Signal Transduction Solubility
Subjects: diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Egeblad lab
Depositing User: Matt Covey
Date: 2006
Date Deposited: 14 Mar 2013 19:48
Last Modified: 14 Mar 2013 19:48
PMCID: PMC1345647
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27815

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