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

• Published in: Molecular biology of the cell 2006-01, Vol.17 (1), p.67-79
• Main Authors: Määttä, Jorma A, Sundvall, Maria, Junttila, Teemu T, Peri, Liisa, Laine, V Jukka O, Isola, Jorma, Egeblad, Mikala, Elenius, Klaus
• Format: Article
• Language: English
• Subjects: ADAM Proteins - metabolism; ADAM17 Protein; Adult; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cell Line, Tumor; Cell Membrane - metabolism; Cell Proliferation; Cell Survival; Dimerization; Endopeptidases - metabolism; Gene Expression Regulation, Neoplastic; Humans; Ligands; Middle Aged; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Phosphorylation; Phosphotyrosine - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Processing, Post-Translational; Receptor, Epidermal Growth Factor - chemistry; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-4; Signal Transduction; Solubility
• ISSN: 1059-1524; 1939-4586; 1059-1524
• DOI: 10.1091/mbc.e05-05-0402

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.