Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth.
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.
Määttä
Jorma A
JA
Medicity Research Laboratory and Department of Medical Biochemistry and Molecular Biology, University of Turku, FIN-20520 Turku, Finland.
Sundvall
Maria
M
Junttila
Teemu T
TT
Peri
Liisa
L
Laine
V Jukka O
VJ
Isola
Jorma
J
Egeblad
Mikala
M
Elenius
Klaus
K
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D019281:Dimerization; D010450:Endopeptidases / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D012995:Solubility
D008024:Ligands; D020033:Protein Isoforms; D019000:Phosphotyrosine; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human