Editors' ChoiceReceptors

Live or Die with ErbB4

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Sci. Signal.  07 Dec 2010:
Vol. 3, Issue 151, pp. ec373
DOI: 10.1126/scisignal.3151ec373

ErbB1-4 are receptor tyrosine kinases that regulate cell proliferation, survival, and differentiation and have been implicated in cancer. ErbB4 undergoes alternative splicing to generate two juxtamembrane variants (JM-a and JM-b) and two cytoplasmic variants (CYT-1 and CYT-2). JM-a isoforms undergo regulated proteolysis to release the ectodomain and the intracellular domain, which translocates to the nucleus and interacts with transcription factors to regulate gene expression. Sundvall et al. transfected NR6 cells that expressed only ErbB2 with either the ErbB4 JM-a CYT-2 or JM-b CYT-2 isoforms and found that only the JM-a CYT-2–expressing cells exhibited constitutive phosphorylation of the receptor in the absence of ligand and produced the cleaved intracellular fragment. Phosphorylation of both receptors was stimulated by the ligand NRG-1. The JM-a CYT-2–expressing cells exhibited increased proliferation, anchorage-independent growth in soft agar, and resistance to starvation-induced cell death compared with either control cells or cells expressing JM-b CYT-2. Indeed, the JM-b CYT-2–expressing cells underwent apoptosis in response to starvation. Treatment of either of the isoform-expressing cells with an inhibitor of the kinase activity of ErbB either prevented the proliferative response (JM-a CYT-2–expressing cells) or partially rescued them from serum deprivation–induced death (JM-b CYT-2–expressing cells), indicating that kinase activity was important for both responses. Transcriptional microarray analysis revealed that expression of the gene encoding the platelet-derived growth factor receptor A (PDGFRA) was increased in the JM-a CYT-2–expressing cells and decreased in the JM-b CYT-2–expressing cells, and Western blotting confirmed this difference at the protein level. Inhibition of the kinase activity of PDGFRA reduced the proliferation of JM-a CYT-2–expressing cells, and application of the PDGFR ligand PDGF-BB rescued the JM-b CYT-2–expressing cells from starvation-induced death. RNA interference experiments targeting ERBB4 in SK-N-MC cells that natively express ErbB4 JM-a isoforms reduced the expression of PDFGRA, and in a reporter assay for the PDGFRA promoter, knockdown of either ErbB4 or AP-2 reduced reporter activity in response to NRG-1. Confocal microscopy indicated that AP-2 and a portion of ErbB4 intracellular domain colocalized in the nucleus, and the interaction was confirmed by pull-down experiments. These experiments suggest that isoform-specific differences in cellular response must be considered when targeting the kinase activity of ErbB4 therapeutically.

M. Sundvall, V. Veikkolainen, K. Kurppa, Z. Salah, D. Tvorogov, E. Joop van Zoelen, R. Aqeilan, K. Elenius, Cell death or survival promoted by alternative isoforms of ErbB4. Mol. Biol. Cell 21, 4275–4286 (2010). [Abstract] [Full Text]

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