Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling.
The receptor-tyrosine kinase ErbB4 was identified as a direct regulator of hypoxia-inducible factor-1α (HIF-1α) signaling. Cleaved intracellular domain of ErbB4 directly interacted with HIF-1α in the nucleus, and stabilized HIF-1α protein in both normoxic and hypoxic conditions by blocking its proteasomal degradation. The mechanism of HIF stabilization was independent of VHL and proline hydroxylation but dependent on RACK1. ErbB4 activity was necessary for efficient HRE-driven promoter activity, transcription of known HIF-1α target genes, and survival of mammary carcinoma cells in vitro. In addition, mammary epithelial specific targeting of Erbb4 in the mouse significantly reduced the amount of HIF-1α protein in vivo. ERBB4 expression also correlated with the expression of HIF-regulated genes in a series of 4552 human normal and cancer tissue samples. These data demonstrate that soluble ErbB4 intracellular domain promotes HIF-1α stability and signaling via a novel mechanism.
Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, FI-20520 Turku, Finland,; Turku Doctoral Programme of Biomedical Sciences, FI-20520 Turku, Finland.
Ilkka
I
Paatero
Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, FI-20520 Turku, Finland.
Anne
A
Jokilammi
Turku Doctoral Programme of Biomedical Sciences, FI-20520 Turku, Finland; Turku Centre for Biotechnology, FI-20520 Turku, Finland.
Pekka T
PT
Heikkinen
Turku Centre for Biotechnology, FI-20520 Turku, Finland; Medical Biotechnology, VTT Technical Research Centre, FI-20520 Turku, Finland.
Kristiina
K
Iljin
Turku Centre for Biotechnology, FI-20520 Turku, Finland; Medical Biotechnology, VTT Technical Research Centre, FI-20520 Turku, Finland,; FIMM - Institute for Molecular Medicine Finland, and the Genome-Scale Biology Research Program, Biomedicum, University of Helsinki, FI-00014 Helsinki, Finland.
Olli-Pekka
OP
Kallioniemi
Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, and.
Frank E
FE
Jones
Turku Centre for Biotechnology, FI-20520 Turku, Finland; Department of Oncology, Turku University Hospital, FI-20520 Turku, Finland.
Panu M
PM
Jaakkola
Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, FI-20520 Turku, Finland,; Department of Oncology, Turku University Hospital, FI-20520 Turku, Finland. Electronic address: klaus.elenius@utu.fi.
Klaus
K
Elenius
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D066247:Receptor, ErbB-4; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D009479:Neuropeptides; C419368:RACK1 protein, human; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins