Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling

Ilkka Paatero; Anne Jokilammi; Pekka T Heikkinen; Kristiina Iljin; Olli-Pekka Kallioniemi; Frank E Jones; Panu M Jaakkola; Klaus Elenius

doi:10.1074/jbc.M111.299537

Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling

J Biol Chem. 2012 Mar 23;287(13):9659-9671. doi: 10.1074/jbc.M111.299537. Epub 2012 Feb 3.

Authors

Ilkka Paatero¹, Anne Jokilammi², Pekka T Heikkinen³, Kristiina Iljin⁴, Olli-Pekka Kallioniemi⁵, Frank E Jones⁶, Panu M Jaakkola⁷, Klaus Elenius⁸

Affiliations

¹ 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.
² Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, FI-20520 Turku, Finland.
³ Turku Doctoral Programme of Biomedical Sciences, FI-20520 Turku, Finland; Turku Centre for Biotechnology, FI-20520 Turku, Finland.
⁴ Turku Centre for Biotechnology, FI-20520 Turku, Finland; Medical Biotechnology, VTT Technical Research Centre, FI-20520 Turku, Finland.
⁵ 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.
⁶ Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, and.
⁷ Turku Centre for Biotechnology, FI-20520 Turku, Finland; Department of Oncology, Turku University Hospital, FI-20520 Turku, Finland.
⁸ 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.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Nucleus / genetics
Cell Nucleus / metabolism*
ErbB Receptors / genetics
ErbB Receptors / metabolism*
Female
GTP-Binding Proteins / genetics
GTP-Binding Proteins / metabolism
Humans
Hydroxylation
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Male
Mice
Mice, Knockout
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Neuropeptides / genetics
Neuropeptides / metabolism
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism
Protein Stability
Protein Structure, Tertiary
Proteolysis*
Receptor, ErbB-4
Receptors for Activated C Kinase
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism
Signal Transduction / physiology*

Substances

HIF1A protein, human
Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
Neoplasm Proteins
Neuropeptides
RACK1 protein, human
RACK1 protein, mouse
Receptors for Activated C Kinase
Receptors, Cell Surface
ERBB4 protein, human
ErbB Receptors
Erbb4 protein, mouse
Receptor, ErbB-4
Proteasome Endopeptidase Complex
GTP-Binding Proteins