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J Biol Chem. 2012 Mar 23;287(13):9659-71. doi: 10.1074/jbc.M111.299537. Epub 2012 Feb 3.

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

Author information

  • 1Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, FI-20520 Turku, Finland.

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.

PMID:
22308027
[PubMed - indexed for MEDLINE]
PMCID:
PMC3322979
Free PMC Article

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