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 (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    40 Citations (Scopus)


    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.
    Original languageEnglish
    Pages (from-to)9659-9671
    JournalJournal of Biological Chemistry
    Issue number13
    Publication statusPublished - 2012
    MoE publication typeA1 Journal article-refereed


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