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

I. Paatero, A. Jokilammi, P.T. Heikkinen, Kristiina Iljin, Olli Kallioniemi, F.J. Jones, P.M. Jaakkola, K. Elenius (Corresponding Author)

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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.
Original languageEnglish
Pages (from-to)9659-9671
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number13
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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Hypoxia-Inducible Factor 1
Genes
Hydroxylation
Receptor Protein-Tyrosine Kinases
Transcription
Proline
Proteins
Breast
Stabilization
Cells
Tissue
Breast Neoplasms
Degradation
Survival
Neoplasms

Cite this

Paatero, I., Jokilammi, A., Heikkinen, P. T., Iljin, K., Kallioniemi, O., Jones, F. J., ... Elenius, K. (2012). Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling. Journal of Biological Chemistry, 287(13), 9659-9671. https://doi.org/10.1074/jbc.M111.299537
Paatero, I. ; Jokilammi, A. ; Heikkinen, P.T. ; Iljin, Kristiina ; Kallioniemi, Olli ; Jones, F.J. ; Jaakkola, P.M. ; Elenius, K. / Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 13. pp. 9659-9671.
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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.",
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Paatero, I, Jokilammi, A, Heikkinen, PT, Iljin, K, Kallioniemi, O, Jones, FJ, Jaakkola, PM & Elenius, K 2012, 'Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling', Journal of Biological Chemistry, vol. 287, no. 13, pp. 9659-9671. https://doi.org/10.1074/jbc.M111.299537

Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling. / Paatero, I.; Jokilammi, A.; Heikkinen, P.T.; Iljin, Kristiina; Kallioniemi, Olli; Jones, F.J.; Jaakkola, P.M.; Elenius, K. (Corresponding Author).

In: Journal of Biological Chemistry, Vol. 287, No. 13, 2012, p. 9659-9671.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling

AU - Paatero, I.

AU - Jokilammi, A.

AU - Heikkinen, P.T.

AU - Iljin, Kristiina

AU - Kallioniemi, Olli

AU - Jones, F.J.

AU - Jaakkola, P.M.

AU - Elenius, K.

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AB - 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.

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