Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β
Daniela Mennerich,* Elitsa Y Dimova,* Thomas Kietzmann
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
*These authors contributed equally to this work
Abstract: Hypoxia-inducible factors (HIFs), consisting of α- and β-subunits, are critical regulators of the transcriptional response to hypoxia under both physiological and pathological conditions. To a large extent, the protein stability and the recruitment of coactivators to the C-terminal transactivation domain of the HIF α-subunits determine overall HIF activity. The regulation of HIF α-subunit protein stability and coactivator recruitment is mainly achieved by oxygen-dependent posttranslational hydroxylation of conserved proline and asparagine residues, respectively. Under hypoxia, the hydroxylation events are inhibited and HIF α-subunits stabilize, translocate to the nucleus, dimerize with the β-subunits, and trigger a transcriptional response. However, under normal oxygen conditions, HIF α-subunits can be activated by various growth and coagulation factors, hormones, cytokines, or stress factors implicating the involvement of different kinase pathways in their regulation, thereby making HIF-α-regulating kinases attractive therapeutic targets. From the kinases known to regulate HIF α-subunits, only a few phosphorylate HIF-α directly. Here, we review the direct phosphorylation of HIF-α with an emphasis on the role of glycogen synthase kinase-3β and the consequences for HIF-1α function.
Keywords: HIF-1, phosphorylation, GSK-3β, kinase, hypoxia, ubiquitinylation, tumor suppressor
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]