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Open AccessArticle

GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress

1
Department of Molecular Biology and Molecular Biology Centre Severo Ochoa (CMBSO), the Spanish National Research Council, the Autonomous University of Madrid (UAM-CSIC), 28049 Madrid, Spain
2
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA
3
Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
4
Department of Cellular and Molecular Mechanisms in Inflammatory and Autoimmune Diseases, Institute of Health Research La Princesa, 28006 Madrid, Spain
5
Department of Anatomy and Cell Biology, CIBER of Neurodegenerative Diseases (CIBERNED), University of Cantabria–IDIVAL, 39011 Santander, Spain
6
CIC bioGUNE, Center for Cooperative Research in Biosciences, Liver Disease and Liver Metabolism Lab, 48160 Derio, Spain
7
Biomedical Research Center Network of Hepatic and Digestive Diseases (CIBERehd), The Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
8
CIBER of Cardiovascular Diseases (CIBERCV), The Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Lead contact.
Cancers 2020, 12(5), 1216; https://doi.org/10.3390/cancers12051216
Received: 1 April 2020 / Revised: 9 May 2020 / Accepted: 11 May 2020 / Published: 13 May 2020
(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)
Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of the mRNA-binding protein HuR, a central HIF-1α modulator. GRK2-mediated HuR phosphorylation increases the total levels and cytoplasmic shuttling of HuR in response to hypoxia, and GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower binding to HIF-1α mRNA in hypoxic Hela cells. Interestingly, enhanced GRK2 and HuR expression correlate in luminal breast cancer patients. GRK2 also promotes the HuR/HIF-1α axis and VEGF-C accumulation in normoxic MCF7 breast luminal cancer cells and is required for the induction of HuR/HIF1-α in response to adrenergic stress. Our results point to a relevant role of the GRK2/HuR/HIF-1α module in the adaptation of malignant cells to tumor microenvironment-related stresses. View Full-Text
Keywords: hypoxia; β-adrenergic signaling; breast cancer; mRNA regulation; nucleocytoplasmic shuttling; GRK2; HuR; HIF1α; VEGF hypoxia; β-adrenergic signaling; breast cancer; mRNA regulation; nucleocytoplasmic shuttling; GRK2; HuR; HIF1α; VEGF
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Reglero, C.; Lafarga, V.; Rivas, V.; Albitre, Á.; Ramos, P.; Berciano, S.R.; Tapia, O.; Martínez-Chantar, M.L.; Mayor Jr, F.; Penela, P. GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress. Cancers 2020, 12, 1216.

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