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

AuthorsReglero, Clara ; Lafarga, Vanesa ; Rivas, Verónica ; Albitre, Ángela; Ramos, Paula ; Berciano, Susana R.; Tapia, Olga; Martínez-Chantar, María L.; Mayor Menéndez, Federico ; Penela, Petronila
β-adrenergic signaling
Breast cancer
mRNA regulation
Nucleocytoplasmic shuttling
Issue Date2020
PublisherMultidisciplinary Digital Publishing Institute
CitationCancers 12(5): 1216 (2020)
AbstractAdaptation 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.
Description© 2020 by the authors.
Publisher version (URL)https://doi.org/10.3390/cancers12051216
Appears in Collections:(CBM) Artículos
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