G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub

Penela, Petronila; Ribas, Catalina; Sánchez-Madrid, Francisco; Mayor, Federico

doi:10.1007/s00018-019-03274-3

Cited by 64 publications

(66 citation statements)

References 224 publications

(250 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Depending on the Gα subunit family, Gα will act to stimulate or inhibit adenylyl cyclase (AC), activate phosphoinositide‐specific phospholipase C (PI‐PLC), or regulate RhoA proteins. Alternatively, Gβγ subunits are thought to play a role in calcium channel activity, and regulate protein kinases and small G‐proteins, such as ERK1/2, JNK, phosphoinositide‐3 kinase (PI3K), and mitogen‐activated protein kinases (MAPKs) …”

Section: Plcβ Generates Ca2+ Signals In Response To Extracellular Sigmentioning

confidence: 99%

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

et al. 2019

View full text Add to dashboard Cite

Some proteins can serve multiple functions depending on different cellularconditions. An example of a bifunctional protein is inositide-specific mammalian phospholipase Cβ (PLCβ). PLCβ is activated by G proteins in response to hormones and neurotransmitters to increase intracellular calcium. Recently, alternate cellular function(s) of PLCβ have become uncovered. However, the conditions that allow these different functions to be operative are unclear. Like many mammalian proteins, PLCβ has a conserved catalytic core along with several regulatory domains. These domains modulate the intensity and duration of calcium signals in response to external sensory information, and allow this enzyme to inhibit protein translation in a noncatalytic manner. In this review, we first describe PLCβ's cellular functions and regulation of the switching between these functions, and then discuss the thermodynamic considerations that offer insight into how cells manage multiple and competitive associations allowing them to rapidly shift between functional states.

show abstract

Section: Plcβ Generates Ca2+ Signals In Response To Extracellular Sigmentioning

confidence: 99%

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

et al. 2019

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…Ser670 phosphorylation is an emerging regulatory switcher in GRK2 substrate specificity and partner association [18]. Context-specific ERK1/2-dependent GRK2 Ser670 phosphorylation is necessary for GRK2 to phosphorylate HDAC6 [21,28], to disrupt its interaction with GIT1 [51], or to allow its HSP90-mediated localization to the mitochondrial membrane [52].…”

Section: Discussionmentioning

confidence: 99%

“…Besides its role in GPCR desensitization, the G protein-coupled receptor kinase 2 (GRK2) is emerging as a key signaling hub. GRK2 can act as a positive effector of certain GPCR and receptor-tyrosine kinases (RTK) transduction cascades [18,19], and also directly interacts/phosphorylates components of signaling networks involved in cell transformation [20]. We have recently shown that GRK2 expression is up-regulated in different breast cancer contexts, playing a driving role in the acquisition of oncogenic features [21,22].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Reglero

Lafarga

Rivas

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…G‐protein‐coupled receptor kinase 2 (GRK2), besides its canonical role in the desensitization of G protein‐coupled receptors (GPCR), is emerging as a potentially relevant oncomodulator given its functional connections with signaling networks related to cell proliferation, survival, migration or invasion . The specific GRK2 interactome involved in those processes appear to depend on the cell type and the physio‐pathological context.…”

Section: Introductionmentioning

confidence: 99%

G‐protein‐coupled receptor kinase 2 safeguards epithelial phenotype in head and neck squamous cell carcinomas

Palacios‐García

Sanz‐Flores

Asensio

et al. 2020

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract and display few treatment options in advanced stages. Despite increased knowledge of HNSCC molecular biology, the identification of new players involved in triggering HNSCC recurrence and metastatic disease is needed. We uncover that G-protein-coupled receptor kinase-2 (GRK2) expression is reduced in undifferentiated, high-grade human HNSCC tumors, whereas its silencing in model human HNSCC cells is sufficient to trigger epithelial-to-mesenchymal transition (EMT) phenotypic features, an EMT-like transcriptional program and enhanced lymph node colonization from orthotopic tongue tumors in mice. Conversely, enhancing GRK2 expression counteracts mesenchymal cells traits by mechanisms involving phosphorylation and decreased functionality of the key EMT inducer Snail1. Our results suggest that GRK2 safeguards the epithelial phenotype, whereas its downregulation contributes to the activation of EMT programs in HNSCC.M.S.-F. and A.A. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

show abstract

G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub

Cited by 64 publications

References 224 publications

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

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

G‐protein‐coupled receptor kinase 2 safeguards epithelial phenotype in head and neck squamous cell carcinomas

Contact Info

Product

Resources

About