Role of G protein-coupled receptor kinases in cell migration

Penela, Petronila; Nogués, Laura; Mayor, Federico

doi:10.1016/j.ceb.2013.10.005

Cited by 55 publications

(49 citation statements)

References 58 publications

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“…G-protein-coupled receptor kinases represent critical nodes in cell migration processes. One of its isoforms, GRK2, has been established to play an effector role in chemotaxis, in the organization of actin and microtubule networks and in adhesion dynamics within an integrated system encompassing a variety of substrates and partners (18). It has been shown that GRK2 and GRK6, along with β-arrestin, bind CXCR4 causing its modulation.…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

Dysplasia of Granulocytes in a Patient with HPV Disease, Recurrent Infections, and B Lymphopenia: A Novel Variant of WHIM Syndrome?

et al. 2017

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WHIM syndrome is a condition in which affected persons have chronic peripheral neutropenia, lymphopenia, abnormal susceptibility to human papilloma virus infection, and myelokathexis. Myelokathexis refers to the retention of mature neutrophils in the bone marrow (BM), which accounts for degenerative changes and hypersegmentation. Most patients present heterozygous autosomal dominant mutations of the gene encoding CXCR4. Consequently, aberrant CXCL12/CXCR4 signaling impairs the receptor downregulation causing hyperactivation (gain-of-function) that affects BM homing for myelopoiesis and lymphopoiesis and the release of neutrophils in the bloodstream. We report the case of a 26-year-old female with severe foot and hand cutaneous warts since childhood, recalcitrant genital condylomatas, bacterial infections, and intraepithelial cervical neoplasia. Laboratory tests revealed severe B lymphopenia and HPV high and low risk types. HIV testing was negative. Not only CXCR4 but also GATA2, NEMO, and CD40L gene mutations were excluded. BM smears revealed, in the presence of a normal cellularity, hyperplasia of myeloid cells (MPO positive) and karyorrhexis, especially in neutrophils and eosinophils. Of note, neutrophils with altered lobation of nuclei connected by long thin chromatin filaments were observed. Our patient presented a clinical and histological picture reminiscent of WHIM in the presence of normal peripheral neutrophil counts and wild-type CXCR4 gene. Although the BM did not reveal a classical pattern of myelokathexis, the observation of consistent signs of neutrophil dysplasia has fuelled the hypothesis of a novel WHIM variant or a novel immunodeficiency. We speculate that abnormalities that affect CXCR4/CXCL12 pair, including GRK levels or activity, might be responsible for this WHIM-like disorder.

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Section: Discussion and Concluding Remarksmentioning

confidence: 99%

Dysplasia of Granulocytes in a Patient with HPV Disease, Recurrent Infections, and B Lymphopenia: A Novel Variant of WHIM Syndrome?

et al. 2017

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“…The astrocytosis observed differed from conventional astrocytosis, which is associated with neuronal loss and neuroinflammation, suggesting that it occurred in a cell-autonomous manner. GIT1 plays a critical role in cell migration and polarization (Penela et al, 2014); therefore, an increase in the number of astrocytes in specific brain regions may be the result of abnormal cell migration. Moreover, the small GTPase, Rac1, is required for cell polarization, directed migration (Fukata et al, 2003), and regulation of astrocytic migration (Etienne-Manneville and Hall, 2001).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Astrocytosis in the Basal Ganglia Pathway of Git1−/− Mice

Lim¹,

Mah²

2015

Molecules and Cells

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Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, affecting approximately 5% of children. However, the neural mechanisms underlying its development and treatment are yet to be elucidated. In this study, we report that an ADHD mouse model, which harbors a deletion in the Git1 locus, exhibits severe astrocytosis in the globus pallidus (GP) and thalamic reticular nucleus (TRN), which send modulatory GABAergic inputs to the thalamus. A moderate level of astrocytosis was displayed in other regions of the basal ganglia pathway, including the ventrobasal thalamus and cortex, but not in other brain regions, such as the caudate putamen, basolateral amygdala, and hippocampal CA1. This basal ganglia circuit-selective astrocytosis was detected in both in adult (2–3 months old) and juvenile (4 weeks old) Git1−/− mice, suggesting a developmental origin. Astrocytes play an active role in the developing synaptic circuit; therefore, we performed an immunohistochemical analysis of synaptic markers. We detected increased and decreased levels of GABA and parvalbumin (PV), respectively, in the GP. This suggests that astrocytosis may alter synaptic transmission in the basal ganglia. Intriguingly, increased GABA expression colocalized with the astrocyte marker, GFAP, indicative of an astrocytic origin. Collectively, these results suggest that defects in basal ganglia circuitry, leading to impaired inhibitory modulation of the thalamus, are neural correlates for the ADHD-associated behavioral manifestations in Git1−/− mice.

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“…Studies have shown that GRK2 is highly expressed in different types of immune cells, and it can attenuate the chemokine-induced migration of T cells and monocytes as a relevant modulator of inflammation [77]. GRK2 phosphorylates chemotactic GPCRs, such as CCR5, CCR2b, CXCR4, and CXCR2, and chemotactic receptors for substance P, S1P or formyl-peptide, and can also modify PDGF or EGF plasma membrane tyrosine kinase receptors, cytoskeleton proteins (ezrin and tubulin), p38MAPK, and metabotropic glutamate receptors, which contribute to leukocyte trafficking to inflammatory foci, T cell egression from lymphoid organs, and leukocyte activation or proliferation [78].…”

Section: Resultsmentioning

confidence: 99%

Development of Inflammatory Immune Response-Related Drugs Based on G Protein-Coupled Receptor Kinase 2

Han¹,

Li²,

Wang³

et al. 2018

Cell Physiol Biochem

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G protein-coupled receptor kinase 2 (GRK2), as a vital Ser/Thr kinase, is an important regulatory protein in the inflammatory immune response (IIR) by maintaining the balance between the function of inflammatory immune cells and non-conventional inflammatory immune cells and regulating inflammatory immune cell infiltration, inflammatory cytokine secretion, and the signaling associated with endothelial function. However, the imbalance of GRK2 expression and activity plays an important role in the development of IIR-related diseases, such as hypertension, heart failure, Alzheimer’s disease, type 2 diabetes mellitus, insulin resistance, rheumatoid arthritis, thyroid cancer, multiple sclerosis, and liver cancer. Small molecule GRK2 inhibitors, including balanol, Takeda inhibitors, paroxetine and derivatives, M119 and gallein, peptides, RNA aptamers, Raf kinase inhibitory protein, and microRNAs, that can directly inhibit GRK2 kinase activity have been identified by different strategies. This review discusses recent progress in one of the hallmark molecular abnormalities of GRK2 in IIR-related diseases and explores the soft regulation of IIR by innovative drugs reducing the excessive activity of GRK2 to basal levels, without damaging normal physiological function, to ameliorate inflammatory disorders.

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Role of G protein-coupled receptor kinases in cell migration

Abstract: Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Current Opinion In Cell Biology 27.1 (2014)

Cited by 55 publications

References 58 publications

Dysplasia of Granulocytes in a Patient with HPV Disease, Recurrent Infections, and B Lymphopenia: A Novel Variant of WHIM Syndrome?

Dysplasia of Granulocytes in a Patient with HPV Disease, Recurrent Infections, and B Lymphopenia: A Novel Variant of WHIM Syndrome?

Abnormal Astrocytosis in the Basal Ganglia Pathway of Git1−/− Mice

Development of Inflammatory Immune Response-Related Drugs Based on G Protein-Coupled Receptor Kinase 2

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