2; CDKN1B/p27Kip1: cyclin dependent kinase inhibitor 1B; CQ: chloroquine; E2F1: E2F transcription factor group box 1; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; IHC: immunohistochemistry; JAK1: Janus kinase 1; LOX: lysyl oxidase; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MKI67 : marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; MAPK: mitogen-activated -4,5-bisphosphate 3-kinase catalytic subunit alpha; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit

Extracellular signal-regulated kinases (ERK), a subset of the mitogen-activated protein kinase (MAPK) Initially, the activation of small GTPases like RAS leads to the activation of the MAP kinase kinase kinases (MAPKKKs), such as RAF. RAF then phosphorylates and activates the MAP kinase kinases (MAPKKs), MEK1 and MEK2, which in turn phosphorylate Extracellular Signal-Regulated Kinase: A Regulator of Cell Growth, Inflammation, Chondrocyte and Bone

September 2022 "Yeast use the G-protein–coupled receptor signaling pathway to detect and track the mating pheromone. The G-protein–coupled receptor pathway is inhibited by the regulator of G-protein signaling (RGS) Sst2 which induces Gα GTPase activity and inactivation of downstream signaling. G-protein signaling activates the MAPK Fus3, which phosphorylates the RGS; however, the role of this modification is unknown. We found that pheromone-induced RGS phosphorylation peaks early; the phospho-state of RGS controls its localization and influences MAPK spatial distribution. Surprisingly, phosphorylation of the RGS promotes completion of cytokinesis before pheromone-induced growth. Completion of cytokinesis in the presence of pheromone is promoted by the kelch-repeat protein, Kel1 and antagonized by the formin Bni1. We found that RGS complexes with Kel1 and prefers the unphosphorylatable RGS mutant. We also found overexpression of unphosphorylatable RGS exacerbates cytokinetic defects, whereas they are rescued by overexpression of Kel1. These data lead us to a model where Kel1 promotes completion of cytokinesis before pheromone-induced polarity but is inhibited by unphosphorylated RGS binding." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Roles of Focal Adhesion Kinase PTK2 and Integrin αIIbβ3 Signaling in Collagen- and GPVI-Dependent Here, we focused on disclosing the integrin-dependent roles of focal adhesion kinase (protein tyrosine kinase 2, PTK2), the shear-dependent collagen receptor GPR56 (ADGRG1 gene), and calcium and integrin-binding

August 2022 "Emerging evidence suggests that G protein-coupled receptor (GPCR) kinases (GRKs) are associated

September 2022 Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer combination of insulin and the GPCR agonist neurotensin induced rapid activation of Src family of tyrosine kinases

September 2022 "G protein-coupled receptor (GPCR) kinases (GRKs) and arrestins mediate GPCR desensitization recruitment of the adaptor protein STAM1 (signal-transducing adaptor molecule) to βarr1 and focal adhesion kinase phosphorylation but not extracellular signal-regulated kinase 1/2 phosphorylation.

Lysophosphatidic Acid and Several Neurotransmitters Converge on Rho-Kinase 2 Signaling to Manage Motoneuron We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment

October 2022 Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein kinase Additionally, using the Gαq/11 inhibitor YM-254890, GPCR kinase 2 and 3 (GRK2 and GRK3) KO cells, and

Among the known effectors recruited by GPCR-bound arrestins are Src family kinases, which regulate cellular Here, we focus on arrestin-3 interactions with Fgr kinase, a member of the Src family.

G protein-coupled receptor kinase 2 is essential to enable vasoconstrictor-mediated arterial smooth muscle GPCR signalling through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) promotes VSMC proliferation In VSMC, G protein-coupled receptor kinase 2 (GRK2) is known to regulate numerous vasoconstrictor GPCRs

August 2022 G protein-coupled receptor kinase type 2 and β-arrestin2: Key players in immune cell functions and inflammation "G protein-coupled receptor kinase type 2 (GRK2) and β-arrestin2 are representative The kinase GRK2 and the multifunctional scaffolding protein β-arrestin2 are key integrated signaling

Sandra Berndt talk about new structural perspectives in GPCR-mediated Src family kinase activation.

August 2022 "Three classes of G-protein-coupled receptor (GPCR) partners - G proteins, GPCR kinases,

October 2022 "The cAMP-dependent protein kinase (PKA) system represents a primary cell-signaling pathway

September 2022 "Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute

October 2022 Coincident Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception "Pain management is a significant problem worldwide. The current frontline approach for pain-management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3), or selective inhibition of Gβγ regulation of PLCβ3, enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in HEK293 cells and found that MOR alone could not stimulate PLC, but rather required a coincident signal from a Gq coupled receptor. Knockout of PLCβ3, or pharmacological inhibition of its upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray (PAG) slices increased the potency of the selective MOR agonist DAMGO in inhibiting presynaptic GABA release. Finally, inhibition of Gq-GPCR coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately this could lead to identification of new non-MOR targets that would allow for lower dose utilization of opioid analgesics. " Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

A role for BET proteins in regulating basal, dopamine-induced and cAMP/PKA-dependent transcription in rat striatal neurons The activity of striatal medium-spiny projection neurons is regulated by D1 and D2 dopamine receptors. The D1 receptor (D1R) is a Gαs/olf-coupled GPCR which activates a cAMP/PKA/DARPP-32 signalling cascade that increases excitability and facilitates plasticity, partly through the regulation of transcription. Upon activation via D1R, PKA can translocate to the nucleus to regulate transcription through the phosphorylation of various targets. One candidate effector of PKA-dependent transcriptional regulation is the BET protein Brd4. It is known that when Brd4 is activated by phosphorylation, it binds more readily to acetylated histones at promoters and enhancers; moreover, in non-neuronal cells, PKA signalling has been shown to increase recruitment of Brd4 to chromatin. However, it is unknown whether BET proteins, or Brd4 specifically, are involved in transcriptional activation by cAMP/PKA in neurons. Here, we demonstrate that in adult rats, inhibition of BET proteins with the bromodomain inhibitor JQ1 suppressed the expression of ~25% of D1R-upregulated genes, while also increasing the expression of a subset of immediate-early genes. We further found that cAMP/PKA signalling promotes Brd4 recruitment to dopamine-induced genes in striatal neurons, and that knockdown of Brd4 attenuates D1R-induced gene expression. Finally, we report that JQ1 treatment downregulated expression of many GPCRs and also impaired ERK1/2 signalling in striatal neurons. Our findings identify the BET protein family, and Brd4 in particular, as novel regulators of basal and D1R-dependent transcription in rat striatal neurons, and delineate complex bi-directional effects of bromodomain inhibitors on neuronal transcription. Read full article

characterize nanobodies as tools for biochemical and structural studies of class IB phosphoinositide 3-kinases One of the most important signaling pathways in higher eukaryotes is the phosphoinositide 3-kinase (PI3K We identify nanobodies that stimulated lipid kinase activity, block Ras activation, and specifically

.- Jan Steyaert , scientific director of the VIB-VUB Center for Structural Biology , Vlaams Instituut Jan Steyaert will be presented with the Gabbay Award at Brandeis University on October 27 when he will

compared to wild type CXCR4 including agonist-promoted calcium flux and extracellular signal-regulated kinase

This effect involves the sequential and additive action of protein kinase A, casein kinase I, and the Fused (FU) kinase.

by 7 α,25-Dihydroxycholesterol Induces Behavioral Hypersensitivity through Mitogen-Activated Protein Kinase at the time of peak hypersensitivity implicate potential contributions of mitogen-activated protein kinase mechano-allodynia was associated with significant activation of MAPKs (extracellular signal-regulated kinase

., for their research on GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the tethered agonist signaling in adhesion G protein-coupled receptors GPCR Activation and Signaling A-Kinase-Anchoring-Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle GRK2 kinases

A series of evidence shows that TGR5 induces protein kinase B (AKT), nuclear factor kappa-B (NF-κB), extracellular regulated protein kinases (ERK1/2), signal transducer and activator of transcription 3

Additionally, GLP-1R couple to G protein-coupled receptor kinases (GRKs) and recruit β-arrestins, adding 1, another endogenous ligand, oxyntomodulin, exhibits a bias towards extracellular signal-regulated kinase McNeill, S.M., et al., The role of G protein-coupled receptor kinases in GLP-1R β-arrestin recruitment

A recent focus on GPCR intracellular-regulating proteins such as GPCR kinases (GRKs) has uncovered GRK2 and maladaptive pathology, and summarizes the ongoing and future research for targeting this critical kinase

Sudarshan Rajagopal, et al. for their finding that GPCR kinases affect biased signaling downstream of Mechanisms of biased agonism by Gαi/o-biased stapled peptide agonists of the relaxin-3 receptor GPCR kinases GPCRs in Cardiology, Endocrinology, and Taste The Role of G Protein-Coupled Receptors and Receptor Kinases