Gq-mediated Akt translocation to the membrane: a novel PIP3-independent mechanism in platelets

Badolia, Rachit; Manne, Bhanu Kanth; Dangelmaier, Carol; Chernoff, Jonathan; Kunapuli, Satya P.

doi:10.1182/blood-2014-05-576306

Cited by 16 publications

(15 citation statements)

References 44 publications

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“…Akt activation in platelets depends on heterotrimeric G protein Gi signaling pathways [28]. Moreover, a recent report shows that there is also a novel PIP 3 -independent and Gq-dependent Akt translocation mechanism in platelets [29]. Treatment of human platelets with SDF-1α induced the phosphorylation of Akt at Thr308 and Ser473 (Fig 2A).…”

Section: Resultsmentioning

confidence: 96%

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation

et al. 2017

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Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3β at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-β-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gβ and 4.0% of PI3Kβ, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.

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Section: Resultsmentioning

confidence: 96%

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation

et al. 2017

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“…PLC then converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Recent evidence also suggests that α q can promote Akt translocation to the membrane and PI3K-dependent phosphorylation [58;59]. PI3K, which is an upstream mediator of E 2 signaling in the PVN as well as in the vascular endothelium [43;44], is necessary for the facilitation of E 2 uncoupling of GABA B receptors to their GIRK channels leading to GABA B desensitization [45].…”

Section: Discussionmentioning

confidence: 99%

Estradiol Rapidly Attenuates ORL-1 Receptor-Mediated Inhibition of Proopiomelanocortin Neurons via G<sub>q</sub>-Coupled, Membrane-Initiated Signaling

et al. 2016

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Estradiol rapidly regulates the activity of arcuate nucleus (ARH) proopiomelanocortin (POMC) neurons that project to the medial preoptic nucleus (MPN) to regulate lordosis. Orphanin FQ/nociceptin (OFQ/N) acts via opioid receptor-like (ORL)-1 receptors to inhibit these POMC neurons. Therefore, we tested the hypothesis that estradiol excites POMC neurons by rapidly attenuating inhibitory ORL-1 signaling in these cells. Hypothalamic slices through the ARH were prepared from ovariectomized rats injected with Fluorogold into the MPN. Electrophysiological recordings were generated in ARH neurons held at or near -60 mV, and neuronal phenotype was determined post hoc by immunohistofluorescence. OFQ/N application induced robust outward currents and hyperpolarizations via G protein-gated, inwardly rectifying K⁺ (GIRK) channels that were attenuated by pretreatment with either 17-β estradiol (E₂) or E₂ conjugated to bovine serum albumin. This was blocked by the estrogen receptor (ER) antagonist ICI 182,780 and mimicked by the G_q-coupled membrane ER (G_q-mER) ligand STX and the ERα agonist PPT. Inhibiting phosphatidylinositol-3-kinase (PI3K) blocked the estrogenic attenuation of ORL-1/GIRK currents. Antagonizing either phospholipase C (PLC), protein kinase C (PKC), protein kinase A (PKA) or neuronal nitric oxide synthase (nNOS) also abrogated E₂ inhibition of ORL-1/GIRK currents, whereas activation of PKC, PKA, protein kinase B (Akt) and nNOS substrate L-arginine all attenuated the OFQ/N response. This was observed in 92 MPN-projecting, POMC-positive ARH neurons. Thus, ORL-1 receptor-mediated inhibition of POMC neurons is rapidly and negatively modulated by E₂, an effect which is stereoselective and membrane initiated via G_q-mER and ERα activation that signals through PLC, PKC, PKA, PI3K and nNOS.

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“…Assuming effective inhibition of Pak2 kinase activity, these results suggest that Pak2, similar to Pak1, may have kinase-independent functions that affect certain aspects of hematopoiesis in vivo. [38][39][40] Pak2 regulates megakaryocyte maturation Mice with megakaryocyte-specific deletion of Pak-activating proteins, Rac1/Cdc42, are macrothrombocytopenic, with ultrastructurally abnormal megakaryocytes that fail to form proplatelets with defects in microtubule stabilization. 25 As Paks are downstream effectors of these GTPases, we sought to determine whether Pak activation is required for megakaryocyte development and function, as well as to maintain platelet counts.…”

Section: Discussionmentioning

confidence: 99%

Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization

Kosoff

Aslan

Kostyak

et al. 2015

Blood

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Gq-mediated Akt translocation to the membrane: a novel PIP3-independent mechanism in platelets

Abstract: Key Points There is a novel PIP3-independent and Gq-dependent Akt translocation mechanism in the platelets. PAK constitutively associates with Akt, and possibly mediates its membrane translocation independently of PIP3.

Cited by 16 publications

References 44 publications

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation

Estradiol Rapidly Attenuates ORL-1 Receptor-Mediated Inhibition of Proopiomelanocortin Neurons via G<sub>q</sub>-Coupled, Membrane-Initiated Signaling

Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization

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