Molecular regulation of PLCβ signaling

Ubeysinghe, Sithurandi; Wijayaratna, Dhanushan; Kankanamge, Dinesh; Karunarathne, Ajith

doi:10.1016/bs.mie.2023.01.001

Cited by 8 publications

(2 citation statements)

References 143 publications

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“…Previous studies have shown the utility of several optogenetic tools to spatiotemporally control G protein signaling in subcellular locations upon light stimulations. (42)(43)(44)(45) Therefore, next, to examine OptoGDI-induced subcellular G-protein signaling, we examined the ability of OptoGDI to induce subcellular G release and subsequent signaling. In HeLa cells expressing Lyn-CIBN, OptoGDI, and Venus-G9, OptoGDI showed cytosolic, and Venus-G9 displayed primarily plasma membrane distribution (Fig.…”

Section: Optogdi-induced Subcellular Free G Generationmentioning

confidence: 99%

AGS3-based optogenetic GDI induces GPCR-independent Gβγ signaling and macrophage migration

Thotamune,

Ubeysinghe,

Rajarathna

et al. 2024

Preprint

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G protein-coupled receptors (GPCRs) are efficient Guanine nucleotide exchange factors (GEFs) and exchange GDP to GTP on the Gα subunit of G protein heterotrimers in response to various extracellular stimuli, including neurotransmitters and light. GPCRs primarily broadcast signals through activated G proteins, GαGTP, and free Gβγ and are major disease drivers. Evidence shows that the ambient low threshold signaling required for cells is likely supplemented by signaling regulators such as non-GPCR GEFs and Guanine nucleotide Dissociation Inhibitors (GDIs). Activators of G protein Signaling 3 (AGS3) are recognized as a GDI involved in multiple health and disease-related processes. Nevertheless, understanding of AGS3 is limited, and no significant information is available on its structure-function relationship or signaling regulation in living cells. Here, we employedin silicostructure-guided engineering of a novel optogenetic GDI, based on the AGS3’s G protein regulatory (GPR) motif, to understand its GDI activity and induce standalone Gβγ signaling in living cells on optical command. Our results demonstrate that plasma membrane recruitment of OptoGDI efficiently releases Gβγ, and its subcellular targeting generated localized PIP3 and triggered macrophage migration. Therefore, we propose OptoGDI as a powerful tool for optically dissecting GDI-mediated signaling pathways and triggering GPCR-independent Gβγ signaling in cells andin vivo.

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Section: Optogdi-induced Subcellular Free G Generationmentioning

confidence: 99%

AGS3-based optogenetic GDI induces GPCR-independent Gβγ signaling and macrophage migration

Thotamune,

Ubeysinghe,

Rajarathna

et al. 2024

Preprint

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“…The mechanisms involved are not well studied but may involve the induction of ROS [143] and probably also Rho [144]. In this review, we cover primarily the activation of JNK by the Gq group, which has 4 members (Gq, G 11 , G 14 , and G 15/16 ) that act mainly by activating phospholipase C-β (PLCβ), which is mediated by their Gα subunit [145]. The PLCβ then produces the second messengers: inositol trisphospate, which elevates calcium levels, and diacylglycerol, which activates protein kinase C (PKC) and a few other signaling proteins.…”

Section: Jnk-related Induction Of Apoptosis By Gqpcrsmentioning

confidence: 99%

JNK Cascade-Induced Apoptosis—A Unique Role in GqPCR Signaling

Nadel,

Maik-Rachline,

Seger

2023

IJMS

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The response of cells to extracellular signals is mediated by a variety of intracellular signaling pathways that determine stimulus-dependent cell fates. One such pathway is the cJun-N-terminal Kinase (JNK) cascade, which is mainly involved in stress-related processes. The cascade transmits its signals via a sequential activation of protein kinases, organized into three to five tiers. Proper regulation is essential for securing a proper cell fate after stimulation, and the mechanisms that regulate this cascade may involve the following: (1) Activatory or inhibitory phosphorylations, which induce or abolish signal transmission. (2) Regulatory dephosphorylation by various phosphatases. (3) Scaffold proteins that bring distinct components of the cascade in close proximity to each other. (4) Dynamic change of subcellular localization of the cascade’s components. (5) Degradation of some of the components. In this review, we cover these regulatory mechanisms and emphasize the mechanism by which the JNK cascade transmits apoptotic signals. We also describe the newly discovered PP2A switch, which is an important mechanism for JNK activation that induces apoptosis downstream of the Gq protein coupled receptors. Since the JNK cascade is involved in many cellular processes that determine cell fate, addressing its regulatory mechanisms might reveal new ways to treat JNK-dependent pathologies.

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