Regulation of Phospholipase C-δ1 through Direct Interactions with the Small GTPase Ral and Calmodulin

Sidhu, Ranjinder S.; Clough, Richard R.; Bhullar, Rajinder P.

doi:10.1074/jbc.m412966200

Cited by 73 publications

(44 citation statements)

References 52 publications

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“…We found that depletion of RalGDS also inhibits IP production of agonist-stimulated AT 1 R. This suggests that RalA activity is necessary for activation of PLC-␦1. This differs from the in vitro work of Sidhu et al (2005), who demonstrated that, similar to what is observed for Ral interactions with PLD, RalA interacts with PLC-␦1 irrespective of its GDP/GTP state (Luo et al, 1997(Luo et al, , 1998. Thus, we suggest that AT 1 R activation results in the ␤-arrestin-dependent translocation of RalGDS to the plasma, where it associates with the AT 1 R/RalA complex and promotes the RalA-dependent activation of PLC-␦1.…”

Section: Discussioncontrasting

confidence: 55%

“…The observation that siRNA-mediated knockdown of RalA significantly attenuates AT 1 R-mediated IP formation suggested that RalA coupled the receptor to an alternative PLC isoform. Sidhu et al (2005) reported that RalA interacted directly with PLC-␦1 and was sufficient to activate the phospholipase in vitro. Moreover, this effect of RalA was independent of the guanine nucleotide state of the GTPase.…”

Section: Resultsmentioning

confidence: 99%

“…In a recent study, a novel PLC-␦ regulatory mechanism involving the direct interaction of the small GTPases RalA and RalB and calmodulin (CaM) was reported (Sidhu et al, 2005). Ral proteins were reported to bind to and activate PLC-␦, whereas CaM binding to a novel IQ motif identified within the catalytic domain of PLC-␦ inhibited PLC-␦ activity.…”

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confidence: 99%

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The Small GTPase Ral Couples the Angiotensin II Type 1 Receptor to the Activation of Phospholipase C-δ1

Godin¹,

Ferreira²,

Dale³

et al. 2009

Mol Pharmacol

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The angiotensin II type 1 receptor (AT 1 R) plays an important role in cardiovascular function and as such represents a primary target for therapeutic intervention. The AT 1 R has traditionally been considered to be coupled to the activation of phospholipase C (PLC) ␤ via its association with G␣ q/11 , leading to increases in intracellular inositol phosphate (IP) and release of calcium from intracellular stores. In the present study, we investigated whether the small GTPase RalA contributed to the regulation of AT 1 R endocytosis and signaling. We find that neither RalA nor RalB is required for the endocytosis of the AT 1 R, but that RalA expression is required for AT 1 R-stimulated IP formation but not 5-HT 2A receptor-mediated IP formation.AT 1 R-activated IP formation is lost in the absence of Ral guanine nucleotide dissociation stimulator (RalGDS), and requires the ␤-arrestin-dependent plasma membrane translocation of RalGDS. G␣ q/11 small interfering RNA (siRNA) treatment also significantly attenuates both AT 1 R-and 5-HT 2A receptor-stimulated IP formation after 30 min of agonist stimulation. PLC-␦1 has been reported to be activated by RalA, and we show that AT 1 R-stimulated IP formation is attenuated after PLC-␦1 siRNA treatment. Taken together, our results provide evidence for a G protein-coupled recepto-activated and RalGDS/Ral-mediated mechanism for PLC-␦1 stimulation.

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Section: Discussioncontrasting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

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The Small GTPase Ral Couples the Angiotensin II Type 1 Receptor to the Activation of Phospholipase C-δ1

Godin¹,

Ferreira²,

Dale³

et al. 2009

Mol Pharmacol

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show abstract

“…The activity of the enzyme is increased with Ca 2ϩ elevations in the physiological range (33) but not by the G proteins that activate other PLCs (neither the heterotrimeric, nor the small forms). However, it was suggested that PLC␦1 is activated by the atypical G protein, transglutaminase II, or G␣H (429) or the small GTP binding protein RalA (515,1406). According to current views, PLC␦1 is regulated via its PH domain that recruits the enzyme to the PM.…”

Section: B Plc␦mentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,366

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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“…To date, three Ral effectors have been identified: RalBP1 (6), the exocyst complex (7,8), and the ZonaB transcription factor (9). Both RalA and RalB also bind constitutively to phospholipase D1 and phospholipase C-d1 and are needed for their activation (10)(11)(12).…”

mentioning

confidence: 99%

Ral GTPases Regulate Cell-Mediated Cytotoxicity in NK Cells

Sánchez-Ruíz

Mejías

García-Belando

et al. 2011

The Journal of Immunology

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NK cells are key components of the immune response to virally infected and tumor cells. Recognition of target cells initiates a series of events in NK cells that culminates in target destruction via directed secretion of lytic granules. Ral proteins are members of the Ras superfamily of small GTPases; they regulate vesicular trafficking and polarized granule secretion in several cell types. In this study, we address the role of Ral GTPases in cell-mediated cytotoxicity. Using a human NK cell line and human primary NK cells, we show that both Ral isoforms, RalA and RalB, are activated rapidly after target cell recognition. Furthermore, silencing of RalA and RalB impaired NK cell cytotoxicity. RalA regulated granule polarization toward the immunological synapse and the subsequent process of degranulation, whereas RalB regulated degranulation but not polarization of lytic granules. Analysis of the molecular mechanism indicated that Ral activation in NK cells leads to assembly of the exocyst, a protein complex involved in polarized secretion. This assembly is required for degranulation, as interference with expression of the exocyst component Sec5 led to reduced degranulation and impaired cytotoxicity in NK cells. Our results thus identify a role for Ral in cell-mediated cytotoxicity, implicating these GTPases in lymphocyte function.

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Regulation of Phospholipase C-δ1 through Direct Interactions with the Small GTPase Ral and Calmodulin

Cited by 73 publications

References 52 publications

The Small GTPase Ral Couples the Angiotensin II Type 1 Receptor to the Activation of Phospholipase C-δ1

The Small GTPase Ral Couples the Angiotensin II Type 1 Receptor to the Activation of Phospholipase C-δ1

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Ral GTPases Regulate Cell-Mediated Cytotoxicity in NK Cells

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