Direct Activation of Phospholipase C-ϵ by Rho

Wing, Michele R.; Snyder, Jason T.; Sondek, John; Harden, T. Kendall

doi:10.1074/jbc.m306904200

Cited by 107 publications

(118 citation statements)

References 38 publications

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“…4A). Treatment with C3 significantly impaired production of InsPs in response to thrombin (68 Ϯ 13% inhibition), which is consistent with evidence that RhoA binds to and can directly activate PLC (13). In contrast, the InsP response to S1P and LPA was unaffected by C3 pretreatment (Fig.…”

supporting

confidence: 86%

“…Studies using heterologous expression demonstrate that, in contrast to PLC␤, PLC is not activated by G␣ q but rather by G␤␥ and G␣ 12 signaling (5, 9). Most remarkably, PLC is activated by direct binding of small GTPases, including Ras, Rap1, and Rap2B (6,7,(10)(11)(12) as well as by RhoA (13). Thus, PLC appears to serve as a nexus for signaling, responding to inputs from a broad range of receptor activation and uniquely linking PLC to small-GTPase pathways (14,15).…”

mentioning

confidence: 99%

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Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Citro

Malik

Oestreich

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Phospholipase C (PLC ) has been suggested to transduce signals from small GTPases, but its biological function has not yet been clarified. Using astrocytes from PLC -deficient mice, we demonstrate that endogenous G protein-coupled receptors (GPCRs) for lysophosphatidic acid, sphingosine 1-phosphate, and thrombin regulate phosphoinositide hydrolysis primarily through PLC . Stimulation by lysophospholipids occurs through Gi, whereas thrombin activates PLC through Rho. Further studies reveal that PLC is required for thrombin-but not LPA-induced sustained ERK activation and DNA synthesis, providing a novel mechanism for GPCR and Rho signaling to cell proliferation. The requirement for PLC in this pathway can be explained by its role as a guanine nucleotide exchange factor for Rap1. Thus, PLC serves to transduce mitogenic signals through a mechanism distinct from its role in generation of PLC-derived second messengers.mitogenesis ͉ small GTPases ͉ thrombin ͉ lysophospholipids ͉ guanine nucleotide exchange factor S timulation of a variety of cell surface receptor types, most prominently G protein-coupled receptors (GPCRs), leads to the activation of phospholipase C (PLC). Hydrolysis of phosphatidylinositol (4,5)bisphosphate (PIP 2 ) generates the second messengers inositol (1,4,5)trisphosphate (InsP 3 ) and diacylglycerol (DAG) (1). Thirteen mammalian PLC isozymes, divided into six families, have been identified. All contain conserved catalytic regions as well as subtype-specific domains that allow for a plethora of specific regulatory mechanisms. The best characterized of these are the PLC␤ family, regulated by direct binding of the heterotrimeric G protein subunits ␣ q and ␤␥, and PLC␥ regulated by receptor and nonreceptor protein tyrosine kinases (2).The same second messengers are generated by all of the PLCs. Thus, regardless of the extracellular signal-and PLC isoform-activated, InsP 3 will be formed and trigger Ca 2ϩ release from intracellular stores, and DAG accumulation will lead to activation of protein kinase C (3). Undoubtedly, there are distinct spatiotemporal aspects to the signals elicited by different receptors and classes of PLC, but it remains unclear why so many PLC isoforms, capable of generating the same signal, should exist.An emerging area in biology has been the recognition that many proteins identified on the basis of a particular activity serve additional functions. The regulators of G protein signaling (RGS) proteins are paradigmatic in this regard. These proteins contain not only canonical RGS sequences dedicated to GTP hydrolysis but also non-RGS domains and motifs with alternative functions. Thus, not only do they turn off GPCR signaling but in addition they can enhance small G protein activation, serve as effectors, and act as scaffold proteins (4). PLC , an isoform of PLC that was discovered fewer than 6 years ago, likewise has the structure of a multifunctional signaling protein (5-7). It contains not only PLC catalytic regions but also, in its N-terminal region, a CDC25 homology domain...

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supporting

confidence: 86%

mentioning

confidence: 99%

Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Citro

Malik

Oestreich

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…An increase in substrate hydrolysis by PLCe in transfected cells have been observed after stimulation by diverse stimuli including epidermal growth factor (EGF), lysophosphatic acid (LPA), sphingosine-1-phosphate (S1P), adrenalin and acetycholine (Schmidt et al, 2001;Evellin et al, 2002;Kelley et al, 2004). Furthermore, these and other studies suggest that signaling pathways triggered by these agonists could be quite broad and in some cases independent of Ras family GTP-ases (Lopez et al, 2001;Wing et al, 2001Wing et al, , 2003Kelley et al, 2004). However, regarding that most approaches involved overexpression of PLCe, it still remains to be established which of the possible regulatory interactions are physiologically relevant.…”

Section: Introductionmentioning

confidence: 93%

Signaling properties and expression in normal and tumor tissues of two phospholipase C epsilon splice variants

et al. 2004

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Phospholipase Ce (PLCe) is a novel member of phosphoinositide-specific phospholipase C enzymes with a unique regulatory link to Ras GTP-ases. In the present studies, we establish existence of two splice variants (PLCe1a and PLCe1b) derived from human PLCe1 gene. When expressed in COS or HEK293 cells, PLCe1a and PLCe1b have similar potential to be stimulated by diverse signaling pathways via tyrosine kinase and G-protein coupled receptors and share the ability to function as an effector of Ras. The expression pattern shows broader mRNA expression of PLCe1a in normal tissues; furthermore, in most cell lines expressing PLCe, PLCe1a is the only splice variant present. Analysis of normal/tumor matched pairs derived from colon and rectum demonstrates greatly reduced expression levels in tumor tissues. Further studies in a colorectal tumor cell line lacking PLCe show restoration of transcription of PLCe1a and PLCe1b by demethylating agent 5-aza-2 0 -deoxycytidine, suggesting epigenetic silencing through hypermethylation. In addition, expression of exogenous PLCe in this cell line demonstrates inhibitory effects of PLCe on cell viability and proliferation. Taken together, our findings suggest that regulatory mechanisms controlling expression of PLCe, broadened by diversity introduced by splice variants, could play important role in PLCe regulation in normal and tumor cells.

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“…The specific role of RhoA in signaling pathways turned on during T cell activation has not been examined thoroughly, although reports have shown that the GTPase is able to activate the NFAT-binding partner AP-1 [15] as well as NF-κB [16 -18]. In addition, RhoA and its upstream activator Gα13 have been shown to increase the activity of phospholipase Cε (PLCε), leading to increased levels of intracellular calcium [19].…”

Section: Introductionmentioning

confidence: 99%

Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells

Helms

Jeffrey

Holmes

et al. 2007

Journal of Leukocyte Biology

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We have reported previously that p115Rho guanine nucleotide exchange factor, its upstream activator Gα13, and its effector RhoA are able to inhibit HIV-1 replication. Here, we show that RhoA is able to inhibit HIV-1 gene expression through the NFAT-binding site in the HIV longterminal repeat. Constitutively active NFAT counteracts the inhibitory activity of RhoA, and inhibition of NFAT activation also inhibits HIV-1 gene expression. We have shown further that RhoA inhibits NFAT-dependent transcription and IL-2 production in human T cells. RhoA does not inhibit nuclear localization of NFAT but rather, inhibits its transcriptional activity. In addition, RhoA decreases the level of acetylated histone H3, but not NFAT occupancy, at the IL-2 promoter. These data suggest that activation of RhoA can modulate IL-2 gene expression by inhibiting the transcriptional activity of NFAT and chromatin structure at the IL-2 promoter during T cell activation.

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Direct Activation of Phospholipase C-ϵ by Rho

Cited by 107 publications

References 38 publications

Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Signaling properties and expression in normal and tumor tissues of two phospholipase C epsilon splice variants

Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells

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