Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase Cε

Song, Chunhua; Satoh, Takaya; Edamatsu, Hironori; Wu, Dongmei; Tadano, Makoto; Gao, Xianlong; Kataoka, Tohru

doi:10.1038/sj.onc.1206003

Cited by 92 publications

(109 citation statements)

References 29 publications

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“…However, Kataoka and co-workers, working with a different amino-terminal splice variant of human PLC-⑀, have suggested that the GEF domain is selective for Rap over Ras (19,27). Although the CDC25 domain of PLC-⑀ could yet prove to interact with Rho GTPases as downstream signaling molecules, this domain clearly is not involved in the activating effects observed with Rho GTPases in our study.…”

Section: Discussioncontrasting

confidence: 41%

Direct Activation of Phospholipase C-ϵ by Rho

Wing

Snyder

Sondek³

et al. 2003

Journal of Biological Chemistry

103

108

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Unique among the phospholipase C isozymes, the recently identified phospholipase C-⑀ (PLC- Comparative sequence analysis of mammalian phospholipase C isozymes revealed a unique ϳ65 amino acid insert within the catalytic core of PLC-⑀ not present in PLC-␤, ␥, ␦, or . A PLC-⑀ construct lacking this region was no longer activated by Rho or G␣ 12/13 but retained regulation by G␤␥ and H-Ras. GTP-dependent interaction of Rho with PLC-⑀ was illustrated in pull-down experiments with GST-Rho, and this interaction was retained in the PLC-⑀ construct lacking the unique insert within the catalytic core. These results are consistent with the conclusion that Rho family GTPases directly interact with PLC-⑀ by a mechanism independent of the CDC25 or RA domains. A unique insert within the catalytic core of PLC-⑀ imparts responsiveness to Rho, which may signal downstream of G␣ 12/13 in the regulation of PLC-⑀, because activation by both Rho and G␣ 12/13 is lost in the absence of this sequence.⑀

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Section: Discussioncontrasting

confidence: 41%

Direct Activation of Phospholipase C-ϵ by Rho

Wing

Snyder

Sondek³

et al. 2003

Journal of Biological Chemistry

103

108

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“…Similar to observations with RASSF/NORE, we also show that exogenous expression of PLCe in colorectal tumor cells results in higher cell death and inhibition of proliferation ( Figure 6). Based on previously published data (Song et al, 2002) and our observations (not shown), this is not a general property of PLCe when introduced to various cell types. However, it remains to be established whether the ability of PLCe to be integrated into different pathways in various cell types determines these different cellular responses.…”

Section: Discussionmentioning

confidence: 89%

“…Within the unique regions, PLCe has CDC25 guanine exchange factor (CDC25 GEF) domain and two Ras-association or Rasbinding (RA/RBD) domains Lopez et al, 2001;Song et al, 2001). Further studies have suggested that CDC25 GEF could function as an exchange factor (Jin et al, 2001), while studies of RA/ RBD domains have shown direct interaction with several Ras family members in GTP-bound form Song et al, 2001Song et al, , 2002. In some of the studies, it was also shown that PI-PLC activity of PLCe can be stimulated by activated Ras when both molecules were introduced into COS cells Song et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Further studies have suggested that CDC25 GEF could function as an exchange factor (Jin et al, 2001), while studies of RA/ RBD domains have shown direct interaction with several Ras family members in GTP-bound form Song et al, 2001Song et al, , 2002. In some of the studies, it was also shown that PI-PLC activity of PLCe can be stimulated by activated Ras when both molecules were introduced into COS cells Song et al, 2002). 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).…”

Section: Introductionmentioning

confidence: 99%

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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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“…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%

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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Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase Cε

Cited by 92 publications

References 29 publications

Direct Activation of Phospholipase C-ϵ by Rho

Direct Activation of Phospholipase C-ϵ by Rho

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

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

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