Ras signaling on the Golgi

Quatela, Steven; Philips, Mark R.

doi:10.1016/j.ceb.2006.02.004

Cited by 55 publications

(40 citation statements)

References 49 publications

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“…Overexpression of Ras-GRP1 leads to Ras activation in the Golgi apparatus [15], and such activation is found to be dependent on PLCγ [16]. Based on these studies, it was proposed that the signaling cascade of "receptors/PLCγ/DAG-Ca 2+ /RasGRP1" is mainly implicated in the activation of Ras signaling in the Golgi apparatus [45]. Consistent with previous reports, we demonstrate that RasGRP1 is also involved in PAQR10/11-mediated activation of Ras signaling in the Golgi apparatus (Figures 5 and 6).…”

Section: Discussionmentioning

confidence: 99%

PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus

et al. 2011

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Ras plays a pivotal role in many cellular activities, and its subcellular compartmentalization provides spatial and temporal selectivity. Here we report a mode of spatial regulation of Ras signaling in the Golgi apparatus by two highly homologous proteins PAQR10 and PAQR11 of the progestin and AdipoQ receptors family. PAQR10 and PAQR11 are exclusively localized in the Golgi apparatus. Overexpression of PAQR10/PAQR11 stimulates basal and EGF-induced ERK phosphorylation and increases the expression of ERK target genes in a dose-dependent manner. Overexpression of PAQR10/PAQR11 markedly elevates Golgi localization of HRas, NRas and KRas4A, but not KRas4B. PAQR10 and PAQR11 can also interact with HRas, NRas and KRas4A, but not KRas4B. The increased Ras protein at the Golgi apparatus by overexpression of PAQR10/PAQR11 is in an active state. Consistently, knockdown of PAQR10 and PAQR11 reduces EGF-stimulated ERK phosphorylation and Ras activation at the Golgi apparatus. Intriguingly, PAQR10 and PAQR11 are able to interact with RasGRP1, a guanine nucleotide exchange protein of Ras, and increase Golgi localization of RasGRP1. The C1 domain of RasGRP1 is both necessary and sufficient for the interaction of RasGRP1 with PAQR10/PAQR11. The simulation of ERK phosphorylation by overexpressed PAQR10/ PAQR11 is abrogated by downregulation of RasGRP1. Furthermore, differentiation of PC12 cells is significantly enhanced by overexpression of PAQR10/PAQR11. Collectively, this study uncovers a new paradigm of spatial regulation of Ras signaling in the Golgi apparatus by PAQR10 and PAQR11.

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Section: Discussionmentioning

confidence: 99%

PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus

et al. 2011

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“…The metabolic steps occurring downstream of farnesyl disphosphate synthase lead to the prenylation of several GTPases important for essential processes, including organelle homeostasis (23)(24)(25). A recent study demonstrated that the UPR is induced in macrophages cultivated in the presence of statins or RNAi against HMG-CoA reductase (13).…”

Section: Inhibition Of Farnesyl Diphosphate Synthase Causes Larval Armentioning

confidence: 99%

Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans

Mörck¹,

Olsen

Kurth

et al. 2009

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

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Statins are compounds prescribed to lower blood cholesterol in millions of patients worldwide. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. The nematode Caenorhabditis elegans possesses a mevalonate pathway that lacks the branch leading to cholesterol synthesis, and thus represents an ideal organism to specifically study the noncholesterol roles of the pathway. Inhibiting HMG-CoA reductase in C. elegans using statins or RNAi leads to developmental arrest and loss of membrane association of a GFP-based prenylation reporter. The unfolded protein response (UPR) is also strongly activated, suggesting that impaired prenylation of small GTPases leads to the accumulation of unfolded proteins and ER stress. UPR induction was also observed upon pharmacological inhibition of farnesyl transferases or RNAi inhibition of a specific isoprenoid transferase (M57.2) and found to be dependent on both ire-1 and xbp-1 but not on pek-1 or atf-6, which are all known regulators of the UPR. The lipid stores and fatty acid composition were unaffected in statin-treated worms, even though they showed reduced staining with Nile red. We conclude that inhibitors of HMG-CoA reductase or of farnesyl transferases induce the UPR by inhibiting the prenylation of M57.2 substrates, resulting in developmental arrest in C. elegans. These results provide a mechanism for the pleiotropic effects of statins and suggest that statins could be used clinically where UPR activation may be of therapeutic benefit.

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“…Furthermore, probing growth-factor-induced Ras activation in COS-1 cells with fluorescent sensors revealed that Ras was activated both on the Golgi and the plasma membrane (Chiu et al, 2002). In Jurkat cells, Ras is restricted to the Golgi where it is activated by its exchange factor RasGRP1, which itself is specifically activated and localised there in response to the signalling cascade initiated by activation of T-cell receptors (Bivona et al, 2003;Quatela and Philips, 2006). Therefore, Ras signalling from the Golgi complex represents a genuine cellular phenomenon.…”

Section: Rasmentioning

confidence: 99%

Signalling to and from the secretory pathway

Farhan

Rabouille

2011

Journal of Cell Science

129

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For growth, survival, communication and homeostasis, cells transport a large number of proteins to the plasma membrane and the extracellular medium by using the secretory pathway. Consequently, to adapt to the surrounding environment and the different intracellular contexts, the secretory pathway needs to accommodate and respond to a plethora of endogenous and exogenous stimuli. It is now well established that several kinases, known to be activated by environmental stimuli, signal from the plasma membrane to the secretory pathway in order to remodel its architecture and modulate the cellular secretion capacity. By contrast, membranes of the early secretory pathway, similar to the endosomal system, can also initiate and modulate signalling cascades, thereby spatially organising cellular signalling and eliciting a different cellular outcome than when signalling is localised to the plasma membrane. This Commentary highlights recent contributions to our understanding of the mutual regulation of the secretory pathway and cellular signalling.

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Ras signaling on the Golgi

Cited by 55 publications

References 49 publications

PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus

PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus

Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans

Signalling to and from the secretory pathway

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