ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

Mitchell, Rory; Robertson, Derek N.; Holland, Pamela J.; Collins, Daniel M.; Lutz, Eve M.; Johnson, Mark

doi:10.1074/jbc.m305825200

Cited by 53 publications

(64 citation statements)

References 71 publications

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“…In some cases, another ARF family member may regulate the process. Indeed, some receptors have been found in complex with ARF1 (31)(32)(33). Even if this ARF isoform is mainly present on membranes of intracellular organelles such as the Golgi (34,35), its presence at the plasma membrane has been previously reported (36).…”

Section: Reduction Of Arf6mentioning

confidence: 99%

G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells

Houndolo

Boulay

Claing

2005

Journal of Biological Chemistry

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The internalization of G protein-coupled receptors is regulated by several important proteins that act in concert to finely control this complex cellular process. Here, we have applied the RNA interference approach to demonstrate that ADP-ribosylation factor 6 (ARF6) is essential for the endocytosis of a broad variety of receptors. Reduction of endogenous expression of ARF6 in HEK 293 cells resulted in a correlated inhibition of the ␤ 2 -adrenergic receptor internalization previously characterized as being sequestered via the clathrin-coated vesicle pathway. Furthermore, other receptors internalizing via this endocytic route, namely the angiotensin type 1 receptor and the vasopressin type 2 receptor, were also impaired in their ability to be sequestered when levels of endogenous ARF6 in cells were reduced. Interestingly, endocytosis of the endothelin type B receptor, characterized as being internalized via the caveolae pathway, was also markedly inhibited in ARF6-depleted cells. In contrast, internalization of the vasoactive intestinal peptide receptor was unaffected by reduced levels of ARF6. Finally, internalization of the acetylcholine-muscarinic type 2 receptor via the non-clathrincoated vesicle pathway was also inhibited in ARF6-depleted cells. Taken together, our results demonstrate that ARF6 proteins play an essential role in the internalization process of most G protein-coupled receptors regardless of the endocytic route being utilized. However, this phenomenon is not general. In some cases, another ARF isoform or other proteins may be essential to regulate the endocytic process.

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Section: Reduction Of Arf6mentioning

confidence: 99%

G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells

Houndolo

Boulay

Claing

2005

Journal of Biological Chemistry

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“…ARF1 is mainly found in the Golgi apparatus and acts to promote carrier vesicle biogenesis by nucleating the assembly of coat protein complexes at sites of vesicle formation (Stearns et al, 1990). Several reports have suggested that ARF1 can also localize to the plasma membrane transmitting signals from transmembrane proteins (Galas et al, 1997;Mitchell et al, 2003;Cohen et al, 2007;Boulay et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

et al. 2011

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The ADP-ribosylation factors (ARFs) 1 and 6 are small GTP-binding proteins, highly expressed and activated in several breast cancer cell lines and are associated with enhanced migration and invasiveness. In this study, we report that ARF1 has a critical role in cell proliferation. Depletion of this GTPase or expression of a dominant negative form, which both resulted in diminished ARF1 activity, led to sustained cell-growth arrest. This cellular response was associated with the induction of senescent markers in highly invasive breast cancer cells as well as in control mammary epithelial cells by a mechanism regulating retinoblastoma protein (pRB) function. When examining the role of ARF1, we found that this GTPase was highly activated in normal proliferative conditions, and that a limited amount could be found in the nucleus, associated with the chromatin of MDA-MB-231 cells. However, when cells were arrested in the G 0 /G 1 phase or transfected with a dominant negative form of ARF1, the total level of activated ARF1 was markedly reduced and the GTPase significantly enriched in the chromatin. Using biochemical approaches, we demonstrated that the GDP-bound form of ARF1 directly interacted with pRB, but not other members of this family of proteins. In addition, depletion of ARF1 or expression of ARF1T 31 N resulted in the constitutive association of pRB and E2F1, thereby stabilizing the interaction of E2F1 as well as pRB at endogenous sites of target gene promoters, preventing expression of E2F target genes, such as cyclin D1, Mcm6 and E2F1, important for cell-cycle progression. These novel findings provide direct physiological and molecular evidence for the role of ARF1 in controlling cell proliferation, dependent on its ability to regulate pRB/E2F1 activity and gene expression for enhanced proliferation and breast cancer progression.

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“…These receptors are members of a family of receptors that are coupled to heterotrimeric transducer G proteins. The M 1 , M 3 , and M 5 acetylcholine receptor subtypes are efficiently coupled to the pertussis toxin-insensitive G␣ q/11 and G 13 subtype G proteins, leading to activations of PLC and PLD, whereas the M 2 , and M 4 receptors are coupled to pertussis toxin-sensitive G i and G 0 subtype G proteins (27)(28)(29). The mechanism of PLD activation by the muscarinic receptor has been mainly studied for the M 3 receptor subtype.…”

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confidence: 99%

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

Chae

Lee

et al. 2005

Journal of Biological Chemistry

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Mammalian phospholipase D (PLD) is considered a key enzyme in the transmission signals from various receptors including muscarinic receptors. PLD activation is a rapid and transient process, but a negative regulator has not been found that inhibits signal-dependent PLD activation. Here, for the first time, we report that tubulin binding to PLD 2 is an inhibition mechanism for muscarinic receptor-linked PLD 2 activation. Tubulin was identified in an immunoprecipitated PLD 2 complex from COS-7 cells by peptide mass fingerprinting. The direct interaction between PLD 2 and tubulin was found to be mediated by a specific region of PLD 2 (amino acids 476 -612). PLD 2 was potently inhibited (IC 50 <10 nM) by tubulin binding in vitro. In cells, the interaction between PLD 2 and tubulin was increased by the microtubule disrupting agent nocodazole and reduced by the microtubule stabilizing agent Taxol. Moreover, PLD 2 activity was found to be inversely correlated with the level of monomeric tubulin. In addition, we found that interaction with and the inhibition of PLD 2 by monomeric tubulin is important for the muscarinic receptor-linked PLD signaling pathway. Interaction between PLD 2 and tubulin was increased only after 1-2 min of carbachol stimulation when carbachol-stimulated PLD 2 activity was decreased. The expression of the tubulin binding region of PLD 2 blocked the later decrease in carbachol-induced PLD activity by masking tubulin binding. Taken together, these results indicate that an increase in local membrane monomeric tubulin concentration inhibits PLD 2 activity, and provides a novel mechanism for the inhibition of muscarinic receptor-induced PLD 2 activation by interaction with tubulin. Mammalian phospholipase D (PLD)1 hydrolyzes membrane phosphatidylcholine to generate phosphatidic acid and choline. PLD activity is dramatically activated in response to a variety of signals, including hormones, neurotransmitters, and growth factors (1). PLD products, phosphatidic acid itself or the hydrolyzed product diacylglycerol, have been known to act as intracellular lipid second messengers and to be involved in multiple physiological events, such as, the promotion of mitogenesis, stimulation of respiratory bursts, secretory processes, and actin cytoskeletal reorganization (2-7). Therefore, signal-dependent PLD activity must be tightly controlled in cells.Many reports have been issued about the mechanisms of receptor-mediated PLD activation. Although the mammalian PLD isozymes, PLD 1 and PLD 2 , have some different regulatory properties, in general, agonist-induced PLD is activated by various protein kinases, including protein kinase C, proteintyrosine kinase, and the MAP kinase family, in addition to small G proteins of the ARF, Rho, and Ras families (8 -13). The signal-dependent activation of PLD is rapid and transient. Although, the activation kinetics depend on the stimulus and cell type, the PLD signal is usually diminished within 10 min (14). However, the mechanisms involved in PLD signal inhibition remain unknow...

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ADP-ribosylation Factor-dependent Phospholipase D Activation by the M3 Muscarinic Receptor

Cited by 53 publications

References 71 publications

G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells

G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

Inhibition of Muscarinic Receptor-linked Phospholipase D Activation by Association with Tubulin

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