HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: fj.06-6624hypv1 21/3/638    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goetzl, E. J. Search for Related Content PubMed PubMed Citation Articles by Goetzl, E. J.

Diverse pathways for nuclear signaling by G protein-coupled receptors and their ligands

Departments of Medicine and Microbiology-Immunology, University of California, San Francisco, California, USA

¹Correspondence: Rm. UB8B, UC Box 0711, 533 Parnassus Ave. at 4th Ave., San Francisco, CA 94143-0711, USA. E-mail: edward.goetzl{at}ucsf.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION Signaling of nuclear events... Signaling of nuclear events... Implications of nuclear... REFERENCES

 
Recent realization that plasma membrane G protein-coupled receptors (GPCRs) may translocate and establish ligand-responsive signaling complexes in other cellular structures has motivated studies of site-specific differences in transductional pathways. GPCRs and their ligands may signal transcription and other nuclear events by two basic mechanisms. The first consists of GPCR-complex activation of messengers that enter the nucleus and there initiate cell-modifying processes without the GPCR leaving the plasma membrane. The second encompasses entry into the nuclear membranes or matrix of either GPCR ligands, which bind to non-GPCR nuclear signaling proteins, proteolytic fragments of GPCRs capable of ligand-independent signaling, or intact GPCRs with transduction-competent factors that directly initiate or regulate transcriptional events. With the second mechanism, often concurrent down-regulation of plasma membrane GPCRs terminates signaling from the cell-surface and moves it into the nuclear domain. Site-dependent differences in signals from the same GPCR provide potentials for unique cellular abnormalities attributable to defective intracellular movement and distribution of a GPCR, site-specific alterations in ligand concentration, and limited intracellular bioavailability of pharmacological agents that can interact specifically with both nuclear and plasma membrane forms of a GPCR. Goetzl, E. J. Diverse pathways for nuclear signaling by G Protein-coupled receptors and their ligands.

Key Words: signal transduction • lipid mediators • receptor downregulation • MAP kinases • peroxisome proliferator-activated receptor • transcription

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Signaling of nuclear events... Signaling of nuclear events... Implications of nuclear... REFERENCES

 
CELLULAR G PROTEIN-COUPLED RECEPTORS (GPCRs) constitute a prominent family because of their large total number, protean involvement in physiological processes, frequent roles in disease pathogenesis and ideal suitability as targets for drug development (1 2 3 4 5 6) . Although these and other properties of GPCRs have been reviewed extensively, results of several recent investigations suggest that a major additional dimension should be included in the GPCR conceptual framework if we are to understand fully their roles in cell biology. Until now, each GPCR and associated sets of heterotrimeric G proteins on the cell surface had been proven to initiate one or more chains of intracellular signaling events mediated by complexes of GTPases, kinases, and linking proteins. The distinctive nature of any GPCR signaling pathway is specified predominantly by the chain of the heterotrimeric G protein, other protein factors and characteristics of the target cell. In addition, occupancy of a GPCR by its complementary ligand stimulates down-regulation of expression of the GPCR, by processes that include a brief intracellular cycle through endosomes and perinuclear vesiculotubular structures, and thereby lead to proteolysis or reinsertion in the plasma membrane. Down-regulation of a GPCR and the rapid reconstitution of its plasma membrane signaling unit are dependent on separate cellular and biochemical determinants. No major effects on cellular functions have been attributed previously solely to the process of GPCR down-regulation and recovery.

Now studies of intracellular trafficking of a few different GPCRs, evoked by exposure to ligand or by cellular activation through ligand-independent mechanisms, have shown that GPCRs may be inserted into nuclear membranes for prolonged periods, compose distinctive signaling units there, and respond to specific intracellular ligand by transducing nuclear transcriptional signals that differ from those sent by their plasma membrane complexes (7 8 9) . To provide a context for this brief portrayal of our evolving understanding of nuclear GPCR complexes, I present first two examples of many instances where GPCR complexes and their ligands signal principally from the plasma membrane but significantly influence nuclear events through several mechanisms. Then I describe, in as much detail as current knowledge permits, the respective means by which a GPCR ligand, an intact GPCR, and a fragment of a GPCR enter the nuclear domain and signal nuclear events by direct mechanisms distinct from those available to the corresponding plasma membrane GPCR. After depicting available evidence for direct nuclear signaling by GPCRs, the implications are discussed in terms of normal cell biology, pathophysiology, and GPCR pharmacology.

	Signaling of nuclear events by plasma membrane GPCR complexes

TOP ABSTRACT INTRODUCTION Signaling of nuclear events... Signaling of nuclear events... Implications of nuclear... REFERENCES

 
The first example of induction of an intranuclear factor by a cell-surface GPCR is activation of phospholipase D-1 (PLD-1) in vascular smooth muscle cell (VSMC) nuclei by signals from the respective GPCRs for angiotensin II and the lipid growth factor lysophosphatidic acid (LPA), but not by signals from plasma membrane receptors for two different protein growth factors (10) (Fig. 1 A). Application of several specific inhibitors of intracellular messengers implicated Go/i, PI3K/PKC, and RhoA in the transmission of activating signals from plasma membrane LPA GPCRs to nuclear PLD-1. As signals from LPA GPCRs failed to activate cytosolic PLD-1, nuclear selectivity was postulated and proven by finding active PLD-1 but no PLD-2 in nuclei isolated from LPA-stimulated VSMCs along with translocated PKC and RhoA. Active PLD-1 further was postulated to generate from nuclear phosphatidylcholine (PC) the potent signaling lipids phosphatidic acid (PA), a biosynthetic precursor of LPA, and diacylglycerol (DAG) that evokes PKC activity. Thus activation of a nuclear phospholipase by a cell-surface GPCR may affect many cell signaling pathways. These findings also are a reminder that the nucleus is a site of intense lipid metabolism where high levels of glycerophospholipids and sphingophospholipids associate with chromatin to influence DNA replication and transcription, as well as interact with RNA to limit RNase effects (11 , 12) . These observations foreshadow the presence of nuclear membrane GPCRs for LPA and sphingosine 1-phosphate (S1P) to be discussed in the next section.

View larger version (18K): [in this window] [in a new window]   Figure 1. Activation of nuclear factors by messengers from cell-surface stimulated GPCRs. A) Plasma membrane GPCR activation of a nuclear enzyme. Protein kinase C (PKC) and RhoA are activated by a cell-surface LPA GPCR-Gi/o complex through a phosphatidylinositol-3 kinase (PI3K)-dependent pathway. PKC and RhoA then are translocated to the nucleus, where they evoke PLD1 activity, which in turn initiates a lipid mediator signaling cascade in the nucleus involving conversion of phosphatidylcholine (PC) to phosphatidic acid (PA) and then DAG. B) Cell-surface GPCR control of nuclearization of a transcription initiator. The chemokine GPCR complex CXCR4-Gi/o elicits and facilitates nuclear translocation of the transcription initiators types 1 and 2 extracellular signal-regulated kinase (Erk ) in two separate steps. First, phosphorylation of Erk in the cytoplasm is attained through a Ras/Raf-dependent and Src/Rho kinase-enhanced pathway. Second, a concerted action of Src/RhoA and elements of the cytoskeleton augment translocation of P- Erk into the nucleus, where its activities are redirected to proliferation-related transcriptional events. PM = plasma membrane. N = Nucleus.

The second example is nuclear signaling by plasma membrane CXCR4 GPCR for the chemokine SDF-1, which both elicits phosphorylation of cytoplasmic extracellular signal-regulated kinase (Erk) and facilitates translocation of P-Erk into the nucleus, where it serves as a transcription initiator (13) (Fig. 1B ). CXCR4-evoked phosphorylation of types 1 and 2 Erk (Erk ) is dependent on Gi/o and Ras/Raf activities and enhanced by Src-kinase and Rho-kinase. Inhibitory effects of specific pharmacological agents and dominant-negative proteins proved that nuclear translocation of P-Erk and its phosphorylation of the transcription factor Elk in the nucleus require Src-kinase, Rho-kinase, and an intact cytoskeleton. Two other mechanisms critical to the control by GPCRs of nuclear traffic of phosphorylated messengers lacking nuclear localization signals, such as P-Erk , are illustrated by these results. One broad mechanism is an involvement of multiple cytoplasmic proteins and nuclear factors in establishing the equilibrium between cytoplasmic and nuclear sets of activated messengers, such as P-Erk . Specific cytoplasmic proteins bind and may catalyze phosphorylation of Erk , but also retain and sequester it in the cytoplasm in opposition to the nuclearizing actions of Src, Rho, and some nuclear-localizing proteins. Examples of Erk cytoplasmic retention factors are the Erk kinase MEK, which bind unphosphorylated Erk , ß-arrestin, and some nuclear export factors, such as PEA-15 (14 15 16) . The net effect of some intracellular Erk localizing factors, exemplified by ß-arrestin, is dependent on the specific GPCR. ß-arrestin stabilizes cytoplasmic retention of Erk activated by the neurokinin 1 GPCR, enhances nuclear translocation of Erk1/2 mediated by the ß2-adrenergic GPCR, and has no effect on activation or nuclear translocation of Erk initiated by the formyl-peptide GPCR (17 18 19) . A second widely used mechanism is coupling of a phosphorylated messenger to one set of cellular responses when signaling from the cytoplasm and to another from the nucleus. Cytoplasmic P-Erk is restricted to signaling pathways that inhibit apoptosis but induce senescence by association with plasma membrane scaffolds such as those constituted by GPCRs and ß-arrestin, whereas nuclear P-Erk is coupled to cellular proliferation and a wide range of related transcriptional events (19 20 21) . The second mechanism is vital to cellular signaling when nuclearized GPCR complexes predominate as will be described in the next section.

	Signaling of nuclear events by nuclear GPCRs or their ligands

TOP ABSTRACT INTRODUCTION Signaling of nuclear events... Signaling of nuclear events... Implications of nuclear... REFERENCES

 
Unsaturated acyl forms of LPA (LPA-UA) and alkyl ether analogs of LPA (LPA-AE), but not a range of protein growth factors, stimulate progressive formation of neointima, including dedifferentiation and proliferation of vascular smooth muscle cells (VSMCs), in a rat carotid artery model of atherosclerosis (22 , 23) (Fig. 2 A). This effect and dedifferentiation of cultured VSMCs are attributed to LPA binding to nuclear peroxisome proliferator-activated receptor (PPAR) in a heterodimer with nuclear retinoic acid X receptor, rather than LPA binding to one of its cognate GPCRs. This conclusion is based on findings that LPA structural determinants of PPAR-binding activity do not fit those of binding to any LPA GPCR, and inhibitors of LPA GPCR signaling do not suppress neointima formation. Further, PPAR is up-regulated in neointimal cells exposed to the atherogenic forms of LPA, but not to LPA. PPAR agonists mimic and PPAR antagonists inhibit the neointimal effect, and there is concurrent up-regulation of PPAR-activated genes in neointimal cells. Thus, in this first example of nuclear signaling by an intranuclear ligand, modified forms of LPA found at high levels in atherosclerosis lesions enter the nucleus, bind to and activate the transcription factor PPAR, and thereby evoke transcriptional events through known PPAR-response elements (22) (Fig. 2A ). Other lipids act through PPAR to influence immunity and inflammation by mechanisms that range widely from altered differentiation of dendritic antigen-presenting cells to repression of transcription of inflammatory response genes in macrophages (24 , 25) . In the other two examples, a fragment of a GPCR or an intact GPCR enter the nuclear domain, are occupied by intracellular ligand, and there signal transcriptional events directly.

View larger version (20K): [in this window] [in a new window]   Figure 2. Signaling of transcription by nuclear GPCRs, substituent fragments of GPCRs, or their ligands. A) Direct activation of type peroxisome proliferator-activated receptor (PPAR ) by nuclear LPA. Two specific types of LPA have specialized atherogenic functions in the vasculature, namely alkyl ether analogs of LPA (LPA-AE) that constitute the neointima-evoking factors in minimally oxidized low-density lipoproteins (mox-LDL) and unsaturated acyl forms of LPA (LPA-UA) that are the predominant products of platelet activation. LPA-AE and LPA-UA enter the nucleus and bind to the complex of PPAR and retinoic acid receptor X (RAx), which initiate transcription of a select set of genes by interacting with the PPAR-response element (PPRE). B) Nuclearization of a transcription signaling-competent fragment of a Drosophila GPCR. Wingless (Wg) from developing presynaptic cells binds to the D-Frizzled 2 GPCR (DFz 2-Wg) on postsynaptic cells, which then is internalized and cleaved intracellularly. The amino-terminal fragment (DFz 2-N) remains in perinuclear spaces, whereas the carboxyl-terminal fragment (DFz 2-C) enters the nucleus to initiate transcriptional events required for synaptic development. C) Regulation of transcription by GPCRs translocated from the plasma membrane to nuclear membranes. The type 1 LPA GPCR (LPA1) activated by ligand and the type 1 S1P GPCR (S1P1) activated by nonligand cellular stimuli insert in nuclear membranes as complexes with Gi/o. The intranuclear signaling pathways of LPA1 transduce ligand activation of inducible NO synthetase (iNOS) and other proinflammatory factors, whereas S1P1 down-regulates P-Erk as well as P-c-Jun and other downstream factors essential for proliferation and thereby suppresses cellular proliferation. PM = plasma membrane. N = Nucleus.

Developmentally critical transcriptional signals in the Drosophila nervous system are initiated when presynaptic cells in larval neuromuscular junctions secrete the WNT homologue Wingless (Wg) that binds to its GPCR DFrizzled2 (DFz2) to begin differentiation of specialized features in numerous structures (26) . Recent evidence has shown that signaling-competent DFz2-Wg complexes are endocytosed at the postsynaptic membrane, transported to the nucleus, and cleaved (27) . The N-terminal portion of DFz2 remains at the nuclear surface, but the C-terminal fragment enters the nucleus in a cell type-specific process and localizes in regions of high transcriptional activity. This C-terminal domain of DFz2 is presumed to regulate transcriptional events of synaptic development in its intranuclear location, but these have not been defined as yet (Fig. 2B ).

Studies begun concurrently with those of the DFz2-Wg system have shown that some mammalian intact GPCRs for phospholipid mediators localize in nuclear membranes of activated cells, assemble signaling complexes there, bind their respective cognate mediators in the nuclear domain, and transduce transcriptional signals different from those sent to the nucleus by the same GPCRs in the plasma membrane (Fig. 2C ). Initially, the hepatocyte and endothelial cell type 1 GPCR for LPA termed LPA₁ was identified in nuclear fractions, solely in association with caveolin-1, as well as in plasma membrane fractions, in association with caveolin-1 and clathrin (7) . Engagement of cell-surface proteins other than LPA₁, such as integrins, also evokes its nuclearization (28) . Membrane-enveloped nuclei isolated from hepatocytes and free of plasma membrane proteins respond to LPA with increases in Ca²⁺ concentration and in inducible NOS (iNOS) mRNA and protein, which were prevented by pretreatment with inhibitors of LPA₁ signaling that target G proteins, Ca²⁺ channels, or PI3K. Subsequent studies also have shown nuclear translocation and colocalization of endothelial NOS (eNOS) and LPA₁ in LPA-stimulated endothelial cells, LPA₁-transduced enhancement of eNOS activity in nuclei isolated from LPA-stimulated endothelial cells, and resultant NO-mediated increases in nuclear concentrations of Ca²⁺ and P-Erk 2 along with transcriptional activation of immediate early genes encoding iNOS and COX-2 (9) .

More recently, enhancement of T cell proliferation by S1P has been linked to signals from type 1 GPCR for S1P (S1P₁) in the plasma membrane, whereas S1P₁ in nuclear membranes transduces intracellular S1P suppression of proliferation (29; Fig. 2C ). T cells generate little or no endogenous S1P, but their intracellular concentration of S1P taken up from extracellular fluid ranges from 10^–8 M to 3 x 10^–6 M. Membrane-enveloped nuclei isolated from T cells activated through the T cell antigen receptor (TCR) and free of plasma membrane proteins contain native S1P₁ coupled to Gi/o and MEK, which transduce S1P-evoked decreases in nuclear levels of P-Erk and the transcription factor P-c-Jun. Control nuclei from unstimulated T cells lack sufficient S1P₁ to support any effects of S1P on transcriptional events. In contrast, plasma membrane S1P₁ transduces S1P-elicited increases in nuclear levels of P-Erk and the transcription factor P-c-Jun. Although many of the characteristics of the pathways of nuclearization of S1P₁ and of its nuclear signaling remain to be elucidated, it is already clear that this is an example of one major mechanism for nuclear signaling by a subset of GPCRs where their ligand attains intracellular concentrations required to initiate signaling.

	Implications of nuclear signaling by GPCRs

TOP ABSTRACT INTRODUCTION Signaling of nuclear events... Signaling of nuclear events... Implications of nuclear... REFERENCES

 
Two completely new aspects aid our understanding of nuclear signaling by some GPCRs and their ligands (Fig. 2) . One is the possibility that a single member of the PPAR family of nuclear receptors may selectively transduce transcriptional signals from intranuclear LPA to a wide range of metabolic pathways and immunological processes. The other is the capacity of a select group of GPCRs to translocate from the plasma membrane to nuclear membranes and there constitute complexes that sense and transduce distinctive signals in relation to the intracellular levels of their cognate ligands. These nuclear GPCR complexes signal transcriptional events differently than the corresponding plasma membrane GPCRs. The potential biological importance of the second group of GPCRs may be considered on three different levels. First, these GPCRs operate differently in pre- and postcell activation stages, both in terms of their mechanisms of signal transduction and the functional consequences. Prior to cell activation by a GPCR ligand or other mechanism, plasma membrane GPCRs of this group send one type of nuclear signal, whereas after cell activation and GPCR nuclearization the subsequent nuclear signals may have different or even opposite cellular effects. Thus ongoing research must elucidate characteristics of these separate signaling pathways and of the nuclearization events. Second, where the signal transduced late in activated cells by a nuclear GPCR evokes a response opposite to that transduced early in unstimulated cells by the same GPCR in the plasma membrane, then one may consider the early signal to be activating and the late to be regulatory by decreasing or terminating the early responses. In this framework, one also may envision disorders of intracellular distribution of a GPCR, such as excessive early nuclearization leading to abnormally diminished responses or defective nuclearization and consequent failure to limit or terminate the early response. One example here may be the human airway smooth muscle cell (ASMC) hyperplasia and remodeling observed in some patients with severe asthma that has become resistant to bronchodilators. The S1P-S1P GPCR axes are prominent in airway smooth muscle cells, S1P levels in airway fluids are high in asthma, and S1P induces hyperplasia of human ASMCs (30) . The process would intensify substantially if S1P GPCRs on airway smooth muscle cells failed to nuclearize and thereby to transduce negative feedback signals that suppress S1P-evoked hyperplasia. Third, drugs expected to target S1P GPCRs would act differently if they did not permeate cells and thereby had access only to plasma membrane GPCRs but not to nuclear membrane GPCRs. Thus bioavailability should here be defined not only in the usual terms of systemic absorption and tissue distribution but also in terms of access to intracellular domains.

Received for publication July 31, 2006. Accepted for publication September 14, 2006.

	REFERENCES

TOP ABSTRACT INTRODUCTION Signaling of nuclear events... Signaling of nuclear events... Implications of nuclear... REFERENCES

 

1. Dohlman, H. G., Caron, M. G., Lefkowitz, R. J. (1987) A family of receptors coupled to guanine nucleotide regulatory proteins. Biochemistry 26,2657-2664[CrossRef][Medline]
2. Lefkowitz, R. J. (1993) G protein-coupled receptor kinases. Cell 74,409-412[CrossRef][Medline]
3. Neer, E. J. (1995) Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80,249-257[CrossRef][Medline]
4. Dohlman, H. G., Thorner, J. (1997) RGS proteins and signaling by heterotrimeric G proteins. J. Biol. Chem. 272,3871-3874[Free Full Text]
5. Ferguson, S. S. (2001) Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol. Rev. 53,1-24[Abstract/Free Full Text]
6. Claing, A., Laporte, S. A., Caron, M. G., Lefkowitz, R. J. (2002) Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins. Prog. Neurobiol. 66,61-79[CrossRef][Medline]
7. Gobeil, F., Jr, Bernier, S. G., Vazquez-Tello, A., Brault, S., Beauchamp, M. H., Quiniou, C., Marrache, A. M., Checchin, D., Sennlaub, F., Hou, X., et al (2003) Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. J. Biol. Chem. 278,38875-38883[Abstract/Free Full Text]
8. Bkaily, G., Sleiman, S., Stephan, J., Asselin, C., Choufani, S., Kamal, M., Jacques, D., Gobeil, F., Jr, D’Orleans-Juste, P. (2003) Angiotensin II AT1 receptor internalization, translocation and de novo synthesis modulate cytosolic and nuclear calcium in human vascular smooth muscle cells. Can. J. Physiol. Pharmacol. 81,274-287[CrossRef][Medline]
9. Gobeil, F., Jr, Zhu, T., Brault, S., Geha, A., Vazquez-Tello, A., Fortier, A., Barbaz, D., Checchin, D., Hou, X., Nader, M., et al (2006) Nitric oxide signaling via nuclearized endothelial nitric-oxide synthase modulates expression of the immediate early genes iNOS and mPGES-1. J. Biol. Chem. 281,16058-16067[Abstract/Free Full Text]
10. Gayral, S., Deleris, P., Laulagnier, K., Laffargue, M., Salles, J. P., Perret, B., Record, M., Breton-Douillon, M. (2006) Selective activation of nuclear phospholipase D-1 by g protein-coupled receptor agonists in vascular smooth muscle cells. Circ. Res. 99,132-139[Abstract/Free Full Text]
11. Irvine, R. F. (2003) Nuclear lipid signalling. Nat. Rev. Mol. Cell. Biol. 4,349-360[CrossRef][Medline]
12. Ledeen, R. W., Wu, G. (2006) Sphingolipids of the nucleus and their role in nuclear signaling. Biochim. Biophys. Acta 1761,588-598[Medline]
13. Zhao, M., Discipio, R. G., Wimmer, A. G., Schraufstatter, I. U. (2006) Regulation of CXCR4-mediated nuclear translocation of extracellular signal-related kinases 1 and 2. Mol. Pharmacol. 69,66-75[Abstract/Free Full Text]
14. Fukuda, M., Gotoh, Y., Nishida, E. (1997) Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J. 16,1901-1908[CrossRef][Medline]
15. DeFea, K. A., Zalevsky, J., Thoma, M. S., Dery, O., Mullins, R. D., Bunnett, N. W. (2000) Beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J. Cell Biol. 148,1267-1281[Abstract/Free Full Text]
16. Formstecher, E., Ramos, J. W., Fauquet, M., Calderwood, D. A., Hsieh, J. C., Canton, B., Nguyen, X. T., Barnier, J. V., Camonis, J., Ginsberg, M. H., Chneiweiss, H. (2001) PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev. Cell. 1,239-250[CrossRef][Medline]
17. Kobayashi, H., Narita, Y., Nishida, M., Kurose, H. (2005) Beta-arrestin2 enhances beta2-adrenergic receptor-mediated nuclear translocation of ERK. Cell. Signal 17,1248-1253[CrossRef][Medline]
18. Gripentrog, J. M., Miettinen, H. M. (2005) Activation and nuclear translocation of ERK1/2 by the formyl peptide receptor is regulated by G protein and is not dependent on beta-arrestin translocation or receptor endocytosis. Cell. Signal. 17,1300-1311[CrossRef][Medline]
19. Jafri, F., El-Shewy, H. M., Lee, M. H., Kelly, M., Luttrell, D. K., Luttrell, L. M. (2006) Constitutive ERK1/2 activation by a chimeric neurokinin 1 receptor-beta-arrestin1 fusion protein. Probing the composition and function of the G protein-coupled receptor "signalsome". J. Biol. Chem. 281,19346-19357[Abstract/Free Full Text]
20. Gaumont-Leclerc, M. F., Mukhopadhyay, U. K., Goumard, S., Ferbeyre, G. (2004) PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence. J. Biol. Chem. 279,46802-46809[Abstract/Free Full Text]
21. Ajenjo, N., Canon, E., Sanchez-Perez, I., Matallanas, D., Leon, J., Perona, R., Crespo, P. (2004) Subcellular localization determines the protective effects of activated ERK2 against distinct apoptogenic stimuli in myeloid leukemia cells. J. Biol. Chem. 279,32813-32823[Abstract/Free Full Text]
22. Zhang, C., Baker, D. L., Yasuda, S., Makarova, N., Balazs, L., Johnson, L. R., Marathe, G. K., McIntyre, T. M., Xu, Y., Prestwich, G. D., Byun, H. S., Bittman, R., Tigyi, G. (2004) Lysophosphatidic acid induces neointima formation through PPARgamma activation. J. Exp. Med. 199,763-774[Abstract/Free Full Text]
23. Tsukahara, T., Tsukahara, R., Yasuda, S., Makarova, N., Valentine, W. J., Allison, P., Yuan, H., Baker, D. L., Li, Z., Bittman, R., Parrill, A., Tigyi, G. (2006) Different residues mediate recognition of 1-O-oleyllysophosphatidic acid and rosiglitazone in the ligand binding domain of peroxisome proliferator-activated receptor gamma. J. Biol. Chem. 281,3398-3407[Abstract/Free Full Text]
24. Pascual, G., Fong, A. L., Ogawa, S., Gamliel, A., Li, A. C., Perissi, V., Rose, D. W., Willson, T. M., Rosenfeld, M. G., Glass, C. K. (2005) A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437,759-763[CrossRef][Medline]
25. Gogolak, P., Rethi, B., Szatmari, I., Lanyi, A., Dezso, B., Nagy, L., Rajnavolgyi, E. (2006) Differentiation of CD1a- and CD1a+ monocyte-derived dendritic cells is biased by lipid environment and PPAR{gamma}. Blood in press
26. Packard, M., Koo, E. S., Gorczyca, M., Sharpe, J., Cumberledge, S., Budnik, V. (2002) The Drosophila Wnt, wingless, provides an essential signal for pre- and postsynaptic differentiation. Cell 111,319-330[CrossRef][Medline]
27. Mathew, D., Ataman, B., Chen, J., Zhang, Y., Cumberledge, S., Budnik, V. (2005) Wingless signaling at synapses is through cleavage and nuclear import of receptor DFrizzled2. Science 310,1344-1347[Abstract/Free Full Text]
28. Waters, C. M., Saatian, B., Moughal, N. A., Zhao, Y., Tigyi, G., Natarajan, V., Pyne, S., Pyne, N. J. (2006) Integrin signalling regulates the nuclear localization and function of the lysophosphatidic acid receptor-1 (LPA1) in mammalian cells. Biochem. J. 398,55-62[CrossRef][Medline]
29. Liao, J.-J., Huang, M.-C., Graler, M., Huang, Y., Qiu, H., Goetzl, E. J. () Distinctive T cell suppressive signals from nuclearized type 1 sphingosine 1-phoshate G protein-coupled receptors. J. Biol. Chem. in press.
30. Rosenfeldt, H. M., Amrani, Y., Watterson, K. R., Murthy, K. S., Panettieri, R. A., Jr, Spiegel, S. (2003) Sphingosine-1-phosphate stimulates contraction of human airway smooth muscle cells. FASEB J. 17,1789-1799[Abstract/Free Full Text]

This article has been cited by other articles:

				C. Magnusson, R. Ehrnstrom, J. Olsen, and A. Sjolander An Increased Expression of Cysteinyl Leukotriene 2 Receptor in Colorectal Adenocarcinomas Correlates with High Differentiation Cancer Res., October 1, 2007; 67(19): 9190 - 9198. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: fj.06-6624hypv1 21/3/638    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goetzl, E. J. Search for Related Content PubMed PubMed Citation Articles by Goetzl, E. J.