Mitogenic Signaling via G Protein-Coupled Receptors

Biesen, Tim van; Luttrell, Louis M.; Hawes, Brian E.; Lefkowitz, Robert J.

doi:10.1210/edrv-17-6-698

Cited by 388 publications

(224 citation statements)

References 254 publications

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“…In CHO cells ERK activation via primarily G q/11 -coupled receptors has been reported to involve G o proteins (van Biesen et al, 1996;, while in most other cell systems G q/11 -coupled receptor signal to ERK in a strictly G q/11 /phospholipase C-bdependent manner (Grosse et al, 2000a,b). As G o proteins are not expressed in most other ®broblast cell lines used to express recombinant G-protein-coupled receptors, the CHO cell model represents a rare exception rather than the rule, but nevertheless illustrates that signaling pathways can be a ected by the cellular background.…”

Section: Discussionmentioning

confidence: 99%

“…Both, Ga-GTP and Gbg are signaling molecules in their own right and activate a diverse array of e ector systems such as enzymes and ion channels (Birnbaumer et al, 1990;Clapham and Neer, 1997;Gautam et al, 1998;Hepler and Gilman, 1992). In recent years it has become evident that receptor/G protein systems play an important role in cell di erentiation, proliferation and even in transformation by engaging signal transduction pathways like MAPK cascades which are classically employed by growth factors such as EGF or PDGF (Dhanasekaran et al, , 1998Gutkind, 1998;van Biesen et al, 1996). In addition, GTPase-de®cient G-protein a subunits can induce a transformed phenotype in certain ®broblast cell lines, and mutationally activated G-protein a subunits have been identi®ed in human tumors (Dhanasekaran et al, , 1998.…”

Section: Introductionmentioning

confidence: 99%

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The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

et al. 2000

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Neuropeptides like galanin produced and released by small cell lung cancer (SCLC) cells are considered principal mitogens in these tumors. We identi®ed the galanin receptor type 2 (GALR2) as the only galanin receptor expressed in H69 and H510 cells. Photoa nity labeling of G proteins in H69 cell membranes revealed that GALR2 activates G proteins of three subfamilies: G q , G i , and G 12 . In H69 cells, galanin-induced Ca 2+ mobilization was pertussis toxin-insensitive. While phorbol ester-induced extracellular signal-regulated kinase (ERK) activation required protein kinase C (PKC) activity, preincubation of H69 cells with the PKCinhibitor GF109203X had no e ect on galanin-dependent ERK activity. A rise of the intracellular calcium concentration was necessary and su cient to mediate galanin-induced ERK activation. In support of G i coupling, stimulation of GALR2 expressed in HEK293 cells inhibited isoproterenol-induced cAMP accumulation and raised cAMP levels in COS-7 cells when coexpressed with a chimeric Ga S -Ga i protein. In H69 cells, galanin activated the monomeric GTPase RhoA and induced stress ®ber formation in Swiss 3T3 cells expressing GALR2. Thus, we provide the ®rst direct evidence that in SCLC the mitogenic neuropeptide galanin, interacting with GALR2, simultaneously activates multiple classes of G proteins and signals through the G q phospholipase C/calcium sequence and a G 12 /Rho pathway. Oncogene (2000) 19, 4199 ± 4209.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

et al. 2000

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“…It is generally accepted that G i -coupled receptors use the ␤␥ subunits of G protein to activate MAPK via a mechanism involving the following pathway: G␤␥3 Src3 Shc/Grb/SOS3 Ras3 Raf3 MEK3 ERK (26). In neutrophils, PI3 kinase is involved in fMLP-induced ERK phosphorylation, possibly via its direct effect on MEK (G␤␥3 PI3 kinase3 MEK3 ERK) (8).…”

Section: Discussionmentioning

confidence: 99%

Chemokine Production by G Protein-Coupled Receptor Activation in a Human Mast Cell Line: Roles of Extracellular Signal-Regulated Kinase and NFAT

Ali

Ahamed

Hernández-Munaín

et al. 2000

The Journal of Immunology

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Chemoattractants are thought to be the first mediators generated at sites of bacterial infection. We hypothesized that signaling through G protein-coupled chemoattractant receptors may stimulate cytokine production. To test this hypothesis, a human mast cell line (HMC-1) that normally expresses receptors for complement components C3a and C5a at low levels was stably transfected to express physiologic levels of fMLP receptors. We found that fMLP, but not C3a or C5a, induced macrophage inflammatory protein (MIP)-1β (CCL4) and monocyte chemoattractant protein-1 (CCL2) mRNA and protein. Although fMLP stimulated both sustained Ca2+ mobilization and phosphorylation of extracellular signal-regulated kinase (ERK), these responses to C3a or C5a were transient. However, transient expression of C3a receptors in HMC-1 cells rendered the cells responsive to C3a for sustained Ca2+ mobilization and MIP-1β production. The fMLP-induced chemokine production was blocked by pertussis toxin, PD98059, and cyclosporin A, which respectively inhibit Giα activation, mitgen-activated protein kinase kinase-mediated ERK phosphorylation, and calcineurin-mediated activation of NFAT. Furthermore, fMLP, but not C5a, stimulated NFAT activation in HMC-1 cells. These data indicate that chemoattractant receptors induce chemokine production in HMC-1 cells with a selectivity that depends on the level of receptor expression, the length of their signaling time, and the synergistic interaction of multiple signaling pathways, including extracellular signal-regulated kinase phosphorylation, sustained Ca2+ mobilization and NFAT activation.

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“…The latter can act in their own right as signal transducers, interacting for example with PI-3-kinase and tyrosine kinases (Van Biesen et al, 1996), and could theoretically be required for the mitogenic response in primary cells. However, this would not explain the lack of sustained proliferation following administration of agents, notably cholera toxin (Wynford-Thomas, 1993) which activate endogenous Gs and closely mimic the e ect of Gas mutation.…”

Section: Constitutive Tshr Activity Provides a Signal Not Mimicked Bymentioning

confidence: 99%

Contrasting effects of activating mutations of GαS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells

et al. 1999

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The cyclic AMP pathway is a major regulator of thyrocyte function and proliferation and, predictably, its inappropriate activation is associated with a sub-set of human thyroid tumours. Activating mutations are, however, more common in the thyrotropin receptor (TSHR) than in its downstream transducer, Gas. To investigate whether this re¯ects an inherent di erence in their oncogenic potency, we compared the e ects of retrovirally-transduced mutant (A623I) TSHR or (Q227L) Gas (GSP), using the rat thyroid cell line FRTL5 and primary human thyrocytes. In FRTL5, expression of GSP or mutant (m) TSHR induced a 2 ± 3-fold increase in basal levels of cAMP. This was associated with TSH-independent proliferation (assessed by both cell number and DNA synthesis) and function (as shown by increased expression of thyroglobulin (Tg) and the sodium/iodide symporter). In primary cultures, expression of mTSHR, but not GSP, consistently induced formation of colonies with epithelial morphology and thyroglobulin expression, capable of 10 ± 15 population doublings (PD) compared to less than three in controls. Thus, while mTSHR and GSP exert similar e ects in FRTL5, use of primary cultures reveals a major di erence in their ability to induce sustained proliferation in normal human thyrocytes, and provides the ®rst direct evidence that mTSHR is su cient to initiate thyroid tumorigenesis.

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Mitogenic Signaling via G Protein-Coupled Receptors

Cited by 388 publications

References 254 publications

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

Chemokine Production by G Protein-Coupled Receptor Activation in a Human Mast Cell Line: Roles of Extracellular Signal-Regulated Kinase and NFAT

Contrasting effects of activating mutations of GαS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells

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