Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

Gutkind, J. Silvio

doi:10.1038/sj.onc.1202186

Cited by 242 publications

(173 citation statements)

References 105 publications

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“…Phosphorylation of tyrosine residues on the OSMR also provides binding sites for a variety of signalling molecules containing SH2 domains, including those that activate the ras-MAPK pathway. In mammalian cells, three distinct MAPK families exist, p42/p44 MAPK, p38 MAPK and JNK (Gutkind, 1998). However, it is the p42/p44 MAPK that plays a pivotal role in stimulating ®broblasts to re-enter the cell cycle (Pages et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Scaffidi

Mutsaers

Moodley

et al. 2002

British J Pharmacology

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6JJ1 Oncostatin M (OSM), a member of the interleukin-6 (IL-6) cytokine family, acts on a variety of cells and elicits diversi®ed biological responses, suggesting potential roles in the regulation of cell survival, di erentiation and proliferation. 2 We have examined the e ect of OSM on the regulation of human lung ®broblast proliferation, collagen production and spontaneous apoptosis. The proliferative e ects of OSM (0.5 ± 100 ng ml 71 ) were assessed using a MTS assay as well as [ 3 H]-thymidine incorporation and cell counts at 24 and 48 h. Hydroxyproline was measured as an index of procollagen production by high pressure liquid chromotography (HPLC). Apoptosis was determined by annexin staining. 3 OSM enhanced the mitotic activity of lung ®broblasts in a time and dose dependent manner. Maximum proliferation of 57% above control was observed after incubation for 48 h with 2 ng ml 71 OSM (P50.05). 4 Incubation with the mitogen activated protein kinase (MAPK) kinase inhibitor, PD98059 or the tyrosine kinase inhibitor, genestein both signi®cantly reduced the mitogenic e ect of OSM (P50.05). 5 In contrast, proliferation in response to OSM was not regulated by induction of cyclo-oxygenase and subsequent prostaglandin E 2 (PGE 2 ) release or by IL-6. 6 OSM also stimulated ®broblasts to synthesize pro-collagen by a maximum of 35% above control levels after 48 h (P50.05). 7 OSM signi®cantly inhibited the spontaneous apoptosis of ®broblasts at 24 and 48 h. 8 These results provide evidence that OSM has pro-®brotic properties and suggest that it may play a role in normal lung wound repair and ®brosis.

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Section: Discussionmentioning

confidence: 99%

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Scaffidi

Mutsaers

Moodley

et al. 2002

British J Pharmacology

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“…The CA3 region was also implicated in mediating the translocation of KSR to the cell membrane in an independent study, probably via an interaction with the β subunit of heterotrimeric G-proteins [113]. The β\γ dimer is located at the cell membrane and is responsible for stimulation of the ERK pathway by G-protein-coupled receptors [114]. Curiously, the Raf-1 CRD also was reported to bind to the same type of β subunit as KSR in itro and in co-expression systems [115], but is not not clear whether this interaction occurs between endogenous proteins and what the functional significance is.…”

Section: Holding It Together : Scaffolds and Adapters Ksr And Cnk (Comentioning

confidence: 99%

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Kölch

2000

Biochemical Journal

1,035

116

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The Ras\Raf\MEK (mitogen-activated protein kinase\ERK kinase)\ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein-protein interactions in the regulation of this pathway, INTRODUCTIONThe mitogen-activated protein kinase (MAPK) pathway is one of the primordial signalling systems that Nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as proliferation, differentiation, survival and apoptosis. The basic arrangement includes a G-protein working upstream of a core module consisting of three kinases : a MAPK kinase kinase (MAPKKK) that phosphorylates and activates a MAPK kinase (MAPKK), which in turn activates MAPK ( Figure 1). This set-up provides not only for signal amplification, but, maybe even more importantly, for additional regulatory interfaces that allow the kinetics, duration and amplitude of the activity to be precisely tuned. At present we can distinguish six MAPK modules, which share structurally related components, but seem to mediate specific biological responses. For recent reviews on MAPK pathways, the reader is referred to references [1][2][3]. Here we will focus on the regulation of the ERK (extracellular-signal-regulated kinase) pathway, which features Ras as G-protein, Raf as MAPKKK, MEK (MAPK\ERK kinase) as MAPKK and ERK as MAPK.Despite enjoying a decade in the limelight of scientific interest and revealing a plethora of new insights into the circuitry of signalling pathways in general, this pathway still holds many secrets. These pertain mainly to the regulation of Raf, and to a deeper understanding of how specific biological responses are encoded by spatial and temporal changes in the activity and subcellular distribution of the pathway components, and how these fluctuations are orchestrated at the molecular level. Work from many laboratories has highlighted protein-protein interactions as powerful means of co-ordinating signalling processes, most strikingly exemplified by the assembly of multi-protein signalling complexes on activated receptors, or of transcriptionfactor complexes on gene promoters. However, it is becoming Abbreviations used : Bcr, Breakpoint cluster region ; BXB, isolated Raf-1 kinase domain ; CNK, connector-enhancer of KSR ; CK2, casein kinase 2 ; CRD, cysteine-rich domain ; DEF, docking site for ERK, FxFP ; DLK, dual leucine-zipper-bearing kinase ; ERK, extracellular-signal-regulated kinase ; Hsp, heat-shock protein ; KIM, kinase interaction motif ; IκB, inhibitor of NF-κB ; JNK, c-Jun N-terminal kinase ; KSR, kinase suppressor of Ras ; MAPK, mitogen-activated protein kinase ; MAPKK, MAPK kinase ; MAPKKK, MAPK kinase kinase ; MEK, MAPK/ERK kinase ; MEKK, MEK kinase ; MP1, MEK partner 1 ; MUK, MAPK upstream kin...

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“…GPCRs have been related to a variety of cellular functions, including cell proliferation, differentiation, survival, and migration. 39,40 To study the role of the peripheral cannabinoid receptor when overexpressed on myeloid cells, we investigated the effects of cannabinoid ligands on the myeloid cell line NFS 78 and on 32D/G-CSF-R cells transfected with the Cb2 exon-1B/exon-2 splice variant. We demonstrate that stimulation of Cb2-overexpressing cells by its potent agonist 2-AG induces migration in vitro at nanomolar concentrations.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

Jordà

Verbakel

Valk

et al. 2002

Blood

145

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Cb2 is a novel protooncogene encoding the peripheral cannabinoid receptor. Previous studies demonstrated that 2 distinct noncoding first exons exist: exon-1A and exon-1B, which both splice to proteincoding exon-2. We demonstrate that in retrovirally induced murine myeloid leukemia cells with proviral insertion in Cb2, exon-1B/exon-2 Cb2 messenger RNA levels have been increased, resulting in high receptor numbers. In myeloid leukemia cells without virus insertion in this locus, low levels of only exon-1A/exon-2 Cb2 transcripts were present and receptors could not be detected. To elucidate the function of Cb2 in myeloid leukemia cells, a set of in vitro experiments was carried out using 32D/G-CSF-R (granulocyte colony-stimulating factor receptor) cells transfected with exon-1B/exon-2 Cb2 complementary DNA and a myeloid cell line carrying a virus insertion in Cb2 (ie, NFS 78). We demonstrate that a major function of the Cb2 receptor is stimulation of migration as determined in a transwell assay. The cannabinoid receptors belong to the superfamily of 7-transmembrane G protein-coupled receptors (GPCRs). Several GPCRs have been shown to be involved in cell growth and oncogenesis as the result of aberrant expression. [5][6][7] Examples of GPCRs with transforming ability are the ␣1B-adrenergic, 8 thrombin, 9 and serotonin 1c receptors 10 and the receptor encoded by MAS oncogene. 11,12 Our previous observation that Cb2 is a common virus integration site suggests that aberrant expression of this 7-transmembrane receptor may be a critical event in transformation in certain cases of leukemia. 3 The protein-coding region of Cb2 is located on a single exon (exon-2) of approximately 4 kilobases. Recently we identified 2 distinct 5Ј noncoding exons (ie, exon-1A and exon-1B) previously designated exon-1 and exon-1Ј, respectively. 3 In the study presented here we first carried out experiments to investigate Cb2 messenger RNA (mRNA) transcripts and protein expression in leukemic cells with or without retroviral insertion in the Cb2 locus. Secondly, we performed studies to determine the function of the peripheral cannabinoid receptor when overexpressed in myeloid cells.GPCRs have been related to many functions, including cell proliferation, maturation, survival, apoptosis, or migration. 6,13,14 In the present study, we investigated the function of the peripheral cannabinoid receptor when overexpressed on myeloid cells (ie, 32D/G-CSF-R [granulocyte colony-stimulating factor receptor]) in which we overexpressed exon-1B/exon-2 Cb2 splice variant and a myeloid leukemia cell line containing a virus insertion in the Cb2 locus, NFS 78. We also wished to determine which of the large panel of Cb2 ligands that have been identified previously is the true agonist of the receptor. We investigated the effects of natural (␦ 8 24 ) cannabinoids. We show that 2-AG is the most potent agonist for the Cb2 receptor and that a major function of 2-AG is stimulation of migration. We further studied whether 2-AG acts as a chemotactic or chemokinetic age...

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Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

Cited by 242 publications

References 105 publications

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

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