Mitogenic signaling pathways induced by G protein‐coupled receptors

Rozengurt, Enrique

doi:10.1002/jcp.21246

Cited by 417 publications

(424 citation statements)

References 285 publications

(366 reference statements)

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“…Although in our experiments the tyrosine phosphorylation appeared to display a stronger signal than that of serine/threonine phosphorylation, this is likely due to merely the higher efficiency of antibodies used for precipitating and detecting tyrosine-phosphorylated proteins. The finding of decreased tyrosine phosphorylation in PI3Kg-deficient cells adds a new signaling pathway to the previously described GPCR-dependent induction of protein tyrosine kinases [36]. As a potential explanation, pleckstrin homology domain containing tyrosine kinases, like members of the Tec family [2], might be activated by PI3Kg-mediated PtdIns(3,4,5)P 3 production and be involved in the observed PI3K-dependent tyrosine phosphorylation.…”

Section: Discussionmentioning

confidence: 73%

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

et al. 2009

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Phosphoinositide 3-kinase c (PI3Kc) plays a fundamental role in mediating leukocyte migration to inflammation sites. However, the downstream cytoplasmic events triggered by its signaling activity are still largely obscure. To address this issue, tyrosine and serine/threonine phosphorylated proteins of chemokine-stimulated WT or PI3Kc-null macrophages were investigated. Among the proteins analyzed, the intermediate filament vimentin was found as a downstream effector of the PI3Kc signaling pathway. Specific analysis of the phosphorylation state of vimentin in macrophages showed that this protein becomes rapidly phosphorylated in both tyrosine and serine residues upon chemokine stimulation. In the absence of PI3Kc or the kinase activity of PI3Kc (PI3Kc KD/KD ), phosphorylation of vimentin was reduced. PI3Kc-null macrophages displayed impaired chemokine-driven vimentin fiber disassembly as well as reduced ability to transmigrate across endothelial cells. While WT macrophages infected with a vimentin mutant resistant to N-terminal serine phosphorylation showed a reduction in transendothelial migration, infection of PI3Kc-null macrophages with a vimentin mutant mimicking serine phosphorylation of N-terminal residues rescued the transendothelial migration defect. These results define vimentin N-terminal phosphorylation and fiber reorganization as a target of chemokine-dependent PI3Kc signaling in leukocytes.Key words: Cell migration . Intermediate filaments . Phosphoinositide 3-kinases .Signal transduction IntroductionPhosphoinositide 3-kinases (PI3K) are a family of ubiquitously expressed lipid and protein kinases. They are activated downstream transmembrane receptors [1] and are involved in several cellular responses such as metabolic regulation, survival, proliferation, cell migration and adhesion. PI3K convert PtdIns(4,5)P 2 into PtdIns(3,4,5)P 3 , a second lipid messenger product forming a docking site for various proteins harboring lipid binding modules such as the pleckstrin homology domain [2].Ã These authors contributed equally to this work. 1136Class I PI3K are heterodimeric proteins composed of a p110 catalytic subunit (a, b, g and d) and a regulatory adaptor subunit. According to their mechanism of activation, these enzymes can be further classified into two subclasses: while class IA PI3K (PI3Ka, b and d) include an adaptor protein of the p85 family and are activated by tyrosine kinase receptors, the sole known element of class IB, PI3Kg, is specifically activated by G protein-coupled receptors (GPCR) [3]. This effect is regulated by the interaction of PI3Kg with Gbg subunits of active G proteins through the involvement of either the p101 adaptor or its homologue p84/p87 [4]. Among mammalian tissues, the highest level of PI3Kg expression is found in leukocytes where this enzyme directs the chemotactic response to GPCR agonists [3]. Indeed, PI3Kg-null granulocytes show a significant reduction in chemotaxis toward chemokines and severely impaired bacteria-elicited peritoneal recruitment [5,6]. This migrati...

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Section: Discussionmentioning

confidence: 73%

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

et al. 2009

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“…To our knowledge, this is the first observation implicating EGFR activation in IL-17 signaling, and this may account for the effect of IL-17 on ERK activity. Many G protein-coupled receptors activate EGFR and its downstream pathways including ERK, a phenomenon known as transactivation (60). Mechanisms for transactivation include extracellular release of EGFR ligands such as heparinbinding epidermal growth factor-like growth factor (HB-EGF) or TGF-␣, which bind to and activate the EGFR, and activation of Src kinase, which phosphorylates Tyr 845 of EGFR, resulting in EGFR activation (60).…”

Section: Discussionmentioning

confidence: 99%

“…Many G protein-coupled receptors activate EGFR and its downstream pathways including ERK, a phenomenon known as transactivation (60). Mechanisms for transactivation include extracellular release of EGFR ligands such as heparinbinding epidermal growth factor-like growth factor (HB-EGF) or TGF-␣, which bind to and activate the EGFR, and activation of Src kinase, which phosphorylates Tyr 845 of EGFR, resulting in EGFR activation (60). TNF-␣ has been shown to transactivate EGFR in some epithelials cells (61) and to stimulate extracellular release of the EGFR ligand TGF-␣ and activate ERK in HT-29 cells (62).…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Lee

Wang

Kattah³

et al. 2008

The Journal of Immunology

116

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The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-α-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-α for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-α in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells.

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“…Ligand-activated LHR is capable of signaling through Gs, Gq/11, and Gi/o, although the actions mediated by LHR through Gs are the most studied (14)(15)(16). The LHR-initiated second messenger responses, cyclic AMP (cAMP), inositol 1,4,5-trisphosphate (IP3), 1,2-diacylglycerol, and intracellular calcium, stimulate protein kinase cascades that are associated with mitogenic signaling (17). Recently, the actions of LH during ovulation were shown to involve the release of the epidermal growth factor (EGF)-like factors epiregulin and amphiregulin that act as mediators of the ovulatory response (18,19).…”

Section: Introductionmentioning

confidence: 99%

Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells

Warrenfeltz

Lott

Palmer

et al. 2008

Molecular Cancer Research

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The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein -coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2 -overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time-and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A -mediated, protein kinase C -mediated, epidermal growth factor receptor -mediated, and ErbB-2 -mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype.

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Mitogenic signaling pathways induced by G protein‐coupled receptors

Cited by 417 publications

References 285 publications

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells

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