A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation

Nature ◽  
1996 ◽  
Vol 383 (6600) ◽  
pp. 547-550 ◽  
Author(s):  
Ivan Dikic ◽  
George Tokiwa ◽  
Sima Lev ◽  
Sara A. Courtneidge ◽  
Joseph Schlessinger
Keyword(s):  
Map Kinase ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Kinase Activation ◽  
G Protein Coupled

scholarly journals Sphingosine 1-phosphate signalling through the G-protein-coupled receptor Edg-1

1998 ◽  
Vol 330 (2) ◽  
pp. 605-609 ◽  
Author(s):  
C. M. Gerben ZONDAG ◽  
R. Friso POSTMA ◽  
Ingrid VAN ETTEN ◽  
Ingrid VERLAAN ◽  
H. Wouter MOOLENAAR
Keyword(s):  
Adenylate Cyclase ◽  
Map Kinase ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Lpa Receptor ◽  
Kinase Activation ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are structurally related lipid mediators that act on distinct G-protein-coupled receptors to evoke similar responses, including Ca2+ mobilization, adenylate cyclase inhibition, and mitogen-activated protein (MAP) kinase activation. However, little is still known about the respective receptors. A recently cloned putative LPA receptor (Vzg-1/Edg-2) is similar to an orphan Gi-coupled receptor termed Edg-1. Here we show that expression of Edg-1 in Sf9 and COS-7 cells results in inhibition of adenylate cyclase and activation of MAP kinase (Gi-mediated), but not Ca2+ mobilization, in response to S1P. These responses are specific in that (i) S1P action is not mimicked by LPA, and (ii) Vzg-1/Edg-2 cannot substitute for Edg-1. Thus the Edg-1 receptor is capable of mediating a subset of the cellular responses to S1P.

scholarly journals 'Location, location, location': activation and targeting of MAP kinases by G protein-coupled receptors

2003 ◽  
Vol 30 (2) ◽  
pp. 117-126 ◽  
Author(s):  
LM Luttrell
Keyword(s):  
Map Kinase ◽  
G Protein ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Focal Adhesions ◽  
G Protein Coupled Receptors ◽  
Cellular Growth ◽  
Substantial Impact ◽  
Kinase Activation ◽  
G Protein Coupled

A growing body of data supports the conclusion that G protein-coupled receptors can regulate cellular growth and differentiation by controlling the activity of MAP kinases. The activation of heterotrimeric G protein pools initiates a complex network of signals leading to MAP kinase activation that frequently involves cross-talk between G protein-coupled receptors and receptor tyrosine kinases or focal adhesions. The dominant mechanism of MAP kinase activation varies significantly between receptor and cell type. Moreover, the mechanism of MAP kinase activation has a substantial impact on MAP kinase function. Some signals lead to the targeting of activated MAP kinase to specific extranuclear locations, while others activate a MAP kinase pool that is free to translocate to the nucleus and contribute to a mitogenic response.

Activation and targeting of mitogen-activated protein kinases by G-protein-coupled receptors

2002 ◽  
Vol 80 (5) ◽  
pp. 375-382 ◽  
Author(s):  
Louis M Luttrell
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
G Protein ◽  
Map Kinases ◽  
Kinase Activity ◽  
Nuclear Translocation ◽  
G Protein Coupled Receptors ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

Over the past decade, it has become apparent that many G-protein-coupled receptors (GPCRs) generate signals that control cellular differentiation and growth, including stimulation of Ras family GTPases and activation of mitogen-activated protein (MAP) kinase pathways. The mechanisms that GPCRs use to control the activity of MAP kinases vary between receptor and cell type but fall broadly into one of three categories: signals initiated by classical G protein effectors, e.g., protein kinase (PK)A and PKC, signals initiated by cross-talk between GPCRs and classical receptor tyrosine kinases, e.g., "transactivation" of epidermal growth factor (EGF) receptors, and signals initiated by direct interaction between β-arrestins and components of the MAP kinase cascade, e.g., β-arrestin "scaffolds". While each of these pathways results in increased cellular MAP kinase activity, emerging data suggest that they are not functionally redundant. MAP kinase activation occurring via PKC-dependent pathways and EGF receptor transactivation leads to nuclear translocation of the kinase and stimulates cell proliferation, while MAP kinase activation via β-arrestin scaffolds primarily increases cytosolic kinase activity. By controlling the spatial and temporal distribution of MAP kinase activity within the cell, the consequences of GPCR-stimulated MAP kinase activation may be determined by the mechanism by which they are activated.Key words: G-protein-coupled receptor, receptor tyrosine kinase, β-arrestin, mitogen-activated protein kinase, extracellular signal-regulated kinase.

scholarly journals Role of Protein Kinase C, PI3-kinase and Tyrosine Kinase in Activation of MAP Kinase by Glucose and Agonists of G-protein Coupled Receptors in INS-1 Cells

2001 ◽  
Vol 2 (3) ◽  
pp. 233-244 ◽  
Author(s):  
Dietmar Böcker ◽  
Eugen J. Verspohl
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
G Protein ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
G Protein Coupled Receptors ◽  
Kinase C ◽  
G Protein Coupled

MAP (mitogen-activated protein) kinase (also called Erk 1/2) plays a crucial role in cell proliferation and differentiation. Its impact on secretory events is less well established. The interplay of protein kinase C (PKC), PI3-kinase nd cellular tyrosine kinase with MAP kinase activity using inhibitors and compounds such as glucose, phorbol 12-myristate 13-acetate (PMA) and agonists of G-protein coupled receptors like gastrin releasing peptide (GRP), oxytocin (OT) and glucose-dependent insulinotropic peptide (GIP) was investigated in INS-1 cells, an insulin secreting cell line. MAP kinase activity was determined by using a peptide derived from the EGF receptor as a MAP kinase substrate and [P32]ATP. Glucose as well as GRP, OT and GIP exhibited a time-dependent increase in MAP kinase activity with a maximum at time point 2.5 min. All further experiments were performed using 2.5 min incubations. The flavone PD 098059 is known to bind to the inactive forms of MEK1 (MAPK/ERK-Kinase) thus preventing activation by upstream activators. 20 μM PD 098059 (IC50=51 μM) inhibited MAP kinase stimulated by either glucose, GRP, OT, GIP or PMA. Inhibiton (“downregulation”) of PKC by a long term (22h) pretreatment with 1 μM PMA did not influence MAP kinase activity when augmented by either of the above mentioned compound. To investigate whether PI3-kinase and cellular tyrosine kinase are involved in G-protein mediated effects on MAP kinase, inhibitors were used: 100 nM wortmannin (PI3-kinase inhibitor) reduced the effects of GRP, OT and GIP but not that of PMA; 100 μM genistein (tyrosine kinase inhibitor) inhibited the stimulatory effect of either above mentioned compound on MAP kinase activation. Inhibition of MAP kinase by 20 μM PD 098059 did not influence insulin secretion modulated by either compound (glucose, GRP, OT or GIP). [H3]Thymidine incorporation, however, was severely inhibited by PD 098059. Thus MAP kinase is important for INS-1 cell proliferation but not for its insulin secretory response with respect to major initiators and modulators of insulin release. The data indicate that MAP kinase is active and under the control of MAP kinase. PKC is upstream of a genisteinsensitive tyrosine kinase and probably downstream of a PI3-kinase in INS-1 cells.

scholarly journals Ras-dependent Mitogen-activated Protein Kinase Activation by G Protein-coupled Receptors

1997 ◽  
Vol 272 (31) ◽  
pp. 19125-19132 ◽  
Author(s):  
Gregory J. Della Rocca ◽  
Tim van Biesen ◽  
Yehia Daaka ◽  
Deirdre K. Luttrell ◽  
Louis M. Luttrell ◽  
...  
Keyword(s):  
Protein Kinase ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Protein Kinase Activation ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

Differential Signaling of G Protein-Coupled Chemotactic Receptors (CXCR4, cysLT1 and S1P1) Expressed in Hematopoietic Progenitor Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1342-1342
Author(s):  
Xingkui Xue ◽  
Andreas Boehmler ◽  
Lothar Kanz ◽  
Gabriele Seitz ◽  
Robert Mohle
Keyword(s):  
Calcium Signaling ◽  
Map Kinase ◽  
Signaling Pathways ◽  
Progenitor Cells ◽  
G Protein ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Calcium Fluxes ◽  
Kinase Activation ◽  
G Protein Coupled

Abstract We have previously demonstrated consistent and high expression of the G protein-coupled receptors (GPCR) CXCR4, cysLT1 and S1P1 in human hematopoetic progenitor and stem cells (HPC). All of these receptors induced chemotactic responses in mobilized CD34+ HPC. As their ligands are present in the hematopoietic microenvironment, these GPCR may be involved in HPC homing and/or proliferation. Ligands for CXCR4 (SDF-1) and cysLT1 (cys-leukotrienes) are both produced by stromal cells, while the S1P1 ligand (sphingosine 1-phosphate, S1P) is released by megakaryocytes and platelets. As GPCR may activate multiple signaling pathways resulting in different functional effects, we compared the signaling capacities of CXCR4, cysLT1 and S1P1 in CD34+ HPC and CD34+ progenitor cell lines. At optimal ligand concentrations, cysLT1 mediated the strongest intracellular calcium fluxes, in contrast to CXCR4 (intermediate response) and S1P1 (almost absent calcium fluxes). Pertussis toxin (PTX) only partially inhibited cysLT1-mediated calcium signaling, indicating coupling of the receptor to both Gi and Gq proteins, while CXCR4-mediated responses were exclusively PTX-sensitive and therefore only Gi-dependent. Both cysLT1 and CXCR4 induced phosphorylation of the proliferation-related p44/42 (Erk) MAP kinase. Again, much stronger responses were mediated by cysLT1, which again were only partially PTX-sensitive. No Erk/MAP kinase activation was mediated by S1P1. We could demonstrate that pyk2, a kinase that links calcium signaling with Erk/MAP kinase activation, was involved in Gq-mediated signaling of cysLT1, as its phosphorylation was not inhibited by PTX. The fact that cysLT1 employs both Gi and Gq-mediated signaling pathways, while CXCR4 signaling was exclusively Gi-dependent, may explain why enhanced proliferation of CD34+ hematopoietic progenitor cells in cytokine-supplemented serum-free liquid cultures was only seen in response to ligands of cysLT1, but not in response to the CXCR4 ligand SDF-1. Activation of CXCR4 resulted in phosphorylation of Akt, which was not observed in response to ligands of cysLT1, while both GPCR induced translocation of NFkappaB to the nucleus. We conclude that in CD34+ HPC, Gi protein-mediated signaling of CXCR4 is mainly involved in cell migration, while Gi and Gq-mediated signaling of cysLT1 also affects cell proliferation predominantly by combined and profound activation of the Erk/MAP kinase pathway. The signaling capacity of S1P1 however was limited compared to the other GPCRs.

A Conserved Gβ Binding (GBB) Sequence Motif in Ste20p/PAK Family Protein Kinases

2000 ◽  
Vol 381 (5-6) ◽  
pp. 427-431 ◽  
Author(s):  
E. Leberer ◽  
D. Dignard ◽  
D.Y. Thomas ◽  
T. Leeuw
Keyword(s):  
Map Kinase ◽  
Binding Site ◽  
Protein Kinases ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Binding Motif ◽  
Sequence Motif ◽  
Heterotrimeric G Protein ◽  
Family Protein ◽  
G Protein Coupled

Abstract Serine/threonine protein kinases of the Ste20p/PAK family are highly conserved from yeast to man. These protein kinases have been implicated in the signaling from heterotrimeric G proteins to mitogen-activated protein (MAP) kinase cascades and to cytoskeletal components such as myosin-I. In the yeast Saccharomyces cerevisiae, Ste20p is involved in transmitting the mating-pheromone signal from the βγ-subunits of a heterotrimeric G protein to a downstream MAP kinase cascade. We have previously shown that binding of the G-protein β-subunit (Gβ) to a short binding site in the non-catalytic carboxy-terminal region of Ste20p is essential for transmitting the pheromone signal. In this study, we searched protein sequence databases for sequences that are similar to the Gβ binding site in Ste20p. We identified a sequence motif with the consensus sequence S S L ϕP L I/V x ϕϕβ (x: any residue; ϕ: A, I, L, S, or T; β: basic residues) that is solely present in members of Ste20p/PAK family protein kinases. We propose that this sequence motif, which we have designated GBB (G̱β̱ ḇinding) motif, is specifically responsible for binding of Gβ to Ste20p/PAK protein kinases in response to activation of heterotrimeric G protein coupled receptors. Thus, the GBB motif is a novel type of signaling domain that serves to link protein kinases of the Ste20p/PAK family to G protein coupled receptors.

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