scholarly journals Permissive effect of ceramide on growth factor-induced cell proliferation

1995 ◽  
Vol 311 (3) ◽  
pp. 829-834 ◽  
Author(s):  
T Sasaki ◽  
K Hazeki ◽  
O Hazeki ◽  
M Ui ◽  
T Katada
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Growth ◽  
Synergistic Effect ◽  
Map Kinase ◽  
Map Kinases ◽  
Enzyme Reaction ◽  
3T3 Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Addition of bacterial sphingomyelinase to quiescent Swiss 3T3 cells effectively potentiated the platelet-derived growth factor (PDGF)-stimulated cell proliferation, though the enzyme by itself had little effect on the cell proliferation. Such potentiation of the cell growth could also be observed by the addition of ceramide, a product of the sphingomyelinase-catalysed reaction. In contrast, phosphocholine, another product of the enzyme reaction, had no synergistic effect on the action of PDGF. Treatment of the cells with sphingomyelinase or ceramide increased the cellular activity of mitogen-activated protein kinases (MAP kinases), which have been implicated in the regulation of cell proliferation. However, the synergistic effect of sphingomyelinase on the PDGF-induced cell growth could still be observed even when the cellular MAP kinase activity was fully activated by the growth factor alone. These results indicate that a ceramide-mediated cellular event(s) other than the MAP kinase activation is potentially involved in the regulation of cell growth.

scholarly journals The platelet-derived-growth-factor receptor, not the epidermal-growth-factor receptor, is used by lysophosphatidic acid to activate p42/44 mitogen-activated protein kinase and to induce prostaglandin G/H synthase-2 in mesangial cells

2000 ◽  
Vol 345 (2) ◽  
pp. 217-224 ◽  
Author(s):  
Margarete GOPPELT-STRUEBE ◽  
Stefanie FICKEL ◽  
Christian O. A. REISER
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Map Kinases ◽  
Egf Receptor ◽  
Mesangial Cells ◽  
Growth Factor Receptor ◽  
Pdgf Receptor ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

In renal mesangial cells, activation of protein tyrosine kinase receptors may increase the activity of mitogen-activated protein (MAP) kinases and subsequently induce expression of prostaglandin G/H synthase-2 (PGHS-2, cyclo-oxygenase-2). As examples, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) were shown to transiently enhance p42/44 MAP kinase activity, which was an essential step in the induction of PGHS-2 mRNA and protein. Inhibitors of receptor kinase activities, tyrphostins AG1296 and AG1478, specifically inhibited the effects of PDGF and EGF respectively. Activation of p42/44 and p38 MAP kinases and PGHS-2 induction were also mediated by lysophosphatidic acid (LPA), which binds to pertussis-toxin-sensitive G-protein-coupled receptors. LPA stimulation was inhibited by AG1296, but not AG1478, indicating involvement of the PDGF receptor kinase in LPA-mediated signalling. This was confirmed by pertussis-toxin-sensitive tyrosine phosphorylation of the PDGF receptor by LPA, whereas no phosphorylation of the EGF receptor was detected. For comparison, 5-hydroxytryptamine (‘serotonin’)-mediated signalling was only partially inhibited by AG1296, and also not affected by AG1478. A strong basal AG1296-sensitive tyrosine phosphorylation of the PDGF receptor and a set of other proteins was observed, which by itself was not sufficient to induce p42/44 MAP kinase activation, but played an essential role not only in LPA- but also in phorbol ester-mediated activation. Taken together, the PDGF receptor, but not the EGF receptor, is involved in LPA-mediated MAP kinase activation and PGHS-2 induction in primary mesangial cells, where both protein kinase receptors are present and functionally active.

scholarly journals Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.

1996 ◽  
Vol 135 (6) ◽  
pp. 1633-1642 ◽  
Author(s):  
S Miyamoto ◽  
H Teramoto ◽  
J S Gutkind ◽  
K M Yamada
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Kinase Activation ◽  
Transient Activation

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.

scholarly journals Novel members of the mitogen-activated protein kinase activator family in Xenopus laevis

1993 ◽  
Vol 13 (9) ◽  
pp. 5738-5748
Author(s):  
B M Yashar ◽  
C Kelley ◽  
K Yee ◽  
B Errede ◽  
L I Zon
Keyword(s):  
Protein Kinase ◽  
Xenopus Laevis ◽  
Map Kinase ◽  
Protein Kinases ◽  
Map Kinases ◽  
Yeast Cells ◽  
Amino Acid Sequence Similarity ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
Activation Pathways

Mitogen-activated protein (MAP) kinases comprise an evolutionarily conserved family of proteins that includes at least three vertebrate protein kinases (p42, p44, and p55 MAPK) and five yeast protein kinases (SPK1, MPK1, HOG1, FUS3, and KSS1). Members of this family are activated by a variety of extracellular agents that influence cellular proliferation and differentiation. In Saccharomyces cerevisiae, there are multiple physiologically distinct MAP kinase activation pathways composed of structurally related kinases. The recently cloned vertebrate MAP kinase activators are structurally related to MAP kinase activators in these yeast pathways. These similarities suggest that homologous kinase cascades are utilized for signal transduction in many, if not all, eukaryotes. We have identified additional members of the MAP kinase activator family in Xenopus laevis by a polymerase chain reaction-based analysis of embryonic cDNAs. One of the clones identified (XMEK2) encodes a unique predicted protein kinase that is similar to the previously reported activator (MAPKK) in X. laevis. XMEK2, a highly expressed maternal mRNA, is developmentally regulated during embryogenesis and expressed in brain and muscle. Expression of XMEK2 in yeast cells suppressed the growth defect associated with loss of the yeast MAP kinase activator homologs, MKK1 and MKK2. Partial sequence of a second cDNA clone (XMEK3) identified yet another potential MAP kinase activator. The pattern of expression of XMEK3 is distinct from that of p42 MAPK and XMEK2. The high degree of amino acid sequence similarity of XMEK2, XMEK3, and MAPKK suggests that these three are related members of an amphibian family of protein kinases involved in the activation of MAP kinase. Discovery of this family suggests that multiple MAP kinase activation pathways similar to those in yeast cells exist in vertebrates.

B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP

1994 ◽  
Vol 14 (10) ◽  
pp. 6522-6530
Author(s):  
R R Vaillancourt ◽  
A M Gardner ◽  
G L Johnson
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Map Kinase ◽  
Protein Kinase A ◽  
Pc12 Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Camp Levels ◽  
Kinase A

Growth factor receptor tyrosine kinase regulation of the sequential phosphorylation reactions leading to mitogen-activated protein (MAP) kinase activation in PC12 cells has been investigated. In response to epidermal growth factor, nerve growth factor, and platelet-derived growth factor, B-Raf and Raf-1 are activated, phosphorylate recombinant kinase-inactive MEK-1, and activate wild-type MEK-1. MEK-1 is the dual-specificity protein kinase that selectively phosphorylates MAP kinase on tyrosine and threonine, resulting in MAP kinase activation. B-Raf and Raf-1 are growth factor-regulated Raf family members which regulate MEK-1 and MAP kinase activity in PC12 cells. Protein kinase A activation in response to elevated cyclic AMP (cAMP) levels inhibited B-Raf and Raf-1 stimulation in response to growth factors. Ras.GTP loading in response to epidermal growth factor, nerve growth factor, or platelet-derived growth factor was unaffected by protein kinase A activation. Even though elevated cAMP levels inhibited Raf activation, the growth factor activation of MEK-1 and MAP kinase was unaffected in PC12 cells. The results demonstrate that tyrosine kinase receptor activation of MEK-1 and MAP kinase in PC12 cells is regulated by B-Raf and Raf-1, whose activation is inhibited by protein kinase A, and MEK activators, whose activation is independent of cAMP regulation.

scholarly journals Selective activation of p42 mitogen-activated protein (MAP) kinase in murine B lymphoma cell lines by membrane immunoglobulin cross-linking. Evidence for protein kinase C-independent and -dependent mechanisms of activation

1992 ◽  
Vol 287 (1) ◽  
pp. 269-276 ◽  
Author(s):  
M R Gold ◽  
J S Sanghera ◽  
J Stewart ◽  
S L Pelech
Keyword(s):  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Cell Lines ◽  
Map Kinases ◽  
Phorbol Esters ◽  
Cross Linking ◽  
Kinase Activation ◽  
Membrane Immunoglobulin ◽  
Protein Map ◽  
Mitogen Activated Protein

Cross-linking of membrane immunoglobulin (mIg), the B lymphocyte antigen receptor, with anti-receptor antibodies stimulates tyrosine phosphorylation of a number of proteins, including one of 42 kDa. Proteins with a similar molecular mass are tyrosine-phosphorylated in response to receptor stimulation in other cell types and have been identified as serine/threonine kinases, termed mitogen-activated protein (MAP) kinases or extracellular signal-regulated kinases (ERKs). The MAP kinases constitute a family of related kinases, at least three of which have molecular masses of 40-45 kDa. In this paper we show that mIg cross-linking stimulated the myelin basic protein phosphotransferase activity characteristic of MAP kinase in both mature and immature murine B cell lines. This enzyme activity co-purified on three different columns with a 42 kDa protein that was tyrosine-phosphorylated (pp42) in response to mIg cross-linking and which reacted with a panel of anti-(MAP kinase) antibodies. Although immunoblotting with the anti-(MAP kinase) antibodies showed that these B cell lines expressed both 42 kDa and 44 kDa forms of MAP kinase, only the 42 kDa form was activated and tyrosine-phosphorylated to a significant extent. Activation of protein kinase C (PKC) with phorbol esters also resulted in selective tyrosine phosphorylation and activation of the 42 kDa MAP kinase. This suggested that mIg-induced MAP kinase activation could be due to stimulation of PKC by mIg. However, mIg-stimulated MAP kinase activation and pp42 tyrosine phosphorylation was only partially blocked by a PKC inhibitor, the staurosporine analogue Compound 3. In contrast, Compound 3 completely blocked the ability of phorbol esters to stimulate MAP kinase activity and induce tyrosine phosphorylation of pp42. Thus mIg may activate MAP kinase by both PKC-dependent and -independent mechanisms.

scholarly journals Novel members of the mitogen-activated protein kinase activator family in Xenopus laevis.

1993 ◽  
Vol 13 (9) ◽  
pp. 5738-5748 ◽  
Author(s):  
B M Yashar ◽  
C Kelley ◽  
K Yee ◽  
B Errede ◽  
L I Zon
Keyword(s):  
Protein Kinase ◽  
Xenopus Laevis ◽  
Map Kinase ◽  
Protein Kinases ◽  
Map Kinases ◽  
Yeast Cells ◽  
Amino Acid Sequence Similarity ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
Activation Pathways

Mitogen-activated protein (MAP) kinases comprise an evolutionarily conserved family of proteins that includes at least three vertebrate protein kinases (p42, p44, and p55 MAPK) and five yeast protein kinases (SPK1, MPK1, HOG1, FUS3, and KSS1). Members of this family are activated by a variety of extracellular agents that influence cellular proliferation and differentiation. In Saccharomyces cerevisiae, there are multiple physiologically distinct MAP kinase activation pathways composed of structurally related kinases. The recently cloned vertebrate MAP kinase activators are structurally related to MAP kinase activators in these yeast pathways. These similarities suggest that homologous kinase cascades are utilized for signal transduction in many, if not all, eukaryotes. We have identified additional members of the MAP kinase activator family in Xenopus laevis by a polymerase chain reaction-based analysis of embryonic cDNAs. One of the clones identified (XMEK2) encodes a unique predicted protein kinase that is similar to the previously reported activator (MAPKK) in X. laevis. XMEK2, a highly expressed maternal mRNA, is developmentally regulated during embryogenesis and expressed in brain and muscle. Expression of XMEK2 in yeast cells suppressed the growth defect associated with loss of the yeast MAP kinase activator homologs, MKK1 and MKK2. Partial sequence of a second cDNA clone (XMEK3) identified yet another potential MAP kinase activator. The pattern of expression of XMEK3 is distinct from that of p42 MAPK and XMEK2. The high degree of amino acid sequence similarity of XMEK2, XMEK3, and MAPKK suggests that these three are related members of an amphibian family of protein kinases involved in the activation of MAP kinase. Discovery of this family suggests that multiple MAP kinase activation pathways similar to those in yeast cells exist in vertebrates.

Signaling through JAM-1 and αvβ3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and αvβ3 complex

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2108-2114 ◽  
Author(s):  
Meghna U. Naik ◽  
Shaker A. Mousa ◽  
Charles A. Parkos ◽  
Ulhas P. Naik
Keyword(s):  
Endothelial Cell ◽  
Growth Factor ◽  
Map Kinase ◽  
Integrin Αvβ3 ◽  
Tube Formation ◽  
Cell Junctions ◽  
Kinase Activation ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Multistep Process

Abstract Growth factor–induced neovascularization has received a great deal of attention because it is fundamental to the growth and metastasis of solid tumors. This multistep process requires extensive signaling through growth factor receptors and integrins. Among the integrins involved in this process, integrin αvβ3 is specific to basic fibroblast growth factor (bFGF)–induced angiogenesis. Here we show that junctional adhesion molecule 1/A (JAM-1/A) and αvβ3 form a complex in the absence of bFGF. JAM-1, which is normally localized at the cell-cell junctions of quiescent endothelial cells, redistributes to the cell surface on bFGF treatment. Blockage of the extracellular domain of JAM-1 inhibits bFGF-induced endothelial cell morphology, proliferation, and angiogenesis. Additionally, mutation in the JAM-1 cytoplasmic domain blocks bFGF-induced mitogen-activated protein (MAP) kinase activation and ablates its ability to induce endothelial cell tube formation, suggesting that signaling through JAM-1 is key to bFGF-induced signaling. Immunoprecipitation analysis suggests that bFGF signaling dissociates the JAM-1/ αvβ3 complex, allowing for signaling through JAM-1 and αvβ3. In addition, blockage of either JAM-1 or αvβ3 inhibits bFGF-induced MAP kinase activation. Thus, our results suggest that signaling through JAM-1 and αvβ3 is necessary for bFGF-induced angiogenesis.

scholarly journals B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP.

1994 ◽  
Vol 14 (10) ◽  
pp. 6522-6530 ◽  
Author(s):  
R R Vaillancourt ◽  
A M Gardner ◽  
G L Johnson
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Map Kinase ◽  
Protein Kinase A ◽  
Pc12 Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Camp Levels ◽  
Kinase A

Growth factor receptor tyrosine kinase regulation of the sequential phosphorylation reactions leading to mitogen-activated protein (MAP) kinase activation in PC12 cells has been investigated. In response to epidermal growth factor, nerve growth factor, and platelet-derived growth factor, B-Raf and Raf-1 are activated, phosphorylate recombinant kinase-inactive MEK-1, and activate wild-type MEK-1. MEK-1 is the dual-specificity protein kinase that selectively phosphorylates MAP kinase on tyrosine and threonine, resulting in MAP kinase activation. B-Raf and Raf-1 are growth factor-regulated Raf family members which regulate MEK-1 and MAP kinase activity in PC12 cells. Protein kinase A activation in response to elevated cyclic AMP (cAMP) levels inhibited B-Raf and Raf-1 stimulation in response to growth factors. Ras.GTP loading in response to epidermal growth factor, nerve growth factor, or platelet-derived growth factor was unaffected by protein kinase A activation. Even though elevated cAMP levels inhibited Raf activation, the growth factor activation of MEK-1 and MAP kinase was unaffected in PC12 cells. The results demonstrate that tyrosine kinase receptor activation of MEK-1 and MAP kinase in PC12 cells is regulated by B-Raf and Raf-1, whose activation is inhibited by protein kinase A, and MEK activators, whose activation is independent of cAMP regulation.

p42/p44 MAP kinase activation is localized to caveolae-free membrane domains in airway smooth muscle

2007 ◽  
Vol 292 (5) ◽  
pp. L1163-L1172 ◽  
Author(s):  
Reinoud Gosens ◽  
Gordon Dueck ◽  
William T. Gerthoffer ◽  
Helmut Unruh ◽  
Johan Zaagsma ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Plasma Membrane ◽  
Growth Factor ◽  
Map Kinase ◽  
Membrane Domains ◽  
Kinase Activation ◽  
Caveolin 1 ◽  
Free Membrane ◽  
Kinase Phosphorylation

Caveolae are abundant plasma membrane invaginations in airway smooth muscle that may function as preorganized signalosomes by sequestering and regulating proteins that control cell proliferation, including receptor tyrosine kinases (RTKs) and their signaling effectors. We previously demonstrated, however, that p42/p44 MAP kinase, a critical effector for cell proliferation, does not colocalize with RTKs in caveolae of quiescent airway myocytes. Therefore, we investigated the subcellular sites of growth factor-induced MAP kinase activation. In quiescent myocytes, though epidermal growth factor receptor (EGFR) was almost exclusively found in caveolae, p42/p44 MAP kinase, Grb2, and Raf-1 were absent from these membrane domains. EGF induced concomitant phosphorylation of caveolin-1 and p42/p44 MAP kinase; however, EGF did not promote the localization of p42/p44 MAP kinase, Grb2, or Raf-1 to caveolae. Interestingly, stimulation of muscarinic M2 and M3 receptors that were enriched in caveolae-deficient membranes also induced p42/p44 MAP kinase phosphorylation, but this occurred in the absence of caveolin-1 phosphorylation. This suggests that the localization of receptors to caveolae and interaction with caveolin-1 is not directly required for p42/p44 MAP kinase phosphorylation. Furthermore, we found that EGF exposure induced rapid translocation of EGFR from caveolae to caveolae-free membranes. EGFR trafficking coincided temporally with EGFR and p42/p44 MAP kinase phosphorylation. Collectively, this indicates that although caveolae sequester some receptors associated with p42/p44 MAP kinase activation, the site of its activation is associated with caveolae-free membrane domains. This reveals that directed trafficking of plasma membrane EGFR is an essential element of signal transduction leading to p42/p44 MAP kinase activation.

scholarly journals Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA.

1994 ◽  
Vol 5 (4) ◽  
pp. 1074-1080
Author(s):  
Y Wang ◽  
J Pouysségur ◽  
M J Dunn
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Activity ◽  
Mesangial Cells ◽  
Chinese Hamster ◽  
Lung Fibroblasts ◽  
Protein Kinase Activity ◽  
Glomerular Mesangial Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.

Sign in / Sign up

Export Citation Format

Share Document