Activation of mitogen-activated protein kinase pathways by the granulocyte colony-stimulating factor receptor: mechanisms and functional consequences

10.2741/2085 ◽  
2007 ◽  
Vol 12 (1) ◽  
pp. 591 ◽  
Author(s):  
Tulene, S. Kendrick
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Mitogen Activated Protein ◽  
Functional Consequences ◽  
Stimulating Factor

scholarly journals FAS Ligand, Bcl-2, Granulocyte Colony-Stimulating Factor, and p38 Mitogen-Activated Protein Kinase

2000 ◽  
Vol 192 (5) ◽  
pp. 647-658 ◽  
Author(s):  
Andreas Villunger ◽  
Lorraine A. O'Reilly ◽  
Nils Holler ◽  
Jerry Adams ◽  
Andreas Strasser
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Mitogen Activated Protein Kinase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Drug Induced ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Stimulating Factor

The short life span of granulocytes, which limits many inflammatory responses, is thought to be influenced by the Bcl-2 protein family, death receptors such as CD95 (Fas/APO-1), stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), and proinflammatory cytokines like granulocyte colony-stimulating factor (G-CSF). To clarify the roles of these various regulators in granulocyte survival, we have investigated the spontaneous apoptosis of granulocytes in culture and that induced by Fas ligand or chemotherapeutic drugs, using cells from normal, CD95-deficient lpr, or vav-bcl-2 transgenic mice. CD95-induced apoptosis, which required receptor aggregation by recombinant Fas ligand or the membrane-bound ligand, was unaffected by G-CSF treatment or Bcl-2 overexpression. Conversely, spontaneous and drug-induced apoptosis occurred normally in lpr granulocytes but were suppressed by G-CSF treatment or Bcl-2 overexpression. Although activation of p38 MAPK has been implicated in granulocyte death, their apoptosis actually was markedly accelerated by specific inhibitors of this kinase. These results suggest that G-CSF promotes granulocyte survival largely through the Bcl-2–controlled pathway, whereas CD95 regulates a distinct pathway to apoptosis that is not required for either their spontaneous or drug-induced death. Moreover, p38 MAPK signaling contributes to granulocyte survival rather than their apoptosis.

scholarly journals Tyrosine 763 of the murine granulocyte colony-stimulating factor receptor mediates Ras-dependent activation of the JNK/SAPK mitogen-activated protein kinase pathway.

1997 ◽  
Vol 17 (3) ◽  
pp. 1170-1179 ◽  
Author(s):  
O Rausch ◽  
C J Marshall
Keyword(s):  
Amino Acids ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Ras Activation ◽  
Mitogen Activated Protein ◽  
Erk2 Activation ◽  
Stimulating Factor

The receptor for granulocyte colony-stimulating factor (G-CSF) can mediate differentiation and proliferation of hemopoietic cells. A proliferative signal is associated with activation of the ERK mitogen-activated protein kinase (MAPK) pathway. To determine whether other MAPK pathways are activated by G-CSF signalling, we have investigated activation of JNK/SAPK in cells proliferating in response to G-CSF. Here we show that G-CSF and interleukin-3 activate JNK/SAPK in two hemopoietic cell lines. The region of the G-CSF receptor required for G-CSF-induced JNK/SAPK activation is located within the C-terminal 68 amino acids of the cytoplasmic domain, which contains Tyr 763. Mutation of Tyr 763 to Phe completely blocks JNK/SAPK activation. However, the C-terminal 68 amino acids are not required for ERK2 activation. We show that activation of JNK/SAPK, like that of ERK2, is dependent on Ras but that higher levels of Ras-GTP are associated with activation of JNK/SAPK than with activation of ERK2. Two separate functional regions of the G-CSF receptor contribute to activation of Ras. The Y763F mutation reduces G-CSF-induced Ras activation from 30 to 35% Ras-GTP to 10 to 13% Ras-GTP. Low levels of Ras activation (10 to 13% Ras-GTP), which are sufficient for ERK2 activation, require only the 100 membrane-proximal amino acids. High levels of Ras-GTP provided by expression of oncogenic Ras are not sufficient to activate JNK/SAPK. An additional signal, also mediated by Tyr 763, is required for activation of JNK/SAPK.

scholarly journals Specific involvement of tyrosine 764 of human granulocyte colony- stimulating factor receptor in signal transduction mediated by p145/Shc/GRB2 or p90/GRB2 complexes

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 132-140 ◽  
Author(s):  
JP de Koning ◽  
AM Schelen ◽  
F Dong ◽  
C van Buitenen ◽  
BM Burgering ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Phosphorylation ◽  
Sh2 Domain ◽  
Mitogen Activated Protein Kinase ◽  
Terminal Deletion ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Tyrosine Residues ◽  
Mitogen Activated Protein ◽  
Stimulating Factor

Abstract Signal transduction from the granulocyte colony-stimulating factor receptor (G-CSF-R) occurs via multiple pathways, one of which involves activation of p21Ras and mitogen-activated protein kinase. The SH2 domain-containing proteins Shc and GRB2 have been implicated in this latter signaling route. We studied the role of these proteins in signal transduction from wild type (WT) G-CSF-R, C-terminal deletion mutants, and tyrosine-to-phenylalanine substitution mutants in transfectants of the mouse pro-B cell line, BAF3. G-CSF stimulation of BAF3 cells expressing WT G-CSF-R induced tyrosine phosphorylation of Shc. Anti-Shc antibodies co-immunoprecipitated tyrosine-phosphorylated 145-kD proteins (p145), whereas GRB2 immunoprecipitates contained phosphorylated Shc, Syp, and proteins of 145 and 90 kD (p90). Neither of these complexes were detected after activation of a C-terminal deletion mutant of G-CSF-R that lacked all four conserved cytoplasmic tyrosine residues. G-CSF induced formation of Syp/GRB2 complexes in all the tyrosine-substitution mutants, suggesting that this association did not depend on the presence of single specific tyrosine residues in G-CSF-R. In contrast, tyrosine 764 of G-CSF-R appeared to be exclusively required for tyrosine phosphorylation of Shc and its association with p145 and GRB2. In addition, tyrosine 764 also specifically mediated binding of GRB2 to p90 without the involvement of Shc. These findings indicate that tyrosine 764 of G-CSF-R has a prominent role in G-CSF signal transduction.

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