scholarly journals Structure of macrophage colony stimulating factor bound to FMS: Diverse signaling assemblies of class III receptor tyrosine kinases

2008 ◽  
Vol 105 (47) ◽  
pp. 18267-18272 ◽  
Author(s):  
X. Chen ◽  
H. Liu ◽  
P. J. Focia ◽  
A. H.-R. Shim ◽  
X. He
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Colony Stimulating Factor ◽  
Class Iii ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals β2-Integrins and Acquired Glycoprotein IIb/IIIa (GPIIb/IIIa) Receptors Cooperate in NF-κB Activation of Human Neutrophils

2007 ◽  
Vol 282 (38) ◽  
pp. 27960-27969 ◽  
Author(s):  
Birgit Salanova ◽  
Mira Choi ◽  
Susanne Rolle ◽  
Maren Wellner ◽  
Friedrich C. Luft ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Surface Expression ◽  
Human Neutrophils ◽  
Colony Stimulating Factor ◽  
Mobility Shift ◽  
Reverse Transcription Pcr ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Β2 Integrins

Microparticles from various cells are generated during inflammation. Platelet-derived microparticles (PMPs) harbor receptors that are not genuinely expressed by neutrophils. We tested whether or not functional glycoprotein IIb/IIIa (GPIIb/IIIa) receptors can be acquired by neutrophils via PMPs and whether these receptors participate in pro-inflammatory signaling. Surface expression was analyzed by flow cytometry and confocal microscopy. NF-κB activation was analyzed by Western blot experiments, electrophoretic mobility shift assays, and reverse transcription-PCR. Cell adhesion and spreading were estimated by myeloperoxidase assay and light microscopy. We found that PMPs transfer GPIIb/IIIa receptors to isolated and whole blood neutrophils via PMPs. We used specific antibodies in granulocyte macrophage colony-stimulating factor-treated neutrophils and observed that acquired GPIIb/IIIa receptors co-localized with β2-integrins and cooperated in NF-κB activation. We show that Src and Syk non-receptor tyrosine kinases, as well as the actin cytoskeleton, control NF-κB activation. In contrast to NF-κB, acquisition of GPIIb/IIIa receptors was not necessary to induce adhesion to fibronectin or phosphatidylinositol 3-kinase/Akt signaling. When granulocyte macrophage colony-stimulating factor-stimulated neutrophils were incubated on fibronectin, strong NF-κB activation was observed, but only after loading with PMPs. Blocking either β2-integrins or GPIIb/IIIa receptors abrogated this effect. Therapeutic GPIIb/IIIa inhibitors were similarly effective. The compounds also inhibited NF-κB-dependent tumor necrosis factor-α mRNA up-regulation. The data implicate GPIIb/IIIa receptors as new therapeutic targets in neutrophil-induced inflammation.

scholarly journals Tec and Jak2 Kinases Cooperate to Mediate Cytokine-Driven Activation of c-fos Transcription

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1496-1507 ◽  
Author(s):  
Yoshihiro Yamashita ◽  
Sumiko Watanabe ◽  
Akira Miyazato ◽  
Ken-ichi Ohya ◽  
Uichi Ikeda ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Tyrosine Kinases ◽  
Dominant Negative ◽  
Protein Tyrosine Kinases ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Dependent Cell ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Although transcriptional activation of the c-fosproto-oncogene plays an intrinsic role in the mechanism of blood cell growth, it is still obscure how protein-tyrosine kinases (PTKs) regulate the cytokine-driven c-fos activation pathway. We present here that Tec PTK is tyrosine-phosphorylated and activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation in a human GM-CSF–dependent cell line. Moreover, we could show that introduction of Tec into mouse BA/F3-hGMRαβ cells can profoundly activate the c-fos promoter in response to GM-CSF or to interleukin-3 (IL-3). In contrast, introduction of a kinase-deleted Tec could suppress cytokine-driven c-fos activation, indicating that Tec is directly involved in the regulation of c-fos transcription. Interestingly, strong activation by Tec of the c-fos promoter was blocked by the co-expression of dominant negative Jak2. The molecular interaction between Tec and Jak2 was then investigated both in mammalian and insect cell systems, revealing that they can not only bind to each other, but either of the two can phosphorylate the other. Thus, Tec and Jak2 can “cross-talk” in a complexed way to mediate cytokine-driven c-fos activation.

scholarly journals Contribution of both STAT and SRF/TCF to c-fos promoter activation by granulocyte-macrophage colony-stimulating factor

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 2906-2916 ◽  
Author(s):  
D Rajotte ◽  
HB Sadowski ◽  
A Haman ◽  
K Gopalbhai ◽  
S Meloche ◽  
...  
Keyword(s):  
Binding Site ◽  
Tyrosine Kinases ◽  
Cellular Response ◽  
Dominant Negative ◽  
Colony Stimulating Factor ◽  
Promoter Activation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that has been shown to support call proliferation in murine fibroblasts engineered to stably express both chains of the human GM-CSF receptor (NIH-GMR). Because the proto-oncogene c-fos is believed to provide a link between short-term signals elicited at the membrane and long-term cellular response, we chose to study the mechanism of GM-CSF-dependent cell regulation using c-fos promoter activity as a molecular marker in both NIH-GMR transfectants and in the CD34+ cell line TF-1. The importance of c-fos and related AP-1 activity in GM-CSF signalling was suggested by a tight correlation between GM-CSF-dependent activation of the c-fos promoter and cell proliferation and by the inhibitory effect of a trans-dominant c-fos mutant on cell growth. To evaluate the contribution of the serum response factor (SRF) associated with the ternary complex factor (TCF) and of STAT proteins to c-fos promoter activation in response to GM-CSF, the SRF binding site (SRE) and/or the STAT binding site (SIE) were inactivated. In serum-free medium, both SRE and SIE are essential to c-fos promoter activation by GM-CSF in NIH-GMR transfectants and in TF-1 cells. No response to GM-CSF was observed when both sites were mutated. The nature of the STAT family member was further investigated by Wester blots and DNA retardation assays using an SIE probe. Our data indicate that GM-CSF induced DNA binding of both STAT1 and STAT3 in NIH-GMR and mainly of STAT3 in TF-1 cells. STAT5 tyrosine phosphorylation was also observed in TF-1 cells. Finally, expression of a dominant negative MAPK mutant, ERK192A, resulted in a decrease of both SRE- and SIE-dependent activation of c-fos promoter by GM-CSF, suggesting that STAT1/3 are regulated not only by tyrosine kinases, but also partially by MAPK.

scholarly journals Tec and Jak2 Kinases Cooperate to Mediate Cytokine-Driven Activation of c-fos Transcription

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1496-1507 ◽  
Author(s):  
Yoshihiro Yamashita ◽  
Sumiko Watanabe ◽  
Akira Miyazato ◽  
Ken-ichi Ohya ◽  
Uichi Ikeda ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Tyrosine Kinases ◽  
Dominant Negative ◽  
Protein Tyrosine Kinases ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Dependent Cell ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Although transcriptional activation of the c-fosproto-oncogene plays an intrinsic role in the mechanism of blood cell growth, it is still obscure how protein-tyrosine kinases (PTKs) regulate the cytokine-driven c-fos activation pathway. We present here that Tec PTK is tyrosine-phosphorylated and activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation in a human GM-CSF–dependent cell line. Moreover, we could show that introduction of Tec into mouse BA/F3-hGMRαβ cells can profoundly activate the c-fos promoter in response to GM-CSF or to interleukin-3 (IL-3). In contrast, introduction of a kinase-deleted Tec could suppress cytokine-driven c-fos activation, indicating that Tec is directly involved in the regulation of c-fos transcription. Interestingly, strong activation by Tec of the c-fos promoter was blocked by the co-expression of dominant negative Jak2. The molecular interaction between Tec and Jak2 was then investigated both in mammalian and insect cell systems, revealing that they can not only bind to each other, but either of the two can phosphorylate the other. Thus, Tec and Jak2 can “cross-talk” in a complexed way to mediate cytokine-driven c-fos activation.

Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3127-3132 ◽  
Author(s):  
Andrea L. Dewar ◽  
Antony C. Cambareri ◽  
Andrew C. W. Zannettino ◽  
Bernadette L. Miller ◽  
Kathleen V. Doherty ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Kinase Domain ◽  
Colony Stimulating Factor ◽  
Atp Binding Site ◽  
Inflammatory Conditions ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Novel Target ◽  
Stimulating Factor

AbstractImatinib is a tyrosine kinase inhibitor that suppresses the growth of bcr-abl–expressing chronic myeloid leukemia (CML) progenitor cells by blockade of the adenosine triphosphate (ATP)–binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs). Although initially considered to have minimal effects of normal hematopoiesis, recent studies show that imatinib also inhibits the growth of some nonmalignant hematopoietic cells, including monocyte/macrophages. This inhibition could not be attributed to the known activity profile of imatinib. Here, we demonstrate for the first time that imatinib targets the macrophage colony-stimulating factor (M-CSF) receptor c-fms. Phosphorylation of c-fms was inhibited by therapeutic concentrations of imatinib, and this was not due to down-regulation in c-fms expression. Imatinib was also found to inhibit M-CSF–induced proliferation of a cytokine–dependent cell line, further supporting the hypothesis that imatinib affects the growth and development of monocyte and/or macrophages through inhibition of c-fms signaling. Importantly, these results identify an additional biologic target to those already defined for imatinib. Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions.

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