scholarly journals Phorbol 12-Myristate 13-Acetate-Induced Release of the Colony-Stimulating Factor 1 Receptor Cytoplasmic Domain into the Cytosol Involves Two Separate Cleavage Events

2004 ◽  
Vol 24 (1) ◽  
pp. 454-464 ◽  
Author(s):  
Kevin Wilhelmsen ◽  
Peter van der Geer
Keyword(s):  
Protein Tyrosine Kinase ◽  
Transmembrane Domain ◽  
Interleukin 2 ◽  
Extracellular Domain ◽  
Cytoplasmic Domain ◽  
Proteolytic Processing ◽  
Colony Stimulating Factor ◽  
Chimeric Receptors ◽  
Regulated Intramembrane Proteolysis ◽  
Stimulating Factor

ABSTRACT The colony-stimulating factor 1 (CSF-1) receptor is a protein-tyrosine kinase that regulates cell division, differentiation, and development. In response to phorbol 12-myristate 13-acetate (PMA), the CSF-1 receptor is subject to proteolytic processing. Use of chimeric receptors indicates that the CSF-1 receptor is cleaved at least two times, once in the extracellular domain and once in the transmembrane domain. Cleavage in the extracellular domain results in ectodomain shedding while the cytoplasmic domain remains associated with the membrane. Intramembrane cleavage depends on the sequence of the transmembrane domain and results in the release of the cytoplasmic domain. This process can be blocked by γ-secretase inhibitors. The cytoplasmic domain localizes partially to the nucleus, displays limited stability, and is degraded by the proteosome. CSF-1 receptors are continuously subject to down-modulation and regulated intramembrane proteolysis (RIP). RIP is stimulated by granulocyte-macrophage-CSF, CSF-1, interleukin-2 (IL-2), IL-4, lipopolysaccharide, and PMA and may provide the CSF-1 receptor with an additional mechanism for signal transduction.

scholarly journals Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3698-3704 ◽  
Author(s):  
SE Nicholson ◽  
U Novak ◽  
SF Ziegler ◽  
JE Layton
Keyword(s):  
Amino Acids ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Transmembrane Domain ◽  
Cytoplasmic Domain ◽  
Signaling Molecules ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Kinase Activation ◽  
Stimulating Factor

The protein tyrosine kinases JAK1 and JAK2 are phosphorylated tyrosine after the interaction of granulocyte colony-stimulating factor (G-CSF) with its transmembrane receptor. So too is Stat3, a member of the STAT family of transcriptional activators thought to be activated by the JAK kinases. Truncated G-CSF receptor (G-CSF-R) mutants were used to determine the different regions of the cytoplasmic domain necessary for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. We have shown that G-CSF-induced tyrosine phosphorylation and kinase activation of JAK2 requires the membrane proximal 57 amino acids of the cytoplasmic domain. In contrast, maximal Stat3 tyrosine phosphorylation required amino acids 96 to 183 of the G-CSF-R cytoplasmic domain, Stat3 DNA binding could occur with a receptor truncated 96 amino acids from the transmembrane domain and containing a single tyrosine residue, but was reduced in comparison with the full- length receptor. Together with the tyrosine phosphorylation of Stat3, this finding suggests that additional Stat3 does not appear to be required for proliferation. MAP kinase tyrosine phosphorylation correlated with both the proliferative response and JAK2 activation.

scholarly journals Transmembrane signaling of interleukin 2 receptor. Conformation and function of human interleukin 2 receptor (p55)/insulin receptor chimeric molecules.

1987 ◽  
Vol 166 (2) ◽  
pp. 362-375 ◽  
Author(s):  
M Hatakeyama ◽  
T Doi ◽  
T Kono ◽  
M Maruyama ◽  
S Minamoto ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Transmembrane Domain ◽  
Interleukin 2 ◽  
Cytoplasmic Domain ◽  
Chimeric Receptors ◽  
Interleukin 2 Receptor ◽  
Structural Conformation ◽  
Expression Studies ◽  
Human Insulin Receptor ◽  
And Function

Chimeric genes were constructed which gave rise to the expression of novel receptor molecules consisting of the extracellular domain of the human interleukin 2 receptor (IL-2-R; p55 or Tac antigen) joined to the transmembrane domain and either full-length or truncated cytoplasmic domain of the human insulin receptor (Ins-R). Expression studies using mouse T cell line EL-4 revealed that the chimeric receptors are able to manifest properties indistinguishable from the authentic IL-2-R. On the other hand, stimulation of the tyrosine kinase activity by IL-2 was not observed in the chimeric receptor with the entire cytoplasmic domain of the Ins-R. These findings thus shed light on the structural conformation and functioning of the IL-2-R complex.

scholarly journals NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene.

1990 ◽  
Vol 10 (3) ◽  
pp. 1281-1286 ◽  
Author(s):  
R Schreck ◽  
P A Baeuerle
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Interleukin 2 ◽  
Colony Stimulating Factor ◽  
Nf Kappa B ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The expression of the gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) is induced upon activation of T cells with phytohemagglutinin and active phorbolester and upon expression of tax1, a transactivating protein of the human T-cell leukemia virus type I. The same agents induce transcription from the interleukin-2 receptor alpha-chain and interleukin-2 genes, depending on promoter elements that bind the inducible transcription factor NF-kappa B (or an NF-kappa B-like factor). We therefore tested the possibility that the GM-CSF gene is also regulated by a cognate motif for the NF-kappa B transcription factor. A recent functional analysis by Miyatake et al. (S. Miyatake, M. Seiki, M. Yoshida, and K. Arai, Mol. Cell. Biol. 8:5581-5587, 1988) described a short promoter region in the GM-CSF gene that conferred strong inducibility by T-cell-activating signals and tax1, but no NF-kappa B-binding motifs were identified. Using electrophoretic mobility shift assays, we showed binding of purified human NF-kappa B and of the NF-kappa B activated in Jurkat T cells to an oligonucleotide comprising the GM-CSF promoter element responsible for mediating responsiveness to T-cell-activating signals and tax1. As shown by a methylation interference analysis and oligonucleotide competition experiments, purified NF-kappa B binds at positions -82 to -91 (GGGAACTACC) of the GM-CSF promoter sequence with an affinity similar to that with which it binds to the biologically functional kappa B motif in the beta interferon promoter (GGGAAATTCC). Two kappa B-like motifs at positions -98 to -108 of the GM-CSF promoter were also recognized but with much lower affinities. Our data provide strong evidence that the expression of the GM-CSF gene following T-cell activation is controlled by binding of the NF-kappa B transcription factor to a high-affinity binding site in the GM-CSF promoter.

scholarly journals Jak1 Plays an Essential Role for Receptor Phosphorylation and Stat Activation in Response to Granulocyte Colony-Stimulating Factor

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 597-604 ◽  
Author(s):  
Kazuya Shimoda ◽  
Jian Feng ◽  
Hiroshi Murakami ◽  
Shigekazu Nagata ◽  
Diane Watling ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Mutant Cell ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Receptor Phosphorylation ◽  
Signal Transducers ◽  
The Family ◽  
Proliferation And Differentiation ◽  
Stimulating Factor

Abstract The proliferation and differentiation of neutrophils is regulated by granulocyte-specific colony-stimulating factor (G-CSF ). G-CSF uses a receptor of the cytokine receptor superfamily and, in common with all members of the family, induces the tyrosine phosphorylation and activation of members of the Janus protein tyrosine kinase (Jak) family. In both myeloid cells and a human fibrosarcoma cell line expressing the G-CSF receptor, G-CSF induces the tyrosine phosphorylation and activation of Jak1, Jak2, and Tyk2. In addition, G-CSF induces the tyrosine phosphorylation of the receptor and members of the signal transducers and activators of transcription (Stat) family, including Stat3, as well as Stat1 and Stat5, depending on the cells involved. Using mutant cell lines lacking various Jaks, we show here that Jak1 is critical for G-CSF–mediated Stat activation, whereas Jak2 or Tyk2 are either not required or play redundant or ancillary roles. In the absence of Jak1, G-CSF induces activation of Jak2 and Tyk2, but fails to induce receptor tyrosine phosphorylation and induces dramatically reduced levels of Stat activation. A kinase-inactive Jak2, when overexpressed in cells lacking endogenous Jak2, can suppress Jak1 activation, receptor phosphorylation, and Stat activation, suggesting competition in the receptor complex either for Jak1 binding or substrates. Because the requirement for Jak1 is very similar to that previously shown for interleukin-6 signaling, the data support the concept that the G-CSF receptor and gp130 are both structurally and functionally similar.

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