Activation of STAT3 by the c-Fes Protein-tyrosine Kinase

Nelson, Kristie L.; Rogers, Jim; Bowman, Tammy; Jove, Richard; Smithgall, Thomas E.

doi:10.1074/jbc.273.12.7072

Cited by 69 publications

(60 citation statements)

References 33 publications

(37 reference statements)

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“…The most prominent example is v-Src that induces a constitutive activation of STAT3 in the absence of cytokine stimulations (Yu et al, 1995;Cao et al, 1996). PTK other than Src, such as Lck and v-Fps/Fes activate STAT3 and STAT5 in T cells and fibroblasts, respectively (Cirri et al, 1997;Nelson et al, 1998;Lund et al, 1999). In the mouse T-cell lymphoma cell line LYSTRA that overexpresses Lck, both DNA binding activities and tyrosine phosphorylation of STAT3 and STAT5, but not STAT1, are enhanced.…”

Section: Discussionmentioning

confidence: 99%

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

2006

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Engagement of the B-cell antigen receptor (BCR) initiated by the Src kinase Lyn triggers rapid signaling cascades, leading to proliferation, differentiation or growth arrest of B cells. The Janus kinase (JAK)-STAT (signal transducer and activator of transcription) pathway, activated through cytokine receptors, mediates similar responses. Hypothesizing that Src and JAK pathways engage in crosstalk in B-cell signaling, we studied wild-type and Lyn-null B-cell lines, which express BCR. We found that activated BCR results in tyrosine phosphorylation of JAK-STAT, which required Lyn. To confirm that STAT activation is not due to JAK, we cloned the chicken homologs of JAK1 and JAK2 and made their antisense constructs. In cells expressing antisense JAK1 and JAK2, tyrosine phosphorylation of STAT was not inhibited following BCR stimulation. Using activation loop-specific phosphotyrosine antibodies, we did not detect phospho-JAK1 and phospho-JAK2 after BCR stimulation. The JAK inhibitor AG490 did not inhibit the tyrosine phosphorylation of Lyn or STAT after BCR simulation. An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3. In an electrophoretic mobility shift assay, BCR stimulation led to enhanced DNA binding of the STAT3 in DT40, but not in the Lynnull cells. We conclude that BCR engagement activates the STAT pathway via Lyn, independent of JAK.

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Section: Discussionmentioning

confidence: 99%

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

2006

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“…Several other kinases have been implicated in the phosphorylation of STAT3, including members of the Src family (hck, src), Erb2, anaplastic lymphoma kinase, protein kinase C-␦, c-fes, and epidermal growth factor receptor (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). Whether any of these kinases are active in MM cells, and which of these kinases is activated by IL-6, is not fully known.…”

Section: Discussionmentioning

confidence: 99%

Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Bharti

Donato

Aggarwal

2003

The Journal of Immunology

478

304

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Numerous reports suggest that IL-6 promotes survival and proliferation of multiple myeloma (MM) cells through the phosphorylation of a cell signaling protein, STAT3. Thus, agents that suppress STAT3 phosphorylation have potential for the treatment of MM. In the present report, we demonstrate that curcumin (diferuloylmethane), a pharmacologically safe agent in humans, inhibited IL-6–induced STAT3 phosphorylation and consequent STAT3 nuclear translocation. Curcumin had no effect on STAT5 phosphorylation, but inhibited the IFN-α-induced STAT1 phosphorylation. The constitutive phosphorylation of STAT3 found in certain MM cells was also abrogated by treatment with curcumin. Curcumin-induced inhibition of STAT3 phosphorylation was reversible. Compared with AG490, a well-characterized Janus kinase 2 inhibitor, curcumin was a more rapid (30 min vs 8 h) and more potent (10 μM vs 100 μM) inhibitor of STAT3 phosphorylation. In a similar manner, the dose of curcumin completely suppressed proliferation of MM cells; the same dose of AG490 had no effect. In contrast, a cell-permeable STAT3 inhibitor peptide that can inhibit the STAT3 phosphorylation mediated by Src blocked the constitutive phosphorylation of STAT3 and also suppressed the growth of myeloma cells. TNF-α and lymphotoxin also induced the proliferation of MM cells, but through a mechanism independent of STAT3 phosphorylation. In addition, dexamethasone-resistant MM cells were found to be sensitive to curcumin. Overall, our results demonstrated that curcumin was a potent inhibitor of STAT3 phosphorylation, and this plays a role in the suppression of MM proliferation.

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“…Fes expression is su cient to induce di erentiation of K-562 myeloid leukemia cells (Cheng et al, 1999;Yu et al, 1989) and may be required for di erentiation and survival signaling in other myeloid cell lines (Manfredini et al, 1993(Manfredini et al, , 1997. We have observed that Fes strongly induces Stat3 activation following co-expression of the proteins in either 293T cells or using a baculovirus/Sf-9 cell system (Nelson et al, 1998). In addition, expression of constitutively active mutants of Fes is su cient to induce survival and di erentiation responses in the GM-CSF-dependent cell line, TF-1 (Cheng H and Smithgall TE, unpublished data).…”

Section: Stat Activation By Src Kinases In Myeloid Cell Survivalmentioning

confidence: 99%

Control of myeloid differentiation and survival by Stats

et al. 2000

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Hematopoiesis involves a complex array of growth factors that regulate the survival and proliferation of immature progenitors, in¯uence di erentiation commitment, and modulate end-stage cell functions. This minireview is focused on the role of Stat activation in the development of myeloid cells in response to hematopoietic cytokines. Much of the evidence implicating Stats in these cellular processes comes from studies of mutant cytokine receptors selectively uncoupled from Stat activation, dominant-inhibitory Stat mutants, and mice with targeted disruptions of Stat genes. Together these approaches provide strong evidence that Stat activation, particularly of Stat3 and Stat5, plays an important role in myeloid di erentiation and survival. Oncogene (2000) 19, 2612 ± 2618.Keywords: stat; cytokine; di erentiation; survival; tyrosine kinase Mutant cytokine receptors lacking Stat recruitment sites fail to induce di erentiation gp130-based receptor system IL-6 and the related cytokines LIF, CNTF, OSM, IL-11 and CT-1 share structural features and a ect an overlapping set of target cells . The receptors for the IL-6 family of cytokines share a signal transducing subunit known as gp130, which provides a link to multiple signaling pathways via a tyrosine phosphorylation-dependent mechanism. This familiar signaling paradigm, shared by all of the cytokine receptor systems discussed here, is initiated by liganddependent receptor oligomerization, activation of receptor-associated tyrosine kinases, and phosphorylation of speci®c tyrosine residues within the receptor. A subset of these receptor phosphotyrosines recruit cytoplasmic Stats through their SH2 domains. The Stats are then phosphorylated by receptor-associated kinases, inducing dimerization, nuclear translocation, and transcriptional activation at speci®c promoter elements. As described in more detail below, regions of gp130 required for myeloid di erentiation are often required for Stat activation.The cytoplasmic region of gp130 responsible for Stat3 activation is also required for di erentiation signaling in the murine leukemia cell line, M1 . Both IL-6 and LIF induce growth arrest and macrophage di erentiation in this cell line. To avoid the complication of signaling from endogenous gp130, chimeric receptors were constructed in which the cytoplasmic region of gp130 was fused to the extracellular ligand-binding domain of growth hormone. The resulting chimeric receptor generated growth hormone-dependent signals for growth arrest and morphological changes indistinguishable from those of IL-6. Successive C-terminal truncations of the chimeric receptor identi®ed the distal 133 residues of gp130 as critical for the generation of signals for growth arrest, macrophage di erentiation, and Stat3 activation. Phosphorylation of Tyr 126 in this region of gp130 forms a binding site for the Stat3 SH2 domain (Y P XXQ motif) (Stahl et al., 1995). Mutagenesis of this site completely blocked di erentiation signaling and Stat3 activation from the truncated receptor. However, mutagenes...

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Activation of STAT3 by the c-Fes Protein-tyrosine Kinase

Cited by 69 publications

References 33 publications

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Control of myeloid differentiation and survival by Stats

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