Evidence for a Role of MSK1 in Transforming Growth Factor-β-mediated Responses through p38α and Smad Signaling Pathways

Abécassis, Lucile; Rogier, Edith; Vázquez, Aimé; Atfi, Azzedine; Bourgeade, Marie‐Françoise

doi:10.1074/jbc.m403294200

Cited by 41 publications

(34 citation statements)

References 20 publications

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“…This finding has been corroborated by in vivo studies in Xenopus (Pera et al, 2003). In addition, the p38 substrate MSK1 kinase regulates the transcriptional activity of Smad3 by promoting its association with the co-activator p300 (Abecassis et al, 2004). TGF-β-activated JNK can phosphorylate Smad3 and induce its nuclear translocation and transcriptional activity (Engel et al, 1999).…”

Section: Modulation Of Smad Activity By Non-smad Effectorssupporting

confidence: 58%

Non-Smad TGF-β signals

Moustakas

Heldin

2005

Journal of Cell Science

990

812

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During the past 10 years, it has been firmly established that Smad pathways are central mediators of signals from the receptors for transforming growth factor β (TGF-β) superfamily members to the nucleus. However, growing biochemical and developmental evidence supports the notion that alternative, non-Smad pathways also participate in TGF-β signalling. Non-Smad signalling proteins have three general mechanisms by which they contribute to physiological responses to TGF-β: (1) non-Smad signalling pathways directly modify (e.g. phosphorylate) the Smads and thus modulate the activity of the central effectors; (2) Smads directly interact and modulate the activity of other signalling proteins (e.g. kinases), thus transmitting signals to other pathways; and (3) the TGF-β receptors directly interact with or phosphorylate non-Smad proteins, thus initiating parallel signalling that cooperates with the Smad pathway in eliciting physiological responses. Thus, non-Smad signal transducers under the control of TGF-β provide quantitative regulation of the signalling pathway, and serve as nodes for crosstalk with other major signalling pathways, such as tyrosine kinase, G-protein-coupled or cytokine receptors.

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Section: Modulation Of Smad Activity By Non-smad Effectorssupporting

confidence: 58%

Non-Smad TGF-β signals

Moustakas

Heldin

2005

Journal of Cell Science

990

812

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“…Total cell lysates (10/30 mg), obtained as previously described (28), were subjected to SDS-PAGE, electrophoretically transferred into nitrocellulose membranes, and blotted using primary mAbs similar to those used for cytometric analysis or using actin antibody (Santa Cruz Biotechnology). Membranes were revealed with anti-mouse or anti-rabbit IgG horseradish peroxidase-linked antibodies and a chemiluminescence detection kit (ECL-Plus; GE-Healthcare); signals were quantified by using ImageJ software.…”

Section: Western Blotmentioning

confidence: 99%

FLT3-Mediated p38–MAPK Activation Participates in the Control of Megakaryopoiesis in Primary Myelofibrosis

et al. 2011

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Primary myelofibrosis (PMF) is characterized by increased number of hematopoietic progenitors and a dysmegakaryopoiesis which supports the stromal reaction defining this disease. We showed that increased ligand (FL) levels in plasma, hematopoietic progenitors, and stromal cells from PMF patients were associated with upregulation of the cognate Flt3 receptor on megakaryocytic (MK) cells. This connection prompted us to study a functional role for the FL/Flt3 couple in PMF dysmegakaryopoiesis, as a route to reveal insights into pathobiology and therapy in this disease.

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“…To assess whether TGF-h signaling was still intact in the presence of the truncated form of km23 (Dexon3-km23), we did TGF-h-dependent reporter assays in Mv1Lu cells. First, we tested the effect of either wt-km23 or Dexon3-km23 on TGF-h-inducible transcriptional activity of the p3TP-lux reporter, a TGF-h-regulated reporter frequently used to evaluate TGF-h signaling (13,21,22). This reporter construct contains three consecutive 12-O-tetradecanoylphorbol-13-acetate response elements and a TGF-h-inducible 100-bp fragment of the plasminogen activator inhibitor-1 promoter (13).…”

Section: Resultsmentioning

confidence: 99%

A Transforming Growth Factor-β Receptor–Interacting Protein Frequently Mutated in Human Ovarian Cancer

Ding¹,

Tang²,

Espina

et al. 2005

Cancer Research

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Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-B (TGF-B)-mediated growth inhibition. However, mutations in the TGF-B receptor I and receptor II (TbR-I and TbR-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-B-signaling components may play an important role in the loss of TGF-B responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-B receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (#exon3-km23), was found in 2 of 19 tumor tissues from patients with ovarian cancer. In addition to this alteration, a stop codon mutation (TAA ! CAC) was detected in two patients. This alteration results in an elongated protein, encoding 107-amino-acid residues (#107km23), instead of the wild-type 96-amino-acid form of km23. Furthermore, five missense mutations (T38I, S55G, T56S, I89V, and V90A) were detected in four patients, providing a total alteration rate of 42.1% (8 of 19 cases) in ovarian cancer. No km23 alterations were detected in 15 normal tissues. Such a high alteration rate in ovarian cancer suggests that km23 may play an important role in either TGF-B resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the #exon3-km23 and S55G/I89V-km23 mutants displayed a disruption in binding to the dynein intermediate chain in vivo, suggesting a defect in cargo recruitment to the dynein motor complex. In addition, the #exon3-km23 resulted in an inhibition of TGF-B-dependent transcriptional activation of both the p3TP-lux and activin responsive element reporters. Collectively, our results suggest that km23 alterations found in ovarian cancer patients result in altered dynein motor complex formation and/or aberrant transcriptional regulation by TGF-B. (Cancer Res 2005; 65(15): 6526-33)

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Evidence for a Role of MSK1 in Transforming Growth Factor-β-mediated Responses through p38α and Smad Signaling Pathways

Cited by 41 publications

References 20 publications

Non-Smad TGF-β signals

Non-Smad TGF-β signals

FLT3-Mediated p38–MAPK Activation Participates in the Control of Megakaryopoiesis in Primary Myelofibrosis

A Transforming Growth Factor-β Receptor–Interacting Protein Frequently Mutated in Human Ovarian Cancer

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