Evidence for a Role of Rho-like GTPases and Stress-activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK) in Transforming Growth Factor β-mediated Signaling

Atfi, Azeddine; Djelloul, Si Ham; Chastre, Eric; Davis, Roger J.; Gespach, Christian

doi:10.1074/jbc.272.3.1429

Cited by 265 publications

(224 citation statements)

References 39 publications

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“…Previous studies have shown a role of AP-1 in the regulation of TGF␤1 signaling and responsiveness. For example, dominant-negative forms of MEKK-1, JNK-1, and MKK-4 (an upstream activator of JNK) were shown to inhibit TGF␤1-induced gene expression (39)(40)(41). The mechanism involves, at least, Smad7 and Smad3.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

Baugé

Legendre

Leclercq

et al. 2007

Arthritis & Rheumatism

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Objective. Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1␤ (IL-1␤) and transforming growth factor ␤1 (TGF␤1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1␤ on TGF␤ receptor type II (TGF␤RII) regulation and TGF␤1 responsiveness in human articular chondrocytes.Methods. TGF␤1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (RSmad) phosphorylation, TGF␤ receptors, and Smad expression were determined by Western blotting and real-time reverse transcription-polymerase chain reaction techniques. Signaling pathways were investigated using specific inhibitors, messenger RNA (mRNA) silencing, and expression vectors.Results. IL-1␤ down-regulated TGF␤RII expression at both the protein and mRNA levels and led to inhibition of the TGF␤1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1␤ strongly stimulated the expression of inhibitory Smad7.TGF␤RII overexpression abolished the loss of TGF␤1 responsiveness induced by IL-1␤. The decrease in TGF␤RII required de novo protein synthesis and involved both the NF-B and JNK pathways.Conclusion. We demonstrate that IL-1␤ impairs TGF␤1 signaling through down-regulation of TGF␤RII, which is mediated by the p65/NF-B and activator protein 1/JNK pathways, and secondarily through the up-regulation of Smad7. These findings show that there is cross-talk in the signaling of 2 regulatory cytokines involved in inflammation.

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Section: Discussionmentioning

confidence: 99%

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

Baugé

Legendre

Leclercq

et al. 2007

Arthritis & Rheumatism

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“…It is equally interesting to note that TAK1 has been observed to mediate ceramide-activated MKK4-JNK activity (Shirakabe et al, 1997). The observation that Rho mediates TGFbstimulated activation of JNK is of signi®cance here (Afti et al, 1997). Since TGFb activation preferentially involves TAK1, it will be interesting to test whether Rho-activation of MKK4/JNK is speci®cally through TAK1.…”

Section: Map Kinase Kinase-4mentioning

confidence: 92%

Signaling by dual specificity kinases

1998

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Dual speci®city kinases that phosphorylate the Thr-and Tyr-residues within the TXY motif of MAP-kinases of play a central role in the regulation of various processes of cell growth. These dual speci®city kinases also known as MAP kinase kinases are constituents of the sequential kinase signaling modules. Seven distinct mammalian MAP kinases kinases have been identi®ed. Some of the unique signaling properties of these kinases are discussed here.

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“…Such scaffolding function allows MAP3K1 to organize a signaling complex to efficiently transmit the RhoA signal to the downstream MEK4-JNK pathway that is linked to the actin cytoskeleton. TGFβ may utilize such a mechanism to act through RhoA to control c-Jun phosphorylation and actin cytoskeleton (Atfi et al, 1997;Gallagher et al, 2004;Zhang et al, 2005). MAP3K1 can also interact with axin, mediating Wnt signal in JNK activation and planar polarity determination .…”

Section: Map3k1 In Ocular Surface Developmentmentioning

confidence: 99%