The Recruitment of the Interleukin-1 (IL-1) Receptor-associated Kinase (IRAK) into Focal Adhesion Complexes Is Required for IL-1β-induced ERK Activation

MacGillivray, Mairi; Cruz, Tony F.; McCulloch, Christopher A.

doi:10.1074/jbc.m003186200

Cited by 66 publications

(83 citation statements)

References 65 publications

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“…1D), indicating that the endoplasmic reticulum is spatially associated with nascent focal adhesions. These experiments confirmed that the localized generation of focal adhesions on rounded cells was sufficient to restore responsiveness to IL-1 without inducing cell spreading (26) and showed that IL-1-induced Ca 2ϩ release from the endoplasmic reticulum is spatially associated with nascent focal adhesions.…”

Section: Fig 2 Shp-2 Is Required For Il-1-induced Cytosolic Casupporting

confidence: 70%

SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1

Wang

Downey

Herrera-Abreu

et al. 2005

Journal of Biological Chemistry

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Section: Fig 2 Shp-2 Is Required For Il-1-induced Cytosolic Casupporting

confidence: 70%

SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1

Wang

Downey

Herrera-Abreu

et al. 2005

Journal of Biological Chemistry

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“…tion by IL-1 consistent with studies demonstrating that IL-1RI and IRAK are recruited into focal adhesions (52,53). Ras may then activate a MAPKKK which would lead to activation of MKK3 and/or MKK6.…”

Section: Discussionsupporting

confidence: 65%

Ras Participates in the Activation of p38 MAPK by Interleukin-1 by Associating with IRAK, IRAK2, TRAF6, and TAK-1

Mc-Dermott¹,

O’Neill²

2002

Journal of Biological Chemistry

102

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Interleukin-1 (IL-1) activates p38 MAP kinase via the small G protein Ras, and this activity can be down-regulated by another small G protein Rap. Here we have further investigated the role of Ras and Rap in p38 MAPK activation by IL-1. Transient transfection of cells with constitutively active forms of the known IL-1 signaling components MyD88, IRAK, and TRAF-6, or the upstream kinases MKK6 and MKK3, activated p38 MAPK. Dominant negative forms of these were found to inhibit activation of p38 MAPK by IL-1. Dominant negative RasN17 blocked the effect of the active forms of all but MKK3 and MKK6, indicating that Ras lies downstream of TRAF-6 but upstream of MKK3 and MKK6 on the pathway. Furthermore, the activation of p38 MAPK caused by overexpressing active RasVHa could not be inhibited using dominant negative mutants of MyD88, IRAK, or IRAK-2, or TRAF6, but could be inhibited by dominant negative MKK3 or MKK6. In the same manner, the inhibitory effect of Rap on the activation of p38 by IL-1 occurred at a point downstream of MyD88, IRAK, and TRAF6, since the activation of p38 MAPK by these components was inhibited by overexpressing active Rap1AV12, while neither MKK3 nor MKK6 were affected. Active RasVHa associated with IRAK, IRAK2, and TRAF6, but not MyD88. In addition we found a role for TAK-1 in the activation of p38 MAPK by IL-1, with TAK-1 also associating with active Ras. Our study suggests that upon activation Ras becomes associated with IRAK, Traf-6, and TAK-1, possibly aiding the assembly of this multiprotein signaling complex required for p38 MAPK activation by IL-1.As a central proinflammatory mediator, interleukin 1 (IL-1)

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“…ERK activation by IL-1 has recently been shown to depend on establishment of focal adhesions (30), and it is possible that, in the mesangial cell study mentioned, culture conditions were suboptimal for formation of focal adhesion complexes. In this regard it is interesting that we observe maximal COX-2 induction by IL-1 in cells that are 2-3 wk postconfluent.…”

Section: Discussionmentioning

confidence: 99%

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

Mifflin¹,

Saada²,

Mari³

et al. 2002

American Journal of Physiology-Cell Physiology

130

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Elevated mucosal interleukin-1 (IL-1) levels are frequently seen during acute and chronic intestinal inflammation, and IL-1 neutralization lessens the severity of inflammation. One major effect of IL-1 is the increased release of eicosanoid mediators via induction of cyclooxygenase-2 (COX-2). One site of COX-2-derived prostaglandin synthesis during acute and chronic intestinal inflammation is the intestinal myofibroblast. COX-2 expression has also been documented in these cells in colonic neoplasms. Thus an understanding of the regulation of COX-2 expression in human intestinal myofibroblasts is important. As an initial step toward this goal we have characterized IL-1α signaling pathways that induce COX-2 expression in cultured human intestinal myofibroblasts. IL-1 treatment resulted in a dramatic transcriptional induction of COX-2 gene expression. Activation of nuclear factor-κB (NF-κB), extracellular signal-regulated protein kinase (ERK), p38, and protein kinase C (PKC) signaling pathways was each necessary for optimal COX-2 induction. In contrast to what occurs in other cell types, including other myofibroblasts such as renal mesangial cells, PKC inhibition did not prevent IL-1-induced NF-κB or mitogen activated protein kinase/ stress-activated protein kinase activation, suggesting a novel role for PKC isoforms during this process. The stimulatory effects of PKC, NF-κB, ERK-1/2, and presumably c-Jun NH2-terminal kinase activation were exerted at the transcriptional level, whereas p38 activation resulted in increased stability of the COX-2 message. We conclude that, in intestinal myofibroblasts, IL-1-mediated induction of COX-2 expression is a complex process that requires input from multiple signaling pathways. Each parallel pathway acts in relative autonomy, the sum of their actions culminating in a dramatic increase in COX-2 transcription and message stability.

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The Recruitment of the Interleukin-1 (IL-1) Receptor-associated Kinase (IRAK) into Focal Adhesion Complexes Is Required for IL-1β-induced ERK Activation

Cited by 66 publications

References 65 publications

SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1

SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1

Ras Participates in the Activation of p38 MAPK by Interleukin-1 by Associating with IRAK, IRAK2, TRAF6, and TAK-1

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

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