Recruitment of a Heparan Sulfate Subunit to the Interleukin-1 Receptor Complex

Vallés, Soraya L; Tsoi, Christina; Huang, Wenyan; Wyllie, David; Carlotti, Franco; Askari, Janet A.; Humphries, Martin J.; Dower, Steven K.; Qwarnström, Eva E.

doi:10.1074/jbc.274.29.20103

Cited by 16 publications

(39 citation statements)

References 73 publications

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“…We have reported previously that IL-1 receptors are localized to focal adhesions in cells attached to fibronectin and that IL-1 causes rapid phosphorylation of talin and transient changes in cytoskeletal organization (26,48,49). Further, recent data from our laboratory show that there is an attachment-mediated recruitment of a cell surface heparan sulfate to the IL-1 receptor complex, correlating with effects on signaling (29). We therefore speculate that box 3 is (part of) a site that mediates binding of IL-1RI to one or more focal adhesion or cytoskeletal components.…”

Section: Figmentioning

confidence: 64%

“…A recent report has shown that IRAK (Ϫ/Ϫ) cells reconstituted by transfection with a kinase (Ϫ) IRAK mutant respond to IL-1 and that in these cells IRAK is phosphorylated in response to IL-1 (27). Indeed it has been suggested that the kinase activity of IRAK-1 and IRAK-2 is not required for IL-1 signaling (29). These data suggest that there is at least one protein kinase other than IRAK-1 or IRAK-2, possibly IRAK-M, associated with the IL-1 receptor complex, and which by inference participates in IL-1 signaling (46).…”

Section: Figmentioning

confidence: 99%

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Identification of Two Major Sites in the Type I Interleukin-1 Receptor Cytoplasmic Region Responsible for Coupling to Pro-inflammatory Signaling Pathways

Slack¹,

Schooley²,

Bonnert³

et al. 2000

Journal of Biological Chemistry

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277

168

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Type I interleukin-1 receptor is the prototype for a family of proteins, which play a central role in early responses to injury and infection. The similarity of function across the family is reflected in similarity in signaling: all members tested couple to activation of NFB and stress kinases. The coupling to these pathways is mediated by a 200-residue intracellular domain (the Toll/ interleukin-1 receptor domain), in which sequence conservation is primarily confined to three short motifs (boxes 1, 2, and 3) located at amino acid residue positions 10 (box 1), 60 (box 2), and 170 (box 3). We have analyzed the contribution of these motifs to function by alanine scanning mutagenesis of the human interleukin-1 receptor type I. Mutant receptors were tested for expression, ligand binding, activation of receptor-associated kinase(s), NFB, stress kinases, and transcription. Mutations in all three motifs led to low cell surface expression. Mutants in box 3 were, however, wild type for signaling, whereas mutants in boxes 1 and 2 were defective. We conclude that the conserved motifs box 1 and box 2 mediate the coupling of molecules in the family to inflammation signaling pathways.

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Section: Figmentioning

confidence: 64%

Section: Figmentioning

confidence: 99%

Identification of Two Major Sites in the Type I Interleukin-1 Receptor Cytoplasmic Region Responsible for Coupling to Pro-inflammatory Signaling Pathways

Slack¹,

Schooley²,

Bonnert³

et al. 2000

Journal of Biological Chemistry

Self Cite

277

168

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“…This likely involves receptor-associated regulators of the GTPases such as the putative Rap/GTPase activating protein (GAP), IIP-1 (38). Furthermore, the attachment dependence suggests that activation could be induced as a consequence of recruitment of the matrix-dependent, accessory receptor component to the IL-1 receptor complex (17) and thus result from co-regulation through integrin mediated activities. Such effects could be induced following selective activation of signaling components by structural events, as suggested by our data demonstrating specificity for the activities mediated through receptor-associated proteins MyD88 and TRAF6.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of IL-1 receptors are located at focal adhesions (16), and matrix attachment results in alterations in IL-1 receptor function (17). Subsequent IL-1-induced signal transduction and gene activation are regulated by cell attachment and the cytoskeleton (18 -20).…”

mentioning

confidence: 99%

Ras Controls Tumor Necrosis Factor Receptor-associated Factor (TRAF)6-dependent Induction of Nuclear Factor-κB

Caunt

Kiss-Tóth

Carlotti

et al. 2001

Journal of Biological Chemistry

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In the present study, we show that Ras activity differentially controls interleukin ( Cellular responses to cytokines and growth factors are influenced by the extracellular milieu (1). These regulatory effects are mediated to a large extent by receptors of the integrin family and involve modulation of signaling pathways that link receptor activation and changes in cell shape, the cytoskeleton, and gene expression (2, 3). Ras acts cooperatively and/or hierarchically with the Rho subfamily of guanine nucleotide triphosphatases (GTPases) to regulate focal adhesion and polymerized actin turnover (4). It is thought to be in their arrangement of signaling proteins and receptors via the cytoskeleton that the GTPases are able to channel a diverse range of stimuli, from growth factor and cytokines to cell attachment, into common downstream signaling cascades (5) such as the stress-activated protein kinase (6, 7) and nuclear factor-B (NF-B) 1 pathways (8, 9). The membrane proximal molecular events that take place following interleukin-1 receptor (IL-1R) binding and leading to transcription factor activation involves initially the heterodimerization of the IL-1R with accessory protein (IL-1RAcP) (10), followed by binding of the adaptor protein MyD88 (11). MyD88 in turn recruits the Ser/Thr kinases: IL-1R associated kinase (IRAK) 1, IRAK-2, and IRAK-3 or M (11-13), which have recently been shown to be pre-associated with a further adaptor protein, Tollip (14). Subsequently, the IL-1R associated kinase 1s are freed and interact with the tumor necrosis factor receptor-associated factor (TRAF) 6, followed by activation of the stress-activated protein kinase and NF-B pathways (15).The majority of IL-1 receptors are located at focal adhesions (16), and matrix attachment results in alterations in IL-1 receptor function (17). Subsequent IL-1-induced signal transduction and gene activation are regulated by cell attachment and the cytoskeleton (18 -20). Early alterations following IL-1 receptor binding in adherent cells include a rapid and transient phosphorylation of transmembrane linkage protein Talin and changes in the cytoskeleton (21), suggesting an immediate effect on the turnover of structural components at these sites. Aspects of Ras, Rho, Rac, and Cdc42 involvement in downstream IL-1 signaling pathways have recently been elucidated (22-25), suggesting they play a part in mediating these structural changes localized around the receptor complex. This may underpin the, as yet, unclear mechanism by which the GTPases interact with members of the classical IL-1 signaling cascade. So far, however, little is still known of how these effects are initiated, and how they may modulate IL-1 signaling and influence downstream cascades.

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“…Earlier studies have documented pronounced effects of PDGF on type I IL-1 receptor levels (Bonin and Singh, 1988). We have recently demonstrated that matrixinduced enhancement of inflammatory responses cor-relates with recruitment of an attachment-dependent IL-1 receptor complex component, constituting a heparan sulfate (Valles et al, 1999). This study investigates the role of PDGF in regulation of this novel IL-1 receptor component in SMCs.…”

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confidence: 99%

PDGF Enhancement of IL-1 Receptor Levels in Smooth Muscle Cells Involves Induction of an Attachment-Regulated, Heparan Sulfate Binding Site (IL-1RIII)

Valles

Caunt

Walker

et al. 2002

Laboratory Investigation

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SUMMARY:This study shows that increase in IL-1 receptor levels by platelet derived growth factor (PDGF) involves an enhancement of a matrix-dependent, low-affinity receptor that constitutes a heparan sulfate. Fibronectin attachment caused pronounced alterations in IL-1 receptor function in smooth muscle cells, involving a pronounced increase in cell surface binding from an average of 2,000 up to approximately 8,000 receptors/cell and an increase in affinity (K a ) of the type I receptor from 1.8 Ϯ 0.9 ϫ 10 9 to 3.7 Ϯ 0.5 ϫ 10 9 M Ϫ1 . PDGF stimulation similarly enhanced the level of cell surface binding by between 30% and 100%, with, in general, less effect on cells plated on fibronectin. Further, PDGF had a pronounced effect on the type I receptor affinity in the absence of matrix attachment, increasing the K a from 1.77 Ϯ 0.93 ϫ 10 9 to 5.1 Ϯ 2.1 ϫ 10 9 M Ϫ1 . Scatchard analyses revealed that PDGF, similarly to fibronectin attachment, caused enhancement of a second low-affinity binding site. Antibody blocking showed that approximately 50% of the attachment-induced increase was independent of type I receptor binding. Further, a similar fraction of the cell surface interaction was blocked by soluble heparan sulfate and dependent on cell binding to the heparan binding site. Cross-linking demonstrated that, in addition to the type I receptor, IL-1 bound to a second high molecular weight complex of 300 kd, induced by fibronectin attachment as well as by PDGF in the absence of matrix. Biochemical analyses demonstrated that this second site constitutes a heparan sulfate, which directly interacted with the type I receptor after recruitment to the complex, and which bound up to 50% and 25% of the ligand after fibronectin attachment and PDGF stimulation, respectively. The data show that PDGF induces an attachment-regulated low-affinity IL-1 binding site in smooth muscle cells, constituting a heparan sulfate. Correlation of the recruitment of this component to the IL-1 receptor complex with structural regulation of receptor function and enhancement of IL-1-mediated responses suggests that this is a significant mechanism in PDGF augmentation of local inflammatory responses during vessel wall pathogenesis. (Lab Invest 2002, 82:855-862).D evelopment of atherosclerosis has the hallmark of a response to injury, with a significant inflammatory component (Ross, 1993). During this process, smooth muscle cell (SMC) proliferation and migration are mainly regulated by platelet-derived growth factor (PDGF) secreted by activated macrophages (Bornfeldt et al, 1995;Heldin and Westermark, 1990;Raines and Ross, 1993). Further, IL-1, also a macrophage product, induces PDGF secretion from SMCs, thus activating proliferation via an autocrine loop (Dower et al, 1990;Raines et al, 1989). IL-1 also plays a direct role in the development of the disease by affecting the metabolism of extracellular matrix components (Wight, 1995). Many of the regulatory events are mediated through IL-1 induction of NF-B, a pathway strongly activated in SMCs durin...

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Recruitment of a Heparan Sulfate Subunit to the Interleukin-1 Receptor Complex

Cited by 16 publications

References 73 publications

Identification of Two Major Sites in the Type I Interleukin-1 Receptor Cytoplasmic Region Responsible for Coupling to Pro-inflammatory Signaling Pathways

Identification of Two Major Sites in the Type I Interleukin-1 Receptor Cytoplasmic Region Responsible for Coupling to Pro-inflammatory Signaling Pathways

Ras Controls Tumor Necrosis Factor Receptor-associated Factor (TRAF)6-dependent Induction of Nuclear Factor-κB

PDGF Enhancement of IL-1 Receptor Levels in Smooth Muscle Cells Involves Induction of an Attachment-Regulated, Heparan Sulfate Binding Site (IL-1RIII)

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