Scaffolds: interaction platforms for cellular signalling circuits

Zeke, András; Lukács, Miklós; Lim, Wendell A.; Reményi, Attila

doi:10.1016/j.tcb.2009.05.007

Cited by 138 publications

(153 citation statements)

References 78 publications

(81 reference statements)

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“…The Pellino proteins are a family of E3 ubiquitin ligases characterized by their interaction with IRAK molecules downstream of TLR and IL-1R complexes (39). However, in contrast to the catalytic function described for Pellino proteins, classical signaling scaffolds typically do not possess enzyme activity and act primarily as specificity elements to control signaling between binding partners (40). In addition to binding IRAK, Pellino proteins also complex with TRAF6 and TAK1 (41).…”

Section: Discussionmentioning

confidence: 99%

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Dauphinee

Clayton

Hussainkhel

et al. 2013

The Journal of Immunology

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Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase β. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation.

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Section: Discussionmentioning

confidence: 99%

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Dauphinee

Clayton

Hussainkhel

et al. 2013

The Journal of Immunology

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“…Scaffolding proteins have been shown to act as molecular landing pads for metabolic enzymes, trans-membrane receptors and ion channels. 1 Specifically, scaffolding proteins can act by providing platforms in which multiple signaling molecules can assemble by coordinating feedback pathways, modulating the modification of its binding partners and coordinating localization of their substrates. 2 The importance of scaffolding proteins has been further underscored by the discovery that they play critical roles in immune response, mating and G-protein signaling.…”

Section: Rna Templating the Epigenomementioning

confidence: 99%

RNA templating the epigenome

2011

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C ellular pathways must be synergized, -controlled and organized to manage homeostasis. To achieve high selectivity within the crowded cellular milieu the cell utilizes scaffolding complexes whose role is to bring molecules in proximity thereby controlling and enhancing intermolecular interactions and signaling events. To date, scaffolds have been shown to be composed of proteinaceous units; however, recent evidence has supported the idea that non-coding RNAs may also play a similar role. In this Pointof-View article we discuss recent data on ncRNA scaffolds, with particular focus on ncRNA HOTAIR. Using our current knowledge of signaling networks we discuss the role that RNA may play in writing and regulating histone modifications and the information needed for correct gene expression. Further, we speculate on additional, yet undiscovered, roles that ncRNAs may be playing as molecular scaffolds.

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“…Scaffold proteins are important signal transducers that play specific roles by assembling multiple pathway members into functional modules [1,2]. However, the physiological roles of scaffold proteins have been poorly investigated due to a lack of catalytic activity and similarities with known functional domains identified by amino acid sequences [2].…”

Section: Introductionmentioning

confidence: 99%

“…However, the physiological roles of scaffold proteins have been poorly investigated due to a lack of catalytic activity and similarities with known functional domains identified by amino acid sequences [2]. Scaffold proteins of the Ras-extracellular signal-regulated kinase (ERK) pathway, such as kinase suppressor of ras (KSR) or Sur8, play important roles in the differential regulation of the Ras-ERK pathway [1][2][3]. Sur8 originally was identified as one of the genes that suppress the activated form of the EGL-15 fibroblast growth factor (FGF) receptor in Caenorhabditis elegans (C. elegans) [4].…”

Section: Introductionmentioning

confidence: 99%

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

Moon

Kim

et al. 2011

Stem Cells

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Sur8/Shoc2 is a scaffold protein that regulates the Rasextracellular signal-regulated kinase (ERK) pathway. However, the roles of Sur8 in cellular physiologies are poorly understood. In this study, Sur8 was severely repressed in the course of neural progenitor cell (NPC) differentiation in the cerebral cortex of developing rat embryos. Similarly, Sur8 was also critically reduced in cultured NPCs, which were induced differentiation by removal of basic fibroblast growth factor (bFGF). Sur8 regulation occurs at the protein level rather than at the mRNA level as revealed by both in situ hybridization and reverse transcriptase polymerase chain reaction analyses. The role of Sur8 in NPC differentiation was confirmed by lentivirus-mediated Sur8 knockdown, which resulted in increased differentiation, whereas exogenous expression of Sur8 inhibited differentiation. Contrastingly, NPC proliferation was promoted by overexpression, but was suppressed by Sur8 knockdown. The role of Sur8 as an antidifferentiation factor in the developing rat brain was confirmed by an ex vivo embryo culture system combined with the lentivirus-mediated Sur8 knockdown. The numbers and sizes of neurospheres were reduced, but neuronal outgrowth was enhanced by the Sur8 knockdown. The Ras-ERK pathway is involved in Sur8-mediated regulations of differentiation, as the treatment of ERK kinase (MEK) inhibitors blocks the effects of Sur8. The regulations of NPCs' differentiation and proliferation by the Ras-ERK pathway were also shown by the rescues of the effects of bFGF depletion, neuronal differentiation, and antiproliferation by epidermal growth factor. In summary, Sur8 is an antidifferentiation factor that stimulates proliferation for maintenance of self-renewal in NPCs via modulation of the Ras-ERK pathway. STEM CELLS 2011; 29:320-331 Disclosure of potential conflicts of interest is found at the end of this article.

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Scaffolds: interaction platforms for cellular signalling circuits

Cited by 138 publications

References 78 publications

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

RNA templating the epigenome

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

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