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NF-kappaB activating scaffold proteins as signaling molecules and putative therapeutic targets
Alain Chariot1, Marie-Alice Meuwis, Marianne Bonif
1Laboratory of Medical Chemistry and Human Genetics, Center for Cellular and Molecular Therapy, Pathology, CHU Sart-Tilman, 4000 Liège, Belgium. Alain.chariot@ulg.ac.be
Abstract:
Activation of transcription factors such as NF-kappa B occurs through signaling pathways involving sequential phosphorylation of a variety of substrates by distinct kinases. Proper assemby and activation of these kinases require interaction with non-enzymatic and essential partners named scaffold proteins. Here, we describe how the NF-kappa B activating scaffold proteins involved in the signaling pathways triggered by the pro-inflammatory cytokines TNF alpha, IL-1 beta and by the CD40 ligand play such roles. We also illustrate the human genetic diseases that are linked to mutations affecting genes coding for these proteins. We suggest that these scaffold proteins may be specifically targeted by novel therapeutical agents for the treatment of inflammation or cancers.
Insights
Scaffold proteins are essential for activating transcription factors like NF-kappa B. Targeting these proteins could offer new treatments for inflammatory diseases and cancers.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Transcription factor activation, such as for NF-kappa B, relies on complex signaling pathways.
- These pathways involve sequential protein phosphorylation by kinases.
- Kinase assembly and activation depend on non-enzymatic scaffold proteins.
Purpose of the Study:
- To elucidate the role of NF-kappa B activating scaffold proteins in pro-inflammatory cytokine signaling.
- To explore the connection between scaffold protein mutations and human genetic diseases.
- To propose scaffold proteins as therapeutic targets for inflammation and cancer.
Main Methods:
- Descriptive analysis of signaling pathways involving NF-kappa B.
- Review of literature on scaffold proteins and their interactions.
- Illustration of human genetic diseases linked to scaffold protein gene mutations.
Main Results:
- NF-kappa B activating scaffold proteins are crucial for signaling triggered by TNF alpha, IL-1 beta, and CD40 ligand.
- Mutations in genes encoding these scaffold proteins are associated with human genetic disorders.
- Scaffold proteins play a vital role in the proper assembly and activation of kinase signaling complexes.
Conclusions:
- Scaffold proteins are key regulators in inflammatory and immune signaling pathways.
- Genetic defects in scaffold proteins lead to human diseases.
- Targeting scaffold proteins presents a promising therapeutic strategy for inflammatory conditions and cancers.