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Signal Integration Mechanisms in Health and Disease

Research project P6/28 (Research action P6)

Persons :

Description :

Note: collaborating partners are indicated by the numbers assigned under “network composition” (P1-P7); EU1 refers to the European partner.

In this IAP, various aspects of the signal transduction machinery are studied: from the initial effects of biolipids [P2,P3], Ca2+ [P1,P2], IP3 [P1,P6] and TRP channels [P1,P2,P3,P6] to the regulation of the protein phosphorylation state in the cell [P2,P3,P4,P5,EU1] and its effect on protein-protein interaction [P4,P7,EU1], to finally, the regulation of the DNA transcription by covalent modifications [P2,P5,P6]. The major strengths of the proposed IAP network, is that [1] it covers an important part of the signal transduction process, each part of this process being explored by top research teams, [2] it has an very important technological backbone, including the best proteomic equipment currently available worldwide, making such a study feasible, and [3] the link with diseases is made without leaving the track of fundamental/basic research.

Partner 1 (F. Wuytack – K.U.Leuven: oordinator)
The role of Ca2+ and TRP in cellular signalling.

• Gating and modulation of TRP (transient receptor potential) channels by polyphosphoinositides, LPA, lipid kinases/phosphatases and protein kinases/phosphatases (collaborations: P2, P3, P6).
• Post-translational modifications of IP3 receptors and function in apoptosis. (collaboration: P2, P6)
• Functional and structural studies of Ca2+-transport ATPases (SERCA-type and SPCA-type) using genetically modified mice (collaboration: P2).

Partner 2 (E. Waelkens – K.U.Leuvenr)
Regulation of cell functions by post-translational modifications and bioactive lipids.

• Coordination of heritable gene silencing by histone methyltransferases, DNA-methyltransferases and protein phosphorylation (collaboration: P6).
• Signalling by bio-active lipids: development of inhibitors of autotaxin, a metastasis-enhancing lysophospholipase-D. This includes the mapping of lysophosphatidic acid (LPA) binding sites and the design and testing of LPA analogues/derivatives as candidate inhibitors (collaboration: P3).
• Regulation of protein phosphatase 2A (PP2A) by methylation, phosphorylation, Ca2+ and associated proteins (collaboration: P3, P4, EU1); consequences for the dephosphorylation of specific substrates (collaboration: P1, P5, EU1).
• Regulation of ion channels, IP3 receptors and Ca2+- transport ATPases by protein complexes that contain both protein kinases and protein phosphatases (collaboration: P1).

Partner 3 (J. Vandekerckhove – UGent)
Protein processing and phosphorylation as a result of pathogen-host cell interaction., Regulation of cell functions by lipids and methylglyoxal. Application of novel proteomics tools for studying processing by exogenous proteases.

• Analysis of the interaction between LPA and protein ligands, e.g. autotaxin, with the aim to design compounds able to inhibit proliferation and motility of cancer cells (collaboration: P2).
• The role of the glyoxalase system and of AMP-activated protein kinase (AMPK) in a novel signal transduction pathway for cell death by TNF (collaborations: P4 for delineation of the role of the AMPK; EUR1 for production of phospho-specific antibodies against glyoxalase I).
• Application of a peptide-centric proteomics technology here referred to as COFRADIC (COmbined FRActional DIagonal Chromatography) to study on a global, cellular scale protein processing events due to the action of exogenous proteases. Analysis of the targets and the proteases involved (several collaborations throughout the consortium).

Partner 4 (M. Rider – UCL)
The control of cell functions by the AMP-activated protein kinase (AMPK).

• The role of AMPK in the following processes :
- the control of smooth-muscle contraction by vasoconstrictors (collaboration: P1);
- the reorganization of the actin cytoskeleton (collaboration: P2, P3).
- leptin signalling (collaboration: P3)
• Search for new substrates of AMPK using proteomic and mass spectrometry techniques (collaboration: P2, P3).
• Identification and mapping of phosphorylation sites in HDAC7 (collaboration: P5).
• Study of the post-translational modifications of Gata-3 (Collaboration : P5).

Partner 5 (F. Dequiedt – FUSAGx)
Regulation of transcription by reversible covalent modifications of proteins.

• Regulation of histone deacetylase 7 by reversible phosphorylation during negative selection of T-cells; possible extension to other deacetylases (collaboration: P2, P3, P4).
• Regulation of the histone methyltransferase GLP by reversible phosphorylation (collaboration: P2, P3, P4, P6, P7).
• Acetylation of the transcription factor GATA-3 and its role in TH1/TH2 differentiation (collaboration: P4).

Partner 6 (F. Fuks – ULB)
Molecular mechanisms linking DNA methylation and histone modifications.

• Genome-wide analysis of gene silencing by DNA- and histone methyltransferases.
• Dynamics of targeting of DNA- and histone methyltranferases.
• Regulation of the DNA- and histone methyltranferases by post-translational modifications (collaboration: P2, P3, P4, P5).
• Study of the signalling pathways that impinge on DNA methylation (collaboration: P2).
• Functional implications of the deimination of DNA methyltransferases by peptidylarginine deiminase 4 (PADI4).

(C. Erneux – ULB)
Inositol phospholipids and inositol phosphates.

• The role and implication of inositol phospholipids and inositol phosphates in different models: relative expression and phosphorylation status of regulatory proteins (collaborations: P1, P2, P4).
• The implication of inositol-phosphate phosphatases and inositol kinases in Ca2+ signalling (collaboration: P1) with the specific hypothesis that regulators of the IP3 receptor also affect enzymes that metabolize inositol phosphates and lipids. One candidate is the IRBIT protein that binds to the IP3 receptor, and is available in pure form from P1.

Partner 7 (J. Tavernier – UGent)
Study of protein-protein interactions in intact cells. Signalling by the leptin receptor.

• Application of the two-hybrid MAPPIT technology to detect molecular interactions in intact cells (several collaborations throughout the consortium)
• Identification of the mechanisms that couple activated pathways (especially the PI 3-K and AMPK pathways) to the leptin receptor (collaboration: P4).
• The role of negative feedback regulation in leptin resistance (collaboration: P4).

Partner EU1 (S. Dilworth – Imperial College London)
Interaction of viral proteins with protein phosphatase 2A (PP2A).

• Production of monoclonal antibodies to study specific PP2A holoenzymes.
• Screening for PP2A substrates and modulators (collaborations: P2, P3,P4).
• Effects of viral oncoproteins on PP2A composition and substrate specificity (collaborations P2, P3).

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