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Transmembrane transport and protein phosphorylation in steering cell function

Research project P4/23 (Research action P4)

Persons :

Description :

The aim of this research project is to get an integrated picture of control mechanisms and interactions between the various cell signalling and membrane transport systems.

Cell signalling relies notably on reversible protein phosphorylation and changes in ion currents and concentrations. There even exists a reciprocal control of protein phosphorylation by ions. The effector molecules in the pathways controlling cell function and homeostasis, e.g. protein kinases and phosphatases, elements of the cytoskeleton, membrane channels, membrane pumps (transport ATPases), exchangers and cotransporters, play a crucial role in normal cell function and pathological signalling.

The proposed project represents a multidisciplinary effort involving a network of laboratories and fostering collaboration between research groups internationally known for their competence in intracellular regulation and intercellular signalling. This collaboration forms a continuous basis for exchanging specific expertise, techniques, and new biological products. The network is composed of the following laboratoria :

1. One KUL group (Protein Phosphorylation) will focus on the signal transduction pathways controlled by protein phosphorylation. The aim is to assess structure-function relationships in protein kinases and phosphatases involved in these reactions and their effects at the level of the nucleus, cytosol, and membrane. Understanding their role and control, e.g. by sphingolipids, Ca2+, IP3..., in the cellular signal transduction should help shed new light on processes such as cell proliferation and cell transformation, involved in important and lethal diseases.

2. The UCL (FYSA) team will focus on membrane transport ATPases. Of these, the H+-ATPases (proton pumps) in the plasma membrane of plants and yeasts play an important role in controlling the internal pH and activating secondary transport. The team will concentrate on studying the structure and function of these enzymes, elucidating their regulation by nutrients and hormones at enzyme and gene level, and investigating their regulation by (de)phosphorylation. Another focus will be drug transport by another family of plasma membrane transport ATPases (yeast and plant).

3. One KUL team (Physiology) will study cell volume regulation and reaction of cells to mechanical stimuli. Volume regulation and reaction to mechanical stimuli are amongst the most primitive properties, but of vital importance for all cells. The signalling pathways involved in the cellular reaction to these stimuli occurs partially via phosphorylation, and partially via changes in intracellular Ca2+ concentration. Systems modulating the Ca2+ concentration comprise plasma membrane channels, IP3-controlled Ca2+-release channels and Ca2+-transport ATPases.

4. The UCL team (HORM) will study the metabolic adaptation of hepatocytes in response to volume changes. It will examine in detail the signalling pathways and interactions with the cytoskeleton.

5. The RUG team (Physiological Chemistry) will focus on the cytoskeleton, essential to cell structure, motility, and division. The signal transduction cascades, determined by phosphorylation, second messengers such as Ca2+ and phospholipids, are crucial for cellular structure and adaptation to intrinsic and environmental factors. The cytoskeleton is another integrating factor of growing importance in cellular physiology.

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