The research of the group of Jan Willem Kok is aimed at understanding the functional role of membrane lipid rafts and the interactions of lipids and proteins therein. His group studies their main constituent’s sphingolipids and cholesterol in (patho-) physiological processes at the cellular level, in particular in relation to tumour and astrocyte cell biology. Among the proteins of interest are ATP-binding cassette transporters (ABC transporters) and the actin cytoskeleton.
Jan Willem Kok has a longstanding interest in sphingolipids and membrane cell biology, particularly lipid-protein interactions in membrane domains, and including membrane dynamics, trafficking and transport.
He obtained his PhD on ‘Lipid traffic in animal cells’ in 1991. He went on as Research fellow for the Royal Netherlands Academy of Arts and Sciences to combine the fields of lipid traffic and bioactivity of sphingolipids in the context of defence strategies of tumour cells.
As an assistant- (1998) and later associate Professor (2005) he focussed on the role of the membrane environment, lipid rafts and the actin cytoskeleton in ABC transporter modulation and multidrug resistance of tumour cells. Later he applied his expertise on membranes and ABC transporters to the field of astrocyte biology.
The 4-dimensional membrane: Dynamics of protein-lipid interactions in membrane domains
ABC transporters, such as MRP1, are known to confer multidrug resistance to tumour cells and are known to be expressed in the brain, including astrocytes. We have extensively studied MRP1 localization and function in various multidrug resistant human tumour cell lines. The role of sphingolipids, cholesterol and the actin cytoskeleton were investigated in-depth. This research effort resulted in a model for the localization of MRP1 in lipid rafts, which are stabilized by cortical actin.
The central working model in our research is depicted in the following diagrams:
Figure 1: MRP1 is kept in a specific membrane location (lipid rafts) by virtue of lateral interactions in the plane of the membrane with the raft-specific lipids cholesterol and sphingolipids, but also with raft-associated proteins. In addition, localization and stabilization of ABC transporters in a certain membrane area can be established by direct or indirect interactions with the (cortical) actin cytoskeleton, which forms a dense network underlying the plasma membrane and constitutes a transverse coupling system with respect to the plane of the membrane. Thus, the two axes of stabilization around the central lipid raft may together provide a 3D network for correct localization and optimal function of the ABC transporter.
Figure 2: The plasma membrane is viewed from the inside of the cell showing the inner face of the membrane. Three models are depicted. The ABC transporter is restricted in lateral movement by virtue of:
(A) Being in a lipid raft. The lipid raft is stabilized by the cortical actin cytoskeleton through the hypothetical protein RAL, which is linked to actin.
(B) Colliding with picket proteins that are linked to cortical actin and fence the corral in which the ABC transporter is temporarily contained;
(C) The collision of its cytoplasmic domain with cortical actin just underneath the plasma membrane, which forms a fence surrounding the corral in which the ABC transporter is temporarily contained.
RAL = Raft Actin Linker protein; APP = Anchored Protein Picket
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