Personal Scientific Overview
Cell-matrix adhesion: an essential contact for tissue morphogenesis
In multicellular organisms cells form adhesive contacts with other cells and with the extracellular matrix (ECM). The ECM is a meshwork of proteins that surrounds many cell types and serves a variety of functions, such as substrate for stable cell anchorage, a route for cell migration during development and a source of signals to the cells. In all of these processes membrane receptors link the extracellular ligands to the cortical cytoskeleton, enabling a continuous dynamic interaction between cell and ECM. A well-established family of ECM-receptors is the integrin family. The dual role of integrins as adhesion receptors and signal transducers have become one paradigm of how transmembrane proteins function and permit the communication of cells with their environment. In the context of the whole organism, integrins have an essential role in normal development by maintaining tissue integrity. In addition, defects in integrin adhesion cause a number of human diseases such as myopathies, immune disorders (e.g. leukocyte adhesion deficiency), blood clotting defects (e.g. Glanzmann thrombasthenia), skin blistering (e.g. epidermolysis bullosa), kidney degeneration, tumor angiogenesis and cancer metastasis.

Dissecting the function of integrin-associated protein complexes and the requirement of cytoskeleton
Following adhesion to the ECM, integrins cluster and recruit a large number of cytoplasmic proteins that form a link predominantly to actin cytoskeleton. Signalling proteins are also concentrated at sites of integrin adhesion, and it has been suggested that they are involved in the local remodelling of actin filaments and contribute in the intracellular signalling network. The in vivo molecular events required for cell-matrix adhesion, cytoskeleton organization and signal transmission are yet to be elucidated. A well established protein complex that links integrins to actin cytoskeleton and regulates the dynamic changes in cell shape is assembled around integrin-linked kinase (ILK). Currently my group is aimed at-understanding how the ILK-complex is assembled and what regulatory signals permit the linkage of actin filaments to the membrane. We address these questions following a variety of experimental approaches:

1. By constructing and modifying the genes encoding the proteins that interact with ILK and introducing the chimeric genes in the fly genome using standard transgenic techniques, it will be possible to characterise the in vivo function of individual proteins and protein domains.
2. By studing the spatiotemporal molecular organization and function of the ILK-containing complex and actin cytoskeleton in various tissues including muscle and developing epithelia will gain insight in the hierarchy of molecular interactions required for the assembly of the complex.
3. Using a complementary-biochemical approach we can examine the in vitro interactions of the mutated proteins and their effects in cell-culture model systems.