Signaling from microtubules to the actin cytoskeleton

Research project P 14007 Microtubule-actin signaling John-Victor SMALL 11.10.1999 The shape and -movement of cells on an extracellular matrix are dependent on the organisation and dynamic recycling of the actin cytoskeleton. In turn, the architecture of the actin cytoskeleton itself is strongly influenced by the type and pattern of contacts that the cell establishes with the underlying substrate since these contact assemblies couple directly into the actin network. This povital interplay between actin cytoskeleton turnover and substrate- contact dynamics is under the control of regulatory mechanisms at different levels, involving both extrinsic and intrinsic factors and which dictate marked differences in cell behaviour, in motility, growth and malignancy. In consequence, the mechanisms underlying the control of substrate contact dynamics and actin cytoskeleton architecture are the subject of intense and topical interest. Studies in the applicant`s laboratory have provided provocative indications that substrate contact dynamics is under the additional, site-directed control of microtubules. And, more recently, we have obtained evidence suggesting that this control operates by microtubules delivering local signals to reduce actin cytoskeleton contractility, on which substrate contact integrity depends. We aim here to throw more light on this process by: 1, using new methods to measure traction (reflecting contractility) at contact sites; 2, establishing the role of microtubule motors in signal transmission; and 3, probing for the putative signal transmitted along microtubules to contact assemblies. This project is of general significance, since it will contribute to the resolution of the long standing enigma of how microtubules control cell polarisation and directional motility.