Biophysical Society Thematic Meeting | Ascona, Switzerland

Liposomes, Exosomes, and Virosomes: From Modeling Complex Membrane Processes to Medical Diagnostics and Drug Delivery

Monday Speaker Abstracts

The Interdependence of Vesicular Membrane Dynamics and Signal Processing Philippe Bastiaens . Max Planck Institute of Molecular Physiology, Systemic Cell Biology, Dortmund, Germany. Autocatalytic phosphorylation of receptor tyrosine kinases (RTKs) enables diverse, context- dependent responses to extracellular signals but comes at the price of autonomous, ligand- independent activation. Reactions in and on membranes play an important role in extracellular information processing by cells. The local concentration of signaling proteins is maintained by membrane dynamics to tightly control the qualitative response properties of signaling systems. In order to illuminate the relevance of this spatial dimension in signaling, I will describe how vesicular membrane dynamics control the autocatalytic activity of receptor tyrosine kinases such as EGFR and EphA2. Spontaneous RTK activation is suppressed by vesicular recycling and dephosphorylation by protein tyrosine phosphatases (PTPs) at the pericentriolar recycling endosome. This spatial segregation of catalytically superior PTPs from RTKs is essential to preserve ligand responsiveness of receptors at the plasma membrane. Ligand-induced clustering, on the other hand, promotes phosphorylation of c-Cbl docking sites and ubiquitination of the receptors, thereby redirecting them to the late endosome/lysosome. This switch from cyclic to unidirectional receptor trafficking thereby converts a continuous suppressive safeguard mechanism into a finite ligand-responsive signaling mode. By comparing the EGFR phosphorylation patterns upon siRNA-silencing and ectopic expression of PTPs using CA-FLIM we also identified which PTPs regulate EGFR phosphorylation when and where in the cell. EGFR phosphorylation patterns are regulated by the transit via endocytosis to different membrane compartments where the cytosolic phosphatase activity consists of different sets of PTPs. PTP localization thereby dictates when it interacts with the receptor. This spatially exerted control of PTPs on vesicular EGFR activity thereby shapes the finite response to growth factors.

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