Regulation of membrane trafficking and signalling by clathrin light chain phosphorylation

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The Smythe lab is interested in the way in the way in which cells take up material from the external environment in the process of endocytosis. Material to be taken up is packaged into small spherical vesicles that bud into the cell from the cell surface. A protein coat on the inside of the cell surrounds the incoming vesicle and helps it to bud off. Clathrin is one of the major coat proteins and so the vesicles are named clathrin coated vesicles. These vesicles act as transport carriers and deliver material to another compartment within the cell called an endosome, which acts as a major cellular sorting station and either sends the material to be broken down in yet another intracellular compartment, the lysosome, or recycles it back to the cell surface. Clathrin helps vesicles to bud at a number of locations in the cell.The Mundell and Kelly labs study G protein-coupled receptors (GPCRs), which are proteins found on the plasma membrane that respond to a whole range of messages received from the environment. These include hormones, sensory stimuli such as odorants, neurotransmitters and drugs such as morphine. Because of the range of their biological roles, these receptors are major drug targets. When these receptors encounter a signal they respond to it by activating a variety of events within the cell. As part of this process they are also taken up or internalised into the cell by clathrin coated vesicles and there they may either be targeted for destruction in the lysosome (desensitization) or sent back to the cell surface where they can respond to further stimuli (resensitization). The activity of many proteins may be changed if phosphate is added to them in the process of phosphorylation and this is carried out by a group of cellular enzymes called kinases. The aim of this proposal is to understand how the role of clathrin is regulated by phosphorylation. Our recent studies have demonstrated the novel finding that a kinase that adds phosphate to some GPCRs also appears to phosphorylate clathrin. This may act as an address label for these particular GPCRs, sending them on a specific route within the cell. It is becoming increasingly clear that the intracellular routes followed by GPCRs and the rate at which they move along this route affects how they signal because often signals give rise to more than one output. For example in one situation a signal may cause a cell to move and, in another, to divide. We are interested in exploring how modifications of clathrin by phosphorylation may affect the rate of transport of signals. We expect this work to give us important information into how cells respond to signals and in the longer term it is possible that we will identify novel therapeutic targets.