The Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most recently identified death inducing ligands of the TNF cytokine family. TRAIL induces apoptosis in most cancer cells, whereas the majority of normal cells are resistant. TRAIL receptor agonists are therefore considered to be a promising anti-cancer therapeutic. However, because many cancer cells develop resistance to TRAIL, understanding the mechanisms by which resistance is acquired will be critical for the therapeutic use of TRAIL in cancer therapy. We have discovered that Activated Cdc42-associated kinase 1 (Ack1) is required for TRAIL induced apoptosis in human epithelial cells. Ack1 is a non- receptor tyrosine kinase with numerous protein-protein interaction domains, suggested to have a role in several cellular processes such as trafficking, endocytosis and cell motility. Knockdown of Ack1 in various epithelial cell lines leads to significantly impaired TRAIL induced apoptosis as evident by reduced cleavage of Caspase-8 and -3 and surface exposure of phosphatidylserine. Exploring the underlying mechanism we found that Ack1 knockdown leads to impaired TRAIL induced clustering of TRAIL-R1 and a reduction in the recruitment of Caspase-8 to the DISC complex, essential for death inducing signal transduction. Translocation of the TRAIL receptors to lipid rafts in the plasma membrane have been suggested to be crucial for TRAIL receptor dynamics and downstream signalling following TRAIL ligand binding. In this work we show that Ack1 is required for the translocation of the TRAIL receptors to the lipid rafts. In this thesis, a novel regulatory role of Ack1 in apoptosis, death receptor signalling and lipid raft trafficking is presented, contributing further to the understanding of the molecular regulation of TRAIL receptor signalling.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625936 |
| Date | January 2012 |
| Creators | Linderoth, E. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1369879/ |
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