Rab25 is a small GTPase of the Rab11 family that is known to control endosomal trafficking and the return of internalised receptors to the plasma membrane. Recent reports that Rab25 can act as either a promoter or suppressor of tumourigenesis highlight the need for greater understanding of how it controls integrin trafficking. In this thesis I show data indicating that Rab25 permits the sorting of ligand-occupied, active conformation α5β1 integrin to late endosomes/lysosomes. Novel photoactivation and biochemical approaches show that integrins thus sorted are not degraded, but rapidly recycled from late endosomes/lysosomes to the plasma membrane. This requires the Chloride Intracellular Channel 3 (CLIC3); a protein resident in late endosomes/lysosomes of previously unknown function, that is upregulated in Rab25-expressing cells. Here I show that CLIC3 exists in close proximity with active α5β1 in late endosomes/lysosomes and is required for cancer cell invasion into fibronectin–containing three-dimensional matrices. Clinical data indicate that CLIC3 is expressed in ovarian cancers, pancreatic ductal adenocarcinoma (PDAC) and pancreatic intraepithelial neoplasea (PanIN), but is absent from normal pancreas and tumour-associated stroma.Moreover, Kaplan-Maier analyses demonstrate a strong correlation between high levels of CLIC3 (at both mRNA and protein levels) and poor prognosis in operable cases of PDAC. Taken together, the findings presented in this thesis identify CLIC3 both as a regulator and component of a novel vesicular transport route that returns lysosomally-targetted integrins to the plasma membrane, and as an independent prognostic indicator in pancreatic cancer.
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The role of the Chloride Intracellular Channel-3 (CLIC3) in integrin trafficking and tumour progression
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