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Title: Identification and functional characterisation of the novel OCRL1 binding partners IPIP27A and B
Author: Noakes, Christopher
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2011
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Mutation of the inositol polyphosphate 5-phosphatase OCRL1 results in two disorders in humans, namely Lowe syndrome, characterized by ocular, nervous system and renal defects, and Type 2 Dent’s disease, in which only the renal symptoms are evident. The disease mechanisms of these syndromes are poorly understood. In an effort to better understand how Lowe syndrome is caused we have identified two novel OCRL1-binding proteins, termed inositol polyphosphate phosphatase interacting protein of 27kDa (IPIP27) A and B. IPIP27A and B bind to the C-terminal region of OCRL1 via a conserved motif that also binds the signaling adaptor protein APPL1. Both IPIP27A and B localise to early and recycling endosomes and the trans-Golgi network (TGN). We have studied the function of these proteins using a variety of techniques, including overexpression of wild type and mutant IPIP27 constructs and RNAi mediated depletion of endogenous IPIP27A/B in cell-based functional assays. Our studies show that IPIP27A/B are required for efficient receptor recycling from endosomes to the TGN and plasma membrane. In support of this hypothesis, we have now identified several IPIP27A interaction partners including the F-BAR domain protein PACSIN2, which is thought to deform membranes during formation of trafficking intermediates. Our results identify IPIP27A and B as key players in endocytic trafficking, and suggest that they function as scaffolding proteins required for the formation of transport carriers from endosomal and Golgi membranes. Together our results strongly suggest that defects in this process are responsible for pathology of Lowe syndrome and Dent’s disease.
Supervisor: Lowe, Martin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available