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Title: The cellular functions of mammalian type II phosphatidylinositol 4-kinases
Author: Alli-Balogun, Ganiyu Olabanji
ISNI:       0000 0004 7228 4452
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Type II phosphatidylinositol 4-kinases (PI4KIIs), PI4KIIα and PI4KIIβ, both catalyse phosphatidylinositol 4-phosphate (PI(4)P) synthesis and are implicated in the control of trafficking from the trans-Golgi network (TGN) and endosomal membranes. It has been suggested that these closely related isoforms perform redundant roles. This study addresses the issue of functional overlap, by studying the location of the PI(4)P pools synthesised by each isoform, the associated membrane trafficking routes and the functional consequences of loss of these PI4P pools. The TGN localisations of PI4KIIα and PI4KIIβ could be distinguished by co-immunostaining with TGN markers syntaxin 6 and TGN46, indicating that the isoforms localise to separate TGN domains. In addition, depletion of PI4KII isoforms using small interfering RNA (siRNA) had differential effects on TGN pools of PI(4)P, with PI4KIIα loss significantly affecting a syntaxin 6 positive PI(4)P pool while PI4KIIβ depletion altered a TGN46 positive pool; thus indicating the synthesis of metabolically separate PI(4)P pools by these two isoforms. Depletion of either PI4KII isoform also impaired post-TGN traffic of cation independent mannose 6-phosphate receptor (CI-M6PR) and the endo-lysosomal traffic and degradation of the EGF receptor which is suggestive of overlapping roles for both isoforms in post-TGN traffic. PI4KII gene silencing also had differential effects on the actin cytoskeleton. Loss of PI4KIIα led to increased stress fibre formation while PI4KIIβ depletion induced the formation of functional invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP). This was accompanied by decreased colocalization of MT1-MMP with the endosomal markers Rab5 and Rab7 that control lysosomal trafficking and regulate surface levels of MT1-MMP. However, MT1-MMP showed increased colocalisation with Rab8, which mediates exocytic trafficking and pro-invasive activity of MT1-MMP. In addition, depletion of PI4KIIβ conferred a migratory phenotype on minimally invasive HeLa and MCF-7 cell lines. This cell phenotype was substantiated by oncogenomic database analyses showing that loss of PI4KIIβ expression was a risk factor for numerous human carcinomas.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available