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    Rac controls PIP5K localisation and PtdIns(4,5)P₂ synthesis, which modulates vinculin localisation and neurite dynamics.

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    Authors
    Halstead, J R
    Savaskan, N E
    Van den Bout, Iman
    Van Horck, F
    Hajdo-Milasinovic, A
    Snell, M
    Keune, Willem-Jan
    Ten Klooster, J P
    Hordijk, P L
    Divecha, Nullin
    Affiliation
    Division of Cell Biology, The Netherlands Cancer Institute Amsterdam, Amsterdam, 1066 CX, The Netherlands.
    Issue Date
    2010-10-15
    
    Metadata
    Show full item record
    Abstract
    In N1E-115 cells, neurite retraction induced by neurite remodelling factors such as lysophosphatidic acid, sphingosine 1-phosphate and semaphorin 3A require the activity of phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks). PIP5Ks synthesise the phosphoinositide lipid second messenger phosphatidylinositol(4,5)bisphosphate [PtdIns(4,5)P₂], and overexpression of active PIP5K is sufficient to induce neurite retraction in both N1E-115 cells and cerebellar granule neurones. However, how PIP5Ks are regulated or how they induce neurite retraction is not well defined. Here, we show that neurite retraction induced by PIP5Kβ is dependent on its interaction with the low molecular weight G protein Rac. We identified the interaction site between PIP5Kβ and Rac1 and generated a point mutant of PIP5Kβ that no longer interacts with endogenous Rac. Using this mutant, we show that Rac controls the plasma membrane localisation of PIP5Kβ and thereby the localised synthesis of PtdIns(4,5)P₂ required to induce neurite retraction. Mutation of this residue in other PIP5K isoforms also attenuates their ability to induce neurite retraction and to localise at the membrane. To clarify how increased levels of PtdIns(4,5)P₂ induce neurite retraction, we show that mutants of vinculin that are unable to interact with PtdIns(4,5)P₂, attenuate PIP5K- and LPA-induced neurite retraction. Our findings support a role for PtdIns(4,5)P₂ synthesis in the regulation of vinculin localisation at focal complexes and ultimately in the regulation of neurite dynamics.
    Citation
    Rac controls PIP5K localisation and PtdIns(4,5)P₂ synthesis, which modulates vinculin localisation and neurite dynamics. 2010, 123 (Pt 20):3535-46 J Cell Sci
    Journal
    Journal of Cell Science
    URI
    http://hdl.handle.net/10541/115715
    DOI
    10.1242/jcs.062679
    PubMed ID
    20841379
    Type
    Article
    Language
    en
    ISSN
    1477-9137
    ae974a485f413a2113503eed53cd6c53
    10.1242/jcs.062679
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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