title: Phosphatidylinositol 4-kinase IIβ negatively regulates invadopodia formation and suppresses an invasive cellular phenotype.
abstract: The type II phosphatidylinositol 4-kinase (PI4KII) enzymes synthesize the lipid phosphatidylinositol 4-phosphate (PI(4)P), which has been detected at the Golgi complex and endosomal compartments and recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear. We found that depletion of PI4KIIα and PI4KIIβ using small interfering RNA led to actin remodeling. Depletion of PI4KIIβ also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP). Depletion of PI4KII isoforms also differentially affected trans-Golgi network (TGN) pools of PI(4)P and post-TGN traffic. PI4KIIβ depletion caused increased MT1-MMP trafficking to invasive structures at the plasma membrane and was accompanied by reduced colocalization of MT1-MMP with membranes containing the endosomal markers Rab5 and Rab7 but increased localization with the exocytic Rab8. Depletion of PI4KIIβ was sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIβ mRNA are associated with human cancers. This finding supports the cell data and suggests that PI4KIIβ may be a clinically significant suppressor of invasion. We propose that PI4KIIβ synthesizes a pool of PI(4)P that maintains MT1-MMP traffic in the degradative pathway and suppresses the formation of invadopodia.
authors: Lipid and Membrane Biology Group, UCL Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, United Kingdom.
authors: Ganiyu Olabanji
authors: GO
authors: Alli-Balogun
authors: UCL Translational Research Office, London W1T 7JA, United Kingdom.
authors: Christina A
authors: CA
authors: Gewinner
authors: Lipid and Membrane Biology Group, UCL Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, United Kingdom.
authors: Ruth
authors: R
authors: Jacobs
authors: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom.
authors: Janos
authors: J
authors: Kriston-Vizi
authors: Lipid and Membrane Biology Group, UCL Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, United Kingdom.
authors: Mark G
authors: MG
authors: Waugh
authors: Lipid and Membrane Biology Group, UCL Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, United Kingdom s.minogue@ucl.ac.uk.
authors: Shane
authors: S
authors: Minogue
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D000069261:Podosomes / Q000201:enzymology*; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D015778:Minor Histocompatibility Antigens; D018129:Phosphatidylinositol Phosphates; D034741:RNA, Small Interfering; C037178:phosphatidylinositol 4-phosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D053511:Matrix Metalloproteinase 14