PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody.

Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0310 Oslo, Norway.
Nature Cell Biology (Impact Factor: 20.06). 03/2010; 12(4):362-71. DOI: 10.1038/ncb2036
Source: PubMed

ABSTRACT Several subunits of the class III phosphatidylinositol-3-OH kinase (PI(3)K-III) complex are known as tumour suppressors. Here we uncover a function for this complex and its catalytic product phosphatidylinositol-3-phosphate (PtdIns(3)P) in cytokinesis. We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A. Depletion of the VPS34 or Beclin 1 subunits of PI(3)K-III causes cytokinesis arrest and an increased number of binucleate and multinucleate cells, in a similar manner to the depletion of FYVE-CENT, KIF13A or TTC19. These results provide a mechanism for the translocation and docking of a cytokinesis regulatory machinery at the midbody.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Phosphoinositides are low abundant but essential phospholipids in eukaryotic cells and refer to phosphatidylinositol and its seven polyphospho-derivatives. In this review, we summarize our current knowledge on phosphoinositides in multiple aspects of cell division in animal cells, including mitotic cell rounding, longitudinal cell elongation, cytokinesis furrow ingression, intercellular bridge abscission and post-cytokinesis events. PtdIns(4,5)P2 production plays critical roles in spindle orientation, mitotic cell shape and bridge stability after furrow ingression by recruiting force generator complexes and numerous cytoskeleton binding proteins. Later, PtdIns(4,5)P2 hydrolysis and PtdIns3P production are essential for normal cytokinesis abscission. Finally, emerging functions of PtdIns3P and likely PtdIns(4,5)P2 have recently been reported for midbody remnant clearance after abscission. We describe how the multiple functions of phosphoinositides in cell division reflect their distinct roles in local recruitment of protein complexes, membrane traffic and cytoskeleton remodeling. This article is part of a Special Issue entitled Phosphoinositides. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 11/2014; 1851(6). DOI:10.1016/j.bbalip.2014.10.013 · 4.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes—autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic product, the phosphorylated lipid phosphatidylinositol 3-phosphate (PtdIns3P). The activity of the catalytic subunit of the PI3K-III complex, the lipid-kinase VPS34, requires the presence of the membrane-targeting factor VPS15 as well as the adaptor protein Beclin 1. Furthermore, a growing list of regulatory proteins associates with VPS34 via Beclin 1. These accessory factors define distinct subunit compositions and thereby guide the PI3K-III complex to its different cellular and physiological roles. Here we discuss the regulation of the PI3K-III complex components by ubiquitination and SUMOylation. Especially Beclin 1 has emerged as a highly regulated protein, which can be modified with Lys11-, Lys48- or Lys63-linked polyubiquitin chains catalyzed by distinct E3 ligases from the RING-, HECT-, RBR- or Cullin-type. We also point out other cross-links of these ligases with autophagy in order to discuss how these data might be merged into a general concept.
    01/2015; 7(1):1-29. DOI:10.3390/cancers7010001
  • [Show abstract] [Hide abstract]
    ABSTRACT: The myotubularins are a family of phosphatases that dephosphorylate the phosphatidylinositols PI3P and PI3,5P. Several family members are mutated in disease, yet the biological functions of the majority of myotubularins remain unknown. To gain insight into the roles of the individual enzymes, we have used affinity purification coupled to mass spectrometry (AP-MS) to identify protein-protein interactions for the myotubularins. The myotubularin interactome comprises 66 high confidence (FDR ≤1%) interactions, including 18 pairwise interactions between individual myotubularins. The results reveal a number of potential signalling contexts for this family of enzymes, including an intriguing, novel role for MTMR3 and MTMR4 in the regulation of abscission, the final step of mitosis in which the membrane bridge remaining between two daughter cells is cleaved. Both depletion and overexpression of either MTMR3 or MTMR4 result in abnormal midbody morphology and cytokinesis failure. Interestingly, MTMR3 and MTMR4 do not exert their effects through lipid regulation at the midbody, but regulate abscission during early mitosis, by interacting with the mitotic kinase PLK1, and with CEP55, an important regulator of abscission. Structure-function analysis reveals that, consistent with known intramyotubularin interactions, MTMR3 and MTMR4 interact through their respective coiled coil domains. The interaction between MTMR3 and PLK1 relies on the divergent, non-lipid binding FYVE domain of MTMR3, and MTMR4 interacts with CEP55 through a short GPPXXXY motif, analogous to ESCRT-I components. Disruption of any of these interactions results in abscission failure, by disrupting the proper recruitment of CEP55, and subsequently, of ESCRT-I, to the midbody. Our data suggest that MTMR3 and MTMR4 may act as a bridge between CEP55 and PLK1, ensuring proper CEP55 phosphorylation and regulating CEP55 recruitment to the midbody. This work provides a novel role for MTMR3/4 heterodimers, and highlights the temporal and spatial complexity of the regulation of cytokinesis. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Molecular &amp Cellular Proteomics 02/2015; DOI:10.1074/mcp.M114.046086 · 7.25 Impact Factor