Linking Cell Cycle to Asymmetric Division: Aurora-A Phosphorylates the Par Complex to Regulate Numb Localization

Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
Cell (Impact Factor: 33.12). 11/2008; 135(1):161-73. DOI: 10.1016/j.cell.2008.07.049
Source: PubMed

ABSTRACT Drosophila neural precursor cells divide asymmetrically by segregating the Numb protein into one of the two daughter cells. Numb is uniformly cortical in interphase but assumes a polarized localization in mitosis. Here, we show that a phosphorylation cascade triggered by the activation of Aurora-A is responsible for the asymmetric localization of Numb in mitosis. Aurora-A phosphorylates Par-6, a regulatory subunit of atypical protein kinase C (aPKC). This activates aPKC, which initially phosphorylates Lethal (2) giant larvae (Lgl), a cytoskeletal protein that binds and inhibits aPKC during interphase. Phosphorylated Lgl is released from aPKC and thereby allows the PDZ domain protein Bazooka to enter the complex. This changes substrate specificity and allows aPKC to phosphorylate Numb and release the protein from one side of the cell cortex. Our data reveal a molecular mechanism for the asymmetric localization of Numb and show how cell polarity can be coupled to cell-cycle progression.

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    • "In Drosophila, SOP stem cells provide a well-studied biological example model of asymmetric stem cell division, see e.g. [25] [23] [24] and the references therein. "
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    ABSTRACT: During asymmetric stem cell division so-called cell-fate determinants are localised and become inherited into only one of the two daughter cells. In Drosophila SOP precursor cells, this biological mechanism is centred around the phosphorylation of a key protein call Lgl (Lethal giant larvae). In this paper, we present a surface-volume reaction diffusion system, which models the localisation of Lgl within the cell cytoplasm and on the cell cortex. We prove well-posedness of global solutions as well as regularity of the solutions. Moreover, we rigorously perform a fast reaction limit to a reduced quasi-steady-state approximation system, when phosphorylated Lgl is instantaneously expelled from the cortex.
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    • "Overexpression of Lgl partially rescues the slmb polarity phenotype Lgl might play a redundant role in the polarisation of the oocyte, since it localises to the posterior cortex and is a known antagonist of aPKC (Tian and Deng, 2008; Wirtz-Peitz et al., 2008). We examined the effects of overexpressing UAS-Lgl-GFP in slmb mutants. "
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    ABSTRACT: The Drosophila anterior-posterior axis is specified when the posterior follicle cells signal to polarise the oocyte, leading to the anterior/lateral localisation of the Par-6/aPKC complex and the posterior recruitment of Par-1, which induces a microtubule reorganisation that localises bicoid and oskar mRNAs. Here we show that oocyte polarity requires Slmb, the substrate specificity subunit of the SCF E3 ubiquitin ligase that targets proteins for degradation. The Par-6/aPKC complex is ectopically localised to the posterior of slmb mutant oocytes, and Par-1 and oskar mRNA are mislocalised. Slmb appears to play a related role in epithelial follicle cells, as large slmb mutant clones disrupt epithelial organisation, whereas small clones show an expansion of the apical domain, with increased accumulation of apical polarity factors at the apical cortex. The levels of aPKC and Par-6 are significantly increased in slmb mutants, whereas Baz is slightly reduced. Thus, Slmb may induce the polarisation of the anterior-posterior axis of the oocyte by targeting the Par-6/aPKC complex for degradation at the oocyte posterior. Consistent with this, overexpression of the aPKC antagonist Lgl strongly rescues the polarity defects of slmb mutant germline clones. The role of Slmb in oocyte polarity raises an intriguing parallel with C. elegans axis formation, in which PAR-2 excludes the anterior PAR complex from the posterior cortex to induce polarity, but its function can be substituted by overexpressing Lgl.
    Development 08/2014; 141(15):2984-92. DOI:10.1242/dev.109827 · 6.27 Impact Factor
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    • "Both Lgl (via protein interaction) and aPKC (via phosphoregulation ) promote the accumulation of regulators of GMC differentiation at the basal cortex [Ohshiro et al., 2000; Peng et al., 2000; Smith et al., 2007]. Many of the basal determinants can be phosphorylated by aPKC, which keeps them off the apical side of the cell [Betschinger et al., 2003; Smith et al., 2007; Wirtz-Peitz et al., 2008; Atwood and Prehoda, 2009]. Furthermore, the localization of several determinants, including Miranda and Numb, may be regulated by the actomyosin cytoskeleton either through cortical exclusion via active nonmuscle myosin or by active transport [Knoblich et al., 1997; Barros et al., 2003; Petritsch et al., 2003]. "
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    ABSTRACT: Crosstalk between the actin cytoskeleton and microtubules promotes symmetry break to polarize cells for division, shape changes and migration. These cellular events are crucial for forming tissues, and drive the metastasis of cancer cells. Rho GTPases mediate the formation of different types of F-actin that confer changes in cortical tension and contraction, and can also be regulated by microtubules. For example, central spindle microtubules of the mitotic spindle stimulate RhoA activity to form long, unbranched F-actin that is crosslinked by nonmuscle myosin to form the contractile ring in the equatorial plane of the cell. There is greater cortical tension in this area of the cell in comparison to the poles, where the formation of short, branched F-actin is favored. In migrating cells, growing microtubules that reach into the leading edge promote Rac activation and the formation of short, branched F-actin for lamellipodia formation. A common theme that is emerging in many fields is that feedback can also occur from the cortex to alter microtubule stability. In this manner cells can dynamically respond to intrinsic or extrinsic cues to ensure that their division plane is always coupled with the segregation of DNA and cell fate determinants, or that they migrate properly to form a tissue. © 2013 Wiley Periodicals, Inc.
    Cytoskeleton 10/2013; DOI:10.1002/cm.21150 · 3.01 Impact Factor
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