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: 32.24). 11/2008; 135(1):161-73. DOI: 10.1016/j.cell.2008.07.049
Source: PubMed


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 cell-biology, for instance, many phenomena are based on reaction-diffusion processes of proteins within the cell-body and on the cell cortex [21] [22]. Particular examples are systems modeling cell-biological signaling processes [16] or models for asymmetric stem cell division which describe the localization of so-called cell-fate determinants during mitosis [2] [20] [27]. "
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    DESCRIPTION: We consider the numerical solution of coupled volume-surface reaction-diffusion systems having a detailed balance equilibrium. Based on the conservation of mass, an appropriate quadratic entropy functional is identified and an entropy-entropy dissipation inequality is proven. This allows us to show exponential convergence to equilibrium by the entropy method. We then investigate the discretization of the system by a finite element method and an implicit time stepping scheme including the domain approximation by polyhedral meshes. Mass conservation and exponential convergence to equilibrium are established on the discrete level by arguments similar to those on the continuous level and we obtain estimates of optimal order for the discretization error which hold uniformly in time. Some numerical tests are presented to illustrate these theoretical results. The analysis and the numerical approximation are discussed in detail for a simple model problem. The basic arguments however apply also in a more general context. This is demonstrated by investigation of a particular volume-surface reaction-diffusion system arising as a mathematical model for asymmetric stem cell division.
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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.
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