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Frederik Wirtz-Peitz, Takashi Nishimura and Juergen A. Knoblich Cell , 136, 161-173, 2008

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Frederik Wirtz-Peitz, Takashi Nishimura and Juergen A. Knoblich Cell , 136, 161-173, 2008 - PowerPoint PPT Presentation


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Linking Cell Cycle to Asymmteric Division: Aurora-A phosphorylates the Par Complex to Regulate Numb Localization. Frederik Wirtz-Peitz, Takashi Nishimura and Juergen A. Knoblich Cell , 136, 161-173, 2008. Asymmetric cell division. Cells divide into two daughters of different fates

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Linking Cell Cycle to Asymmteric Division: Aurora-A phosphorylates the Par Complex to Regulate Numb Localization

Frederik Wirtz-Peitz, Takashi Nishimura and Juergen A. Knoblich

Cell, 136, 161-173, 2008

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Asymmetric cell division

  • Cells divide into two daughters of different fates
  • Extrinsic and intrinsic regulation of asymmetric cell division
  • Cells segregate cell fate determinants  Numb
  • Drosophila larvael brain: balances differentiation /self renewal

Introduction

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The cell fate determinant Numb

  • Controls integrin endocytosis
  • Repressor of Notch signaling
  • Cell fate determinant in asymmetric cell division

 numb mutant neuroblasts divide symmetrically into two neuroblasts (Lee et al., 2006)

Par complex provides spatial cue for Numb localization:

  • Phosphorylation by aPKC releases Numb into the cytoplasm

 Numb and aPKC localize to opposite sites of the dividing cell

www.biologie.ens.fr/desnpcs/IMG/jpg_fig2.jpg

Introduction

Introduction

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Molecular mechanism for asymmetric localization of Numb during mitosis?

  • Aurora-A is required for Numb asymmetry (Berdnik and Knoblich, 2002)
  • Numb is mislocalized upon expression of Lgl3A (Betschinger et al., 2003)
par6 is phosphorylated by aur a in vivo
Par6 is phosphorylated by Aur-A in vivo

 AurA phosphorylates Par6 in on Ser34 in vitro and in vivo

par6 phosphorylation negatively regulates its physical interaction with apkc
Par6 phosphorylation negatively regulates its physical interaction with aPKC

 AurA activates aPKC by dissociating it from Par6

par6 phosphorylation controls localization of numb during mitosis
Par6 phosphorylation controls localization of Numb during mitosis

 Additional substrates for AurA?

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aPKC releases Lgl from the cell cortex in mitosis

Lgl is insoluble when unphosphorylated (Betschinger et al., 2003)

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Baz acts downstream of Lgl

  • Numb asymmetry requiers Baz (= Par3; Bellaiche et al., 2001)
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Aur-A regulates subunit composistion of the Par Complex

  • Lgl inhibits cortical localization of Baz
  • Interaction of Baz with Par6/aPKC is inhibited by Lgl
  • AurA triggers remodeling of Par complex
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Exchange of Lgl for Baz enables the Par complex to phosphorylate Numb

  • Baz changes the substrate specifity of aPKC
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Interaction of Numb with the Baz complex is essential for its asymmetric localization

  • numbS52F : localizes symmetrically in SOP cells can still be phosphorylated by aPKC
  • AurA induces asymmetric localization of Numb by promoting interaction of Numb with aPKC
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Summary

  • Cascade of interactions that culminate in Numb asymmetric localization
  •  Par6 is a cortical substrate for Aurora-A
  •  Par6 phosphorylation triggers exchange of Lgl for Baz in the Par complex
  •  Bax/Par complex phosphorylates Numb
  •  Restict Numb into a crescent on the opposite site
  • Lgl acts as a inhibitory subunit of the Par complex
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