Linking Cell Cycle to Asymmteric Division: Aurora-A phosphorylates the Par Complex to Regulate Numb ...
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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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Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

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


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

Asymmetric cell division phosphorylates the Par Complex to Regulate Numb Localization

  • 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


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

The cell fate determinant Numb phosphorylates the Par Complex to Regulate Numb Localization

  • 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


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

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)


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

AurA activates aPKC by phosphorylating during mitosis?the aPKC complex

aurA mutants:


Par6 is phosphorylated by aur a in vivo
Par6 is phosphorylated by Aur-A during mitosis?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?


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

aPKC releases Lgl from the cell cortex in mitosis mitosis

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


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

Aur-A is necessary and sufficient to induce mitosis cortical Lgl release


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

  • Numb asymmetry requiers Baz (= Par3; Bellaiche et al., 2001)


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

Aur-A regulates subunit composistion of the Par Complex mitosis

  • Lgl inhibits cortical localization of Baz

  • Interaction of Baz with Par6/aPKC is inhibited by Lgl

  • AurA triggers remodeling of Par complex



Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

Exchange of Lgl for Baz enables the Par complex to phosphorylate Numb

  • Baz changes the substrate specifity of aPKC


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

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


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

Proposed its asymmetric localization mechanism


Frederik wirtz peitz takashi nishimura and juergen a knoblich cell 136 161 173 2008

Summary its asymmetric localization

  • 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