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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. 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

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  1. 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

  2. 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

  3. 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

  4. 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)

  5. AurA activates aPKC by phosphorylating the aPKC complex aurA mutants:

  6. Par6 is phosphorylated by Aur-A in vivo  AurA phosphorylates Par6 in on Ser34 in vitro and in vivo

  7. Par6 phosphorylation negatively regulates its physical interaction with aPKC  AurA activates aPKC by dissociating it from Par6

  8. Par6 phosphorylation controls localization of Numb during mitosis  Additional substrates for AurA?

  9. aPKC releases Lgl from the cell cortex in mitosis Lgl is insoluble when unphosphorylated (Betschinger et al., 2003)

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

  11. Baz acts downstream of Lgl • Numb asymmetry requiers Baz (= Par3; Bellaiche et al., 2001)

  12. 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

  13. Numb localization requires appropiate levels of Baz complex

  14. Exchange of Lgl for Baz enables the Par complex to phosphorylate Numb • Baz changes the substrate specifity of aPKC

  15. 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

  16. Proposed mechanism

  17. 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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