Linking cell cycle to asymmetric division: Aurora-A phosphorylates the Par complex to regulate Numb localization

Cell. 2008 Oct 3;135(1):161-73. doi: 10.1016/j.cell.2008.07.049.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinases
  • Cell Polarity
  • Drosophila Proteins / analysis
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology*
  • Drosophila melanogaster / metabolism
  • Glycogen Synthase Kinase 3
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Juvenile Hormones / analysis
  • Juvenile Hormones / metabolism*
  • Mitosis*
  • Protein Kinase C / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Juvenile Hormones
  • Tumor Suppressor Proteins
  • baz protein, Drosophila
  • l(2)gl protein, Drosophila
  • numb protein, Drosophila
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Par-6 protein, Drosophila
  • Protein Kinase C
  • Glycogen Synthase Kinase 3
  • Par-1 protein, Drosophila