Article
- The EMBO Journal (2007) 26, 468 - 480
- doi:10.1038/sj.emboj.7601495
Published online: 4 January 2007
Subject Categories:
aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb
Christian A Smith1,2,a, Kimberly M Lau1,2,a, Zohra Rahmani3, Sascha E Dho2, Greg Brothers4, Ye Min She4, Donna M Berry2, Eric Bonneil5, Pierre Thibault5, François Schweisguth3, Roland Le Borgne3,b and C Jane McGlade1,2
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Ecole Normale Supérieure. CNRS UMR 8542, Paris Cedex, France
- Advanced Protein Technology Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Quebec, Canada
Correspondence to:
C Jane McGlade, Program in Cell Biology, Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada, M5G 1X8. Tel.: +416 813 8657; Fax: +416 813 8456; E-mail: jmcglade@sickkids.ca
aPresent address: CNRS UMR 6061; Université de Rennes I, 2 avenue du Pr. L. Bernard, CS 34317, 35043 Rennes Cedex, France
bThese authors contributed equally to this work
Received 28 June 2006; Accepted 14 November 2006
Abstract
In Drosophila, the partition defective (Par) complex containing Par3, Par6 and atypical protein kinase C (aPKC) directs the polarized distribution and unequal segregation of the cell fate determinant Numb during asymmetric cell divisions. Unequal segregation of mammalian Numb has also been observed, but the factors involved are unknown. Here, we identify in vivo phosphorylation sites of mammalian Numb and show that both mammalian and Drosophila Numb interact with, and are substrates for aPKC in vitro. A form of mammalian Numb lacking two protein kinase C (PKC) phosphorylation sites (Numb2A) accumulates at the cell membrane and is refractory to PKC activation. In epithelial cells, mammalian Numb localizes to the basolateral membrane and is excluded from the apical domain, which accumulates aPKC. In contrast, Numb2A is distributed uniformly around the cell cortex. Mutational analysis of conserved aPKC phosphorylation sites in Drosophila Numb suggests that phosphorylation contributes to asymmetric localization of Numb, opposite to aPKC in dividing sensory organ precursor cells. These results suggest a model in which phosphorylation of Numb by aPKC regulates its polarized distribution in epithelial cells as well as during asymmetric cell divisions.
Keywords:
- asymmetric cell division,
- epithelial cells,
- Numb,
- phosphorylation,
- PKC
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