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The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl

Abstract

To generate different cell types, some cells can segregate protein determinants into one of their two daughter cells during mitosis. In Drosophila neuroblasts, the Par protein complex localizes apically1,2,3,4,5 and directs localization of the cell fate determinants Prospero6,7,8 and Numb9 and the adaptor proteins Miranda10,11 and Pon12 to the basal cell cortex, to ensure their segregation into the basal daughter cell. The Par protein complex has a conserved function in establishing cell polarity13 but how it directs proteins to the opposite side is unknown. We show here that a principal function of this complex is to phosphorylate the cytoskeletal protein Lethal (2) giant larvae (Lgl; also known as L(2)gl). Phosphorylation by Drosophila atypical protein kinase C (aPKC), a member of the Par protein complex, releases Lgl from its association with membranes and the actin cytoskeleton. Genetic and biochemical experiments show that Lgl phosphorylation prevents the localization of cell fate determinants to the apical cell cortex. Lgl promotes cortical localization of Miranda14,15, and we propose that phosphorylation of Lgl by aPKC at the apical neuroblast cortex restricts Lgl activity and Miranda localization to the opposite, basal side of the cell.

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Figure 1: Lgl is in the Par protein complex.
Figure 2: aPKC phosphorylates Lgl on three conserved serine residues in vitro.
Figure 3: aPKC phosphorylates Lgl in vivo.
Figure 4: N-terminally truncated aPKC and non-phosphorylatable Lgl (Lgl-3A) inhibit asymmetric protein localization.

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Acknowledgements

We thank B. Dickson, M. Glotzer, A. Wutz and D. Berdnik for comments on the manuscript; Y. N. Jan, D. Kiehart, F. Matsuzaki, C. Thummel, the Developmental Studies Hybridoma Bank (DSHB) and the Bloomington Drosophila Stock Center for antibodies and fly stocks; and M. Petronczki for generating mouse anti-Par-6. Work in the laboratory of J.A.K. is supported by Boehringer Ingelheim and the Wiener Wirtschafts Foerderungs Fond (WWFF).

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Correspondence to Juergen A. Knoblich.

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Betschinger, J., Mechtler, K. & Knoblich, J. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003). https://doi.org/10.1038/nature01486

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