1. A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia.
- Author
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Dong W, Zhang X, Liu W, Chen YJ, Huang J, Austin E, Celotto AM, Jiang WZ, Palladino MJ, Jiang Y, Hammond GR, and Hong Y
- Subjects
- Adenosine Triphosphate metabolism, Amino Acid Sequence, Animals, Aurora Kinases metabolism, Drosophila Proteins genetics, Green Fluorescent Proteins genetics, HEK293 Cells, Humans, Molecular Sequence Data, Phosphatidylinositol Phosphates metabolism, Phosphorylation, Protein Kinase C metabolism, Protein Structure, Tertiary, Sequence Alignment, Static Electricity, Tumor Suppressor Proteins genetics, Cell Hypoxia physiology, Cell Membrane metabolism, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Protein Processing, Post-Translational genetics, Tumor Suppressor Proteins metabolism
- Abstract
Lethal giant larvae (Lgl) plays essential and conserved functions in regulating both cell polarity and tumorigenesis in Drosophila melanogaster and vertebrates. It is well recognized that plasma membrane (PM) or cell cortex localization is crucial for Lgl function in vivo, but its membrane-targeting mechanisms remain poorly understood. Here, we discovered that hypoxia acutely and reversibly inhibits Lgl PM targeting through a posttranslational mechanism that is independent of the well-characterized atypical protein kinase C (aPKC) or Aurora kinase-mediated phosphorylations. Instead, we identified an evolutionarily conserved polybasic (PB) domain that targets Lgl to the PM via electrostatic binding to membrane phosphatidylinositol phosphates. Such PB domain-mediated PM targeting is inhibited by hypoxia, which reduces inositol phospholipid levels on the PM through adenosine triphosphate depletion. Moreover, Lgl PB domain contains all the identified phosphorylation sites of aPKC and Aurora kinases, providing a molecular mechanism by which phosphorylations neutralize the positive charges on the PB domain to inhibit Lgl PM targeting., (© 2015 Dong et al.)
- Published
- 2015
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