Cargando…

A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Dong, Wei, Zhang, Xuejing, Liu, Weijie, Chen, Yi-jiun, Huang, Juan, Austin, Erin, Celotto, Alicia M., Jiang, Wendy Z., Palladino, Michael J., Jiang, Yu, Hammond, Gerald R.V., Hong, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621827/
https://www.ncbi.nlm.nih.gov/pubmed/26483556
http://dx.doi.org/10.1083/jcb.201503067
Descripción
Sumario: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.