The Axonal Membrane Protein PRG2 Inhibits PTEN and Directs Growth to Branches
| Autor: | Britta J. Eickholt, Michal Szczepek, Niclas Gimber, Julia Ledderose, Joachim Fuchs, Annika Brosig, Christian Rosenmund, Sandra Schrötter, Mayur Vadhvani, Christian M. T. Spahn, Ivo Lieberam, Hermann-Georg Holzhütter, Thorsten Trimbuch, Jan Schmoranzer, Michiel T. van Diepen, Alexandra Polyzou, George Leondaritis, Patrick Scheerer, Cristina Kroon, Fatih Ipek |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
PTEN Phosphatase Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine branching Pi medicine Axon Gene lcsh:QH301-705.5 PI3K signaling PI3K/AKT/mTOR pathway phosphoinositide signaling biology Chemistry Cell biology 030104 developmental biology medicine.anatomical_structure axon morphogenesis nervous system lcsh:Biology (General) biology.protein neuronal growth homeostasis Filopodia 030217 neurology & neurosurgery Homeostasis plasticity-related gene family |
| Zdroj: | Cell Reports, Vol 29, Iss 7, Pp 2028-2040.e8 (2019) Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary In developing neurons, phosphoinositide 3-kinases (PI3Ks) control axon growth and branching by positively regulating PI3K/PI(3,4,5)P3, but how neurons are able to generate sufficient PI(3,4,5)P3 in the presence of high levels of the antagonizing phosphatase PTEN is difficult to reconcile. We find that normal axon morphogenesis involves homeostasis of elongation and branch growth controlled by accumulation of PI(3,4,5)P3 through PTEN inhibition. We identify a plasma membrane-localized protein-protein interaction of PTEN with plasticity-related gene 2 (PRG2). PRG2 stabilizes membrane PI(3,4,5)P3 by inhibiting PTEN and localizes in nanoclusters along axon membranes when neurons initiate their complex branching behavior. We demonstrate that PRG2 is both sufficient and necessary to account for the ability of neurons to generate axon filopodia and branches in dependence on PI3K/PI(3,4,5)P3 and PTEN. Our data indicate that PRG2 is part of a neuronal growth program that induces collateral branch growth in axons by conferring local inhibition of PTEN. Graphical Abstract Highlights • Neuronal axon growth and branching is globally regulated by PI3K/PTEN signaling • PRG2 inhibits PTEN and stabilizes PIP3 and F-actin • PRG2 localizes to nanoclusters on the axonal membrane and coincides with branching • PRG2 promotes axonal filopodia and branching dependent on PI3K/PTEN PTEN globally suppresses growth in multiple cell types and inhibits neuronal axon growth and branching. Brosig et al. describe a mechanism for developing neurons to inhibit PTEN function by upregulating PRG2 in the axon. Although the overall growth capacity of neurons remains constant, PRG2 redirects growth to axon branches. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|