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PLoS Comput Biol. 2014 Sep 11;10(9):e1003817. doi: 10.1371/journal.pcbi.1003817. eCollection 2014 Sep.

PTEN hopping on the cell membrane is regulated via a positively-charged C2 domain.

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Laboratories for Nanobiology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan; Laboratory for Cell Signaling Dynamics, QBiC (Quantitative Biology Center), RIKEN, Suita, Osaka, Japan; Laboratory of Single Molecule Biology, Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
Laboratory for Cell Signaling Dynamics, QBiC (Quantitative Biology Center), RIKEN, Suita, Osaka, Japan.


PTEN, a tumor suppressor that is frequently mutated in a wide spectrum of cancers, exerts PI(3,4,5)P3 phosphatase activities that are regulated by its dynamic shuttling between the membrane and cytoplasm. Direct observation of PTEN in the interfacial environment can offer quantitative information about the shuttling dynamics, but remains elusive. Here we show that positively charged residues located in the cα2 helix of the C2 domain are necessary for the membrane localization of PTEN via stable electrostatic interactions in Dictyostelium discoideum. Single-molecule imaging analyses revealed that PTEN molecules moved distances much larger than expected had they been caused by lateral diffusion, a phenomenon we call "hopping." Our novel single-particle tracking analysis method found that the cα2 helix aids in regulating the hopping and stable-binding states. The dynamically established membrane localization of PTEN was revealed to be essential for developmental processes and clarified a fundamental regulation mechanism of the protein quantity and activity on the plasma membrane.

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