Abstract
PTEN, a 3-phosphatase of phosphoinositide, regulates asymmetric PI(3,4,5)P3 signaling for the anterior-posterior polarization and migration of motile cells. PTEN acts through posterior localization on the plasma membrane, but the mechanism for this accumulation is poorly understood. Here we developed an in vitro single-molecule imaging assay with various lipid compositions and use it to demonstrate that the enzymatic product, PI(4,5)P2, stabilizes PTEN’s membrane-binding. The dissociation kinetics and lateral mobility of PTEN depended on the PI(4,5)P2 density on artificial lipid bilayers. The basic residues of PTEN were responsible for electrostatic interactions with anionic PI(4,5)P2 and thus the PI(4,5)P2-dependent stabilization. Single-molecule imaging in living Dictyostelium cells revealed that these interactions were indispensable for the stabilization in vivo, which enabled efficient cell migration by accumulating PTEN posteriorly to restrict PI(3,4,5)P3 distribution to the anterior. These results suggest that PI(4,5)P2-mediated positive feedback and PTEN-induced PI(4,5)P2 clustering may be important for anterior-posterior polarization.
Highlights
phosphatase and tensin homolog (PTEN), a 3-phosphatase of phosphoinositide, regulates asymmetric PI(3,4,5)P3 signaling for the anterior-posterior polarization and migration of motile cells
A growing number of studies have reported that PTEN is regulated by PI(4,5)P2 and that PI(4,5)P2 and PI(3,4,5)P3 levels are maintained through positive feedback regulation in a wide spectrum of vital functions, including cell division and migration[45,46]
Several studies have revealed an essential role of the N-terminal motif in the accumulation of PTEN on PI(4,5)P2-containing vesicles and the plasma membrane in living cells based on the steady-state ratio of the lipid bilayerassociated fraction[24,37]
Summary
PTEN, a 3-phosphatase of phosphoinositide, regulates asymmetric PI(3,4,5)P3 signaling for the anterior-posterior polarization and migration of motile cells. Single-molecule imaging in living Dictyostelium cells revealed that these interactions were indispensable for the stabilization in vivo, which enabled efficient cell migration by accumulating PTEN posteriorly to restrict PI(3,4,5)P3 distribution to the anterior These results suggest that PI(4,5)P2-mediated positive feedback and PTEN-induced PI(4,5)P2 clustering may be important for anterior-posterior polarization. Trisphosphate (PI(3,4,5)P3) are localized at the leading edge of cells to regulate Rac-mediated actin polymerization for pseudopodia extension, while inactivated Ras GTPases, phosphatase and tensin homolog (PTEN), PI(4,5)P2, and PI(3,4)P2 are localized at the anterior to suppress lateral pseudopods[6,7] These characteristic features in asymmetric signal generation for cell polarity and motility are shared among evolutionary distant organisms such as mammalian leukocytes and social amoebae Dictyostelium discoideum[5,8,9], the underlying mechanisms of the asymmetric signaling remain unknown.
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