PIP5K-Ras bistability triggers plasma membrane symmetry breaking to define cellular polarity and regulate migration
Abstract
An initial break in plasma membrane symmetry triggers hundreds of spatiotemporally controlled signaling and cytoskeletal events that regulate cell polarization during migration and macropinocytosis. However, the mechanism driving this self-organizing transition remains unknown. Using Dictyostelium amoebae, leukocytes, cancer cells, and 3D organoids, we show that mutual antagonism between activated Ras and phosphatidylinositol 4-phosphate 5-kinase (PIP5K) forms a positive feedback loop fundamental to symmetry breaking and cell polarity. Through dynamic localization mapping, optogenetic perturbation, RasGEF screening, and single-molecule tracking, we reveal that localized Ras activation shortens the membrane lifetime of PIP5K, lowering local PI(4,5)P2, while recruited RasGEF amplifies Ras activation. Dissociated PIP5K redistributes to other membrane domains, suppressing local Ras activation and intrinsically segregating the membrane into complementary activated and inactivated zones, independent of receptor inputs or cytoskeletal dynamics. Incorporating this feedback loop into an excitable network integrated with a reaction-diffusion model and a viscoelastic framework yielded computational simulations that accurately predict spatiotemporal self-organization and polarized cell movement.
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BibTeX
@article{deng2026pip5kras,
title = {{PIP5K-Ras bistability triggers plasma membrane symmetry breaking to define cellular polarity and regulate migration}},
author = {Yu Deng and Tatsat Banerjee and Satomi Matsuoka and Debojyoti Biswas and Liz A. Kurtz and Jane Borleis and Yu Long and Parijat Banerjee and Huiwang Zhan and Dhiman Sankar Pal and Nathan H. Roy and Masahiro Ueda and Pablo A. Iglesias and Peter N. Devreotes},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77894-2},
url = {https://www.nature.com/articles/s41467-026-77894-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - PIP5K-Ras bistability triggers plasma membrane symmetry breaking to define cellular polarity and regulate migration
AU - Yu Deng
AU - Tatsat Banerjee
AU - Satomi Matsuoka
AU - Debojyoti Biswas
AU - Liz A. Kurtz
AU - Jane Borleis
AU - Yu Long
AU - Parijat Banerjee
AU - Huiwang Zhan
AU - Dhiman Sankar Pal
AU - Nathan H. Roy
AU - Masahiro Ueda
AU - Pablo A. Iglesias
AU - Peter N. Devreotes
PY - 2026
DA - 2026/09/30
JO - Nature Communications
DO - 10.1038/s41467-026-77894-2
UR - https://www.nature.com/articles/s41467-026-77894-2
AB - An initial break in plasma membrane symmetry triggers hundreds of spatiotemporally controlled signaling and cytoskeletal events that regulate cell polarization during migration and macropinocytosis. However, the mechanism driving this self-organizing transition remains unknown. Using Dictyostelium amoebae, leukocytes, cancer cells, and 3D organoids, we show that mutual antagonism between activated Ras and phosphatidylinositol 4-phosphate 5-kinase (PIP5K) forms a positive feedback loop fundamental to symmetry breaking and cell polarity. Through dynamic localization mapping, optogenetic perturbation, RasGEF screening, and single-molecule tracking, we reveal that localized Ras activation shortens the membrane lifetime of PIP5K, lowering local PI(4,5)P2, while recruited RasGEF amplifies Ras activation. Dissociated PIP5K redistributes to other membrane domains, suppressing local Ras activation and intrinsically segregating the membrane into complementary activated and inactivated zones, independent of receptor inputs or cytoskeletal dynamics. Incorporating this feedback loop into an excitable network integrated with a reaction-diffusion model and a viscoelastic framework yielded computational simulations that accurately predict spatiotemporal self-organization and polarized cell movement.
SN - 2041-1723
ER -