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PNAS 107 (27): 12399-12404

Copyright © 2010 by the National Academy of Sciences.


Self-organization of the phosphatidylinositol lipids signaling system for random cell migration

Yoshiyuki Araia,b,1, Tatsuo Shibatab,c,d,1, Satomi Matsuokaa,b, Masayuki J. Satoa,b, Toshio Yanagidaa, and Masahiro Uedaa,b,2

aLaboratories for Nanobiology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan; b Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Suita, Osaka 565-0871, Japan; cDepartment of Mathematical and Life Sciences, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan; and dPrecursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 331-0012, Japan

Edited by Lewis Clayton Cantley, Harvard Medical School, Boston, MA, and approved May 20, 2010 (received for review July 23, 2009)

Abstract: Phosphatidylinositol (PtdIns) lipids have been identified as key signaling mediators for random cell migration as well as chemoattractant-induced directional migration. However, how the PtdIns lipids are organized spatiotemporally to regulate cellular motility and polarity remains to be clarified. Here, we found that self-organized waves of PtdIns 3,4,5-trisphosphate [PtdIns(3,4,5)P3] are generated spontaneously on the membrane of Dictyostelium cells in the absence of a chemoattractant. Characteristic oscillatory dynamics within the PtdIns lipids signaling system were determined experimentally by observing the phenotypic variability of PtdIns lipid waves in single cells, which exhibited characteristics of a relaxation oscillator. The enzymes phosphatase and tensin homolog (PTEN) and phosphoinositide-3-kinase (PI3K), which are regulators for PtdIns lipid concentrations along the membrane, were essential for wave generation whereas functional actin cytoskeleton was not. Defects in these enzymes inhibited wave generation as well as actin-based polarization and cell migration. On the basis of these experimental results, we developed a reaction-diffusion model that reproduced the characteristic relaxation oscillation dynamics of the PtdIns lipid system, illustrating that a self-organization mechanism provides the basis for the PtdIns lipids signaling system to generate spontaneous spatiotemporal signals for random cell migration and that molecular noise derived from stochastic fluctuations within the signaling components gives rise to the variability of these spontaneous signals.

Key Words: phosphatase and tensin homolog • spontaneous polarization • relaxation oscillation • traveling wave • noise

Freely available online through the PNAS open access option.

Author contributions: T.S., T.Y., and M.U. designed research; Y.A., T.S., S.M., M.J.S., and M.U. performed research; T.S. contributed new analytic tools; Y.A., T.S., S.M., M.J.S., and M.U. analyzed data; and Y.A., T.S., S.M., M.J.S., and M.U. wrote the paper.

1Y.A. and T.S. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

2To whom correspondence should be addressed. E-mail: ueda{at}

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