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PNAS 102 (47): 16927-16932

Copyright © 2005 by the National Academy of Sciences.


Diffusion-limited phase separation in eukaryotic chemotaxis

Andrea Gamba *, {dagger}, Antonio de Candia {ddagger}, Stefano Di Talia §, Antonio Coniglio {ddagger}, Federico Bussolino ¶, and Guido Serini {dagger}, ¶

*Department of Mathematics, Polytechnic of Torino, 10129 Turin, Italy; {ddagger}Department of Physical Sciences, University of Naples "Federico II," Istituto Nazionale di Fisica Della Materia, and Istituto Nazionale di Fisica Nucleare, Unit of Naples, 80126 Naples, Italy; §Laboratory of Mathematical Physics, The Rockefeller University, New York, NY 10021; and Department of Oncological Sciences and Division of Molecular Angiogenesis, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo, Italy

Edited by H. Eugene Stanley, Boston University, Boston, MA

Accepted for publication September 14, 2005.

Received for publication May 12, 2005.

Abstract: The ability of cells to sense spatial gradients of chemoattractant factors governs the development of complex eukaryotic organisms. Cells exposed to shallow chemoattractant gradients respond with strong accumulation of the enzyme phosphatidylinositol 3-kinase (PI3K) and its D3-phosphoinositide product (PIP3) on the plasma membrane side exposed to the highest chemoattractant concentration, whereas PIP3-degrading enzyme PTEN and its product PIP2 localize in a complementary pattern. Such an early symmetry-breaking event is a mandatory step for directed cell movement elicited by chemoattractants, but its physical origin is still mysterious. Here, we propose that directional sensing is the consequence of a phase-ordering process mediated by phosphoinositide diffusion and driven by the distribution of chemotactic signal. By studying a realistic reaction–diffusion lattice model that describes PI3K and PTEN enzymatic activity, recruitment to the plasma membrane, and diffusion of their phosphoinositide products, we show that the effective enzyme–enzyme interaction induced by catalysis and diffusion introduces an instability of the system toward phase separation for realistic values of physical parameters. In this framework, large reversible amplification of shallow chemotactic gradients, selective localization of chemical factors, macroscopic response timescales, and spontaneous polarization arise naturally. The model is robust with respect to order-of-magnitude variations of the parameters.

Key Words: directional sensing • lattice model • first-order phase transitions

Author contributions: A.G., A.d.C., S.D.T., A.C., F.B., and G.S. designed research, performed research, analyzed data, and wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: PI3K, phosphatidylinositol 3-kinase; PIP3, D3-phosphoinositide product of PI3K.

{dagger} To whom correspondence may be addressed. E-mail: gamba{at} or guido.serini{at}

© 2005 by The National Academy of Sciences of the USA

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