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Finding the way: directional sensing and cell polarization through Ras signalling
Atsuo T Sasaki1, Richard A Firtel
1Section of Cell and Developmental Biology, Division of Biological Sciences and Center for Molecular Genetics, University of California, San Diego, La Jolla 92093, USA.
Novartis Foundation Symposium
|December 17, 2005
Summary
Ras activation at the cell front initiates chemotaxis signaling. This Ras activity, upstream of phosphatidylinositol-3-kinase (PI3K), drives cell polarization and movement by creating a steep phosphoinositide-3,4,5-trisphosphate (PIP3) gradient.
Area of Science:
- Cellular biology
- Biochemistry
- Biophysics
Background:
- Chemotactic eukaryotic cells sense extracellular chemoattractant gradients and create steep intracellular gradients.
- Phosphoinositide-3,4,5-trisphosphate (PIP3) accumulates at the leading edge of polarized cells.
- The localization of phosphatidylinositol-3-kinase (PI3K) and PTEN controls PIP3 gradients, but upstream regulators are unclear.
Purpose of the Study:
- To elucidate the upstream mechanisms controlling localized PI3K and PTEN activation and localization during chemotaxis.
- To investigate the role of Ras in initiating and regulating the PI3K pathway and cell polarity.
Main Methods:
- The study integrates findings from recent research on cell migration and signaling pathways.
- Focuses on the interplay between Ras, PI3K, PTEN, and F-actin dynamics.
Main Results:
- Ras activation at the leading edge initiates the PI3K pathway independently of PI3K/PTEN asymmetric localization.
- Ras acts upstream of PI3K, functioning as a key component of the cell's directional sensing mechanism.
- F-actin polymerization drives PI3K localization to the leading edge, amplifying the PIP3 gradient.
Conclusions:
- Ras is crucial for initiating directed cell movement and polarity by activating the PI3K pathway.
- The reciprocal localization of PI3K and PTEN amplifies, rather than generates, the PIP3 gradient.
- A positive feedback loop involving Ras, PIP3, and F-actin polymerization sustains and amplifies the chemotactic signal.