Negative feedback regulation of Rac in leukocytes from mice expressing a constitutively active phosphatidylinositol 3-kinase gamma

作者：Costa Carlotta; Barberis Laura; Ambrogio Chiara; Manazza Andrea D; Patrucco Enrico; Azzolino Ornella; Neilsen Paul O; Ciraolo Elisa; Altruda Fiorella; Prestwich Glenn D; Chiarle Roberto; Wymann Matthias; Ridley Anne; Hirsch Emilio^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(36): 14354-14359.

DOI：10.1073/pnas.0703175104

• chemotaxis
• signal transduction
• inflammation

Polarization of chernotaxing cells depends on positive feedback loops that amplify shallow gradients of chemoattractants into sharp intracellular responses. In particular, reciprocal activation of phosphaticlylinositol 3-kinases (PI3Ks) and small GTPases like Rac leads to accumulation, at the leading edge, of the PI3K product phosphaticlylinositol 3,4, 5-trisphosphate (PIP3). Mice carrying a "knockin" allele of the G protein-coupled receptor (GPCR)activated PI3K gamma, encoding a plasma membrane-targeted protein appeared normal, but their leukocytes showed GPCR-uncoupled PIP3 accumulation. In vivo, the mutation increased proliferation and decreased apoptosis, leading to leukocytosis and delayed resolution of inflammation in wound healing. Mutant leukocytes showed significantly impaired directional cell migration in response to chemoattractants. Stimulated mutant macrophages did not polarize PIP3 and showed a shortened Rac activation because of enhanced PI3K-dependent activation of RacGAPs. Together with the finding that chemoattractants stimulate a PIP3-dependent GAP activation in wild-type macrophages, these results identify a molecular mechanism involving PI3K- and RacGAP-dependent negative control of Rac that limits and fine-tunes feedback loops promoting cell polarization and directional motility.

• 出版日期2007-9-4