Involvement of Phosphoinositide 3-Kinase γ, Rac, and PAK Signaling in Chemokine-induced Macrophage Migration*

In macrophages, chemotactic stimuli cause the activation of Rac and PAK, but little is known about the signaling pathways involved and their role in chemotactic gradient sensing. Herein, we report that in macrophages, the chemokine RANTES (regulated on activation normal T cell expressed and secreted)/CCL5 activates the small GTPase Rac and its downstream target PAK2 within seconds. This response depends on Gi activation and largely on the subsequent triggering of phosphoinositide 3-kinase γ (PI3Kγ) and Rac. Retroviral transduction of tagged Rac1 and -2 indicates that RANTES/CCL5-mediated activation of PI3Kγ triggers Rac1 but not Rac2. In agreement, silencing of Rac1 by shRNA blocks PAK2 activity and inhibits RANTES/CCL5-induced macrophage polarization and directional migration. On the other hand, the tyrosine kinase receptor agonist CSF-1 activates PAK2 independently of PI3Kγ and Rac. Our results thus demonstrate a chemokine-specific signaling pathway in which Gi and PI3Kγ coordinate to drive Rac1 and PAK2 activation that eventually controls the chemotactic response.

• Publication year

  2004

• Venue

  Journal of Biological Chemistry

• Publication date

  2004-10-08

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M402924200PMID 15292195
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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