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Published online 24 July 2006. doi:10.1083/jcb.200604113
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 3, 437-445
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Article

 To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front

Alexandra Van Keymeulen1,2,3, Kit Wong1,2,3, Zachary A. Knight1,2,3, Cedric Govaerts1,2,3, Klaus M. Hahn4,5, Kevan M. Shokat1,2,3, and Henry R. Bourne1,2,3

1 Department of Cellular and Molecular Pharmacology, 2 Department of Medicine, and 3 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143
4 Department of Pharmacology and 5 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599

Correspondence to Henry R. Bourne: bourne{at}cmp.ucsf.edu

Chemoattractants like f-Met-Leu-Phe (fMLP) induce neutrophils to polarize by triggering divergent signals that promote the formation of protrusive filamentous actin (F-actin; frontness) and RhoA-dependent actomyosin contraction (backness). Frontness locally inhibits backness and vice versa. In neutrophil-like HL60 cells, blocking phosphatidylinositol-3,4,5-tris-phosphate (PIP3) accumulation with selective inhibitors of PIP3 synthesis completely prevents fMLP from activating a PIP3-dependent kinase and Cdc42 but not from stimulating F-actin accumulation. PIP3-deficient cells show reduced fMLP-dependent Rac activity and unstable pseudopods, which is consistent with the established role of PIP3 as a mediator of positive feedback pathways that augment Rac activation at the front. Surprisingly, such cells also show reduced RhoA activation and RhoA-dependent contraction at the trailing edge, leading to the formation of multiple lateral pseudopods. Cdc42 mediates PIP3's positive effect on RhoA activity. Thus, PIP3 and Cdc42 maintain stable polarity with a single front and a single back not only by strengthening pseudopods but also, at longer range, by promoting RhoA-dependent actomyosin contraction at the trailing edge.

A. Van Keymeulen and K. Wong contributed equally to this paper.

Abbreviations used in this paper: CI, chemotactic index; dHL60, differentiated HL60; F-actin, filamentous actin; fMLP, f-Met-Leu-Phe; FRET, fluorescence resonance energy transfer; LatB, latrunculin B; PAK, p21-activated kinase; pAkt, phosphorylated Akt; PBD, p21-binding domain; PH, pleckstrin homology domain; PIP3, phosphatidylinositol-3,4,5-tris-phosphate; PI3K, phosphatidylinositol 3'-kinase; pPAK, phosphorylated PAK; PTEN, phosphatase and tensin homologue; ROCK, Rho-associated coil-containing protein kinase.


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