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Published online
doi:10.1083/jcb.200705044
The Journal of Cell Biology, Vol. 179, No. 7, 1539-1553
The Rockefeller University Press, 0021-9525 $30.00
© Lacalle et al.
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Article

Type I phosphatidylinositol 4-phosphate 5-kinase controls neutrophil polarity and directional movement



Rosa Ana Lacalle1, Rosa M. Peregil1, Juan Pablo Albar2, Ernesto Merino1, Carlos Martínez-A1, Isabel Mérida1, and Santos Mañes1

1 Department of Immunology and Oncology and 2 Proteomic Facility, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, Madrid E-28049, Spain

Correspondence to Santos Mañes: smanes{at}cnb.uam.es

Directional cell movement in response to external chemical gradients requires establishment of front–rear asymmetry, which distinguishes an up-gradient protrusive leading edge, where Rac-induced F-actin polymerization takes place, and a down-gradient retractile tail (uropod in leukocytes), where RhoA-mediated actomyosin contraction occurs. The signals that govern this spatial and functional asymmetry are not entirely understood. We show that the human type I phosphatidylinositol 4-phosphate 5-kinase isoform β (PIPKIβ) has a role in organizing signaling at the cell rear. We found that PIPKIβ polarized at the uropod of neutrophil-differentiated HL60 cells. PIPKIβ localization was independent of its lipid kinase activity, but required the 83 C-terminal amino acids, which are not homologous to other PIPKI isoforms. The PIPKIβ C terminus interacted with EBP50 (4.1-ezrin-radixin-moesin (ERM)-binding phosphoprotein 50), which enabled further interactions with ERM proteins and the Rho-GDP dissociation inhibitor (RhoGDI). Knockdown of PIPKIβ with siRNA inhibited cell polarization and impaired cell directionality during dHL60 chemotaxis, suggesting a role for PIPKIβ in these processes.

Abbreviations used in this paper: dHL60, DMSO-differentiated HL60; ERM, ezrin/radixin/moesin; EBP50, 4.1-ERM-binding phosphoprotein 50; FERM, band 4.1 protein-ezrin-radixin-moesin; fMLP, N-formyl-methionyl-leucyl-phenylalanine; KHD, kinase homology domain; MLC, myosin light chains; PBD, p21-binding domain; p-ERM, phosphorylated-ERM; PH, pleckstrin homology domain; PI3K, phosphatidylinositol 3-kinase; PI(4,5)P2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PIPKI, type I phosphatidylinositol 4-phosphate 5-kinase; PTX, pertussis toxin; RhoGDI, Rho-GDP dissociation inhibitor; ROCK, p160-Rho-associated coil-containing protein kinase.


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