title: Type I phosphatidylinositol 4-phosphate 5-kinase controls neutrophil polarity and directional movement.
abstract: 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 beta (PIPKIbeta) has a role in organizing signaling at the cell rear. We found that PIPKIbeta polarized at the uropod of neutrophil-differentiated HL60 cells. PIPKIbeta 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 PIPKIbeta 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 PIPKIbeta with siRNA inhibited cell polarization and impaired cell directionality during dHL60 chemotaxis, suggesting a role for PIPKIbeta in these processes.
authors.affiliation: Department of Immunology and Oncology, Campus de Cantoblanco, Madrid E-28049, Spain.
authors.forename: Rosa Ana
authors.initials: RA
authors.lastname: Lacalle
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Peregil
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Albar
authors.forename: Ernesto
authors.initials: E
authors.lastname: Merino
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-A
authors.forename: Isabel
authors.initials: I
authors.lastname: Mérida
authors.forename: Santos
authors.initials: S
authors.lastname: Mañes
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000201:enzymology*; D010750:Phosphoproteins / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
chemical_list: C569638:ARHGDIA protein, human; D000199:Actins; D020730:Guanine Nucleotide Dissociation Inhibitors; D007527:Isoenzymes; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D017923:Sodium-Hydrogen Exchangers; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; C093376:sodium-hydrogen exchanger regulatory factor; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase