Journal
FASEB JOURNAL
Volume 24, Issue 9, Pages 3381-3392Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-153106
Keywords
cell migration; NHERF-1; PIPK; polarization
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Funding
- Spanish Ministry of Science and Innovation [SAF2008-00649]
- Carlos III Health Institute RIER network [RD08/0075/0007]
- European Union [LSHB-CT-2005-518167]
- ERAnet program (e-rare) [PI07/1314]
- Comunidad de Madrid (DIFHEMAT) [S-SAL-0304-2006]
- Genoma Espana Foundation (MEICA)
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Type I phosphatidylinositol 4-phosphate 5-kinase (PIP5KI)-beta participates in establishing polarity during leukocyte chemotaxis. Its final 83 amino acids localize PIP5KI beta to the uropod of chemotaxing neutrophils and T cells, and interact with ezrin-radixin-moesin (ERM) proteins and EBP50 (4.1-ERM-binding phosphoprotein 50), a scaffold protein with 2 PDZ (PSD-95, disc large, ZO-1) domains. The structural motifs at the PIP5KI beta C terminus that confer signaling specificity are, nonetheless, unknown. We show that the last 4 residues of PIP5KI beta constitute an atypical PDZ-binding motif, which steers PIP5KI beta to the uropod by binding to both EBP50 PDZ domains. Molecular modeling and mutagenesis indicated that PDZ-binding motif is necessary for PIP5KI beta localization and for chemoattractant-induced neutrophil polarization. Polarity in cells that express PIP5KI beta mutants lacking the PDZ-binding motif was restored by overexpression of PIP5KI beta, but not of PIP5KI gamma_i2, another isoform that localizes to the neutrophil uropod. Our results identify an isoform-specific PDZ-binding motif in PIP5KI beta, which confers specificity for PIP5KI beta signaling at the uropod during leukocyte chemotaxis.-Manes, S., Fuentes, G., Peregil, R. M., Rojas, A. M., Lacalle, R. A. An isoform-specific PDZ-binding motif targets type I PIP5 kinase beta to the uropod and controls polarization of neutrophil-like HL60 cells. FASEB J. 24, 3381-3392 (2010). www.fasebj.org
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