Abstract
Membrane phosphoinositides control a variety of cellular processes through the recruitment and/or regulation of cytosolic proteins1,2,3,4. One mechanism ensuring spatial specificity in phosphoinositide signalling is the targeting of enzymes that mediate their metabolism to specific subcellular sites. Phosphatidylinositol phosphate kinase type 1γ (PtdInsPKIγ) is a phosphatidylinositol-4-phosphate 5-kinase that is expressed at high levels in brain, and is concentrated at synapses5,6. Here we show that the predominant brain splice variant of PtdInsPKIγ (PtdInsPKIγ-90) binds, by means of a short carboxy-terminal peptide, to the FERM domain of talin, and is strongly activated by this interaction. Talin, a principal component of focal adhesion plaques7, is also present at synapses. PtdInsPKIγ-90 is expressed in non-neuronal cells, albeit at much lower levels than in neurons, and is concentrated at focal adhesion plaques, where phosphatidylinositol-4,5-bisphosphate has an important regulatory role. Overexpression of PtdInsPKIγ-90, or expression of its C-terminal domain, disrupts focal adhesion plaques, probably by local disruption of normal phosphoinositide balance. These findings define an interaction that has a regulatory role in cell adhesion and suggest new similarities between molecular interactions underlying synaptic junctions and general mechanisms of cell adhesion.
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Acknowledgements
We thank L. Liu, L. Daniell and M. Caleo for technical help. We also thank T. Nagase for the gift of the human PtdInsPKIγ-90 clone KIAA0589; C. Carpenter for the gift of the PtdInsPKIα and -β cDNAs; R. Hynes for the gift of mouse talin 1 cDNA; G. Cesareni and F. Felici for the phage library; and laboratory members and O. Cremona for critical discussion. This work was supported in part by grants from the NIH and from the American Diabetes Association to P.D.C. L.P and G.C. were supported by postdoctoral fellowships from Telethon-Italia, and K.L. is a Howard Hughes Medical Institute predoctoral fellow. S.C. is a Howard Hughes Medical Institute fellow of the Life Sciences Research foundation.
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Di Paolo, G., Pellegrini, L., Letinic, K. et al. Recruitment and regulation of phosphatidylinositol phosphate kinase type 1γ by the FERM domain of talin. Nature 420, 85–89 (2002). https://doi.org/10.1038/nature01147
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DOI: https://doi.org/10.1038/nature01147
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