Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Recruitment and regulation of phosphatidylinositol phosphate kinase type 1γ by the FERM domain of talin


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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The 90K splice variant of PtdInsPKIγ is targeted to focal adhesion plaques in non-neuronal cells.
Figure 2: Interaction of PtdInsPKIγ-90, via a short amino acid sequence present in its 28aa-tail, with the FERM domain of talin.
Figure 3: The interaction between talin and PtdInsPKIγ-90 occurs physiologically in brain.
Figure 4: Disruption of normal phosphoinositide metabolism at focal adhesion plaques interferes with cell adhesion in NIH 3T3 cells.


  1. De Camilli, P., Emr, S. D., McPherson, P. S. & Novick, P. Phosphoinositides as regulators in membrane traffic. Science 271, 1533–1539 (1996)

    ADS  CAS  Article  Google Scholar 

  2. Hurley, J. H. & Meyer, T. Subcellular targeting by membrane lipids. Curr. Opin. Cell Biol. 13, 146–152 (2001)

    CAS  Article  Google Scholar 

  3. Simonsen, A., Wurmser, A. E., Emr, S. D. & Stenmark, H. The role of phosphoinositides in membrane transport. Curr. Opin. Cell Biol. 13, 485–492 (2001)

    CAS  Article  Google Scholar 

  4. Takenawa, T. & Itoh, T. Phosphoinositides, key molecules for regulation of actin cytoskeletal organization and membrane traffic from the plasma membrane. Biochim. Biophys. Acta 1533, 190–206 (2001)

    CAS  Article  Google Scholar 

  5. Ishihara, H. et al. Type I phosphatidylinositol-4-phosphate 5-kinases. J. Biol. Chem. 273, 8741–8748 (1998)

    CAS  Article  Google Scholar 

  6. Wenk, M. R. et al. PIP kinase Iγ is the major PI(4,5)P(2) synthesizing enzyme at the synapse. Neuron 32, 79–88 (2001)

    CAS  Article  Google Scholar 

  7. Critchley, D. R. Focal adhesions—the cytoskeletal connection. Curr. Opin. Cell Biol. 12, 133–139 (2000)

    CAS  Article  Google Scholar 

  8. Martin, T. F. Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking. Annu. Rev. Cell Dev. Biol. 14, 231–264 (1998)

    CAS  Article  Google Scholar 

  9. Sechi, A. S. & Wehland, J. The actin cytoskeleton and plasma membrane connection: PtdIns(4,5)P(2) influences cytoskeletal protein activity at the plasma membrane. J. Cell Sci. 113, 3685–3695 (2000)

    CAS  PubMed  Google Scholar 

  10. Cremona, O. et al. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 99, 179–188 (1999)

    CAS  Article  Google Scholar 

  11. Anderson, R. A., Boronenkov, I. V., Doughman, S. D., Kunz, J. & Loijens, J. C. Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes. J. Biol. Chem. 274, 9907–9910 (1999)

    CAS  Article  Google Scholar 

  12. McPherson, P. S. et al. A presynaptic inositol-5-phosphatase. Nature 379, 353–357 (1996)

    ADS  CAS  Article  Google Scholar 

  13. Chung, J. K. et al. Synaptojanin inhibition of phospholipase D activity by hydrolysis of phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 272, 15980–15985 (1997)

    CAS  Article  Google Scholar 

  14. Gad, H. et al. Fission and uncoating of synaptic clathrin-coated vesicles are perturbed by disruption of interactions with the SH3 domain of endophilin. Neuron 27, 301–312 (2000)

    CAS  Article  Google Scholar 

  15. Rees, D. J., Ades, S. E., Singer, S. J. & Hynes, R. O. Sequence and domain structure of talin. Nature 347, 685–689 (1990)

    ADS  CAS  Article  Google Scholar 

  16. Hamada, K., Shimizu, T., Matsui, T., Tsukita, S. & Hakoshima, T. Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain. EMBO J. 19, 4449–4462 (2000)

    CAS  Article  Google Scholar 

  17. Pearson, M. A., Reczek, D., Bretscher, A. & Karplus, P. A. Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 101, 259–270 (2000)

    CAS  Article  Google Scholar 

  18. Calderwood, D. A. et al. The phosphotyrosine binding-like domain of talin activates integrins. J. Biol. Chem. 277, 21749–21758 (2002)

    CAS  Article  Google Scholar 

  19. Priddle, H. et al. Disruption of the talin gene compromises focal adhesion assembly in undifferentiated but not differentiated embryonic stem cells. J. Cell Biol. 142, 1121–1133 (1998)

    CAS  Article  Google Scholar 

  20. Chavis, P. & Westbrook, G. Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse. Nature 411, 317–321 (2001)

    ADS  CAS  Article  Google Scholar 

  21. Serra-Pages, C. et al. The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J. 14, 2827–2838 (1995)

    CAS  Article  Google Scholar 

  22. Merilainen, J., Lehto, V. P. & Wasenius, V. M. FAP52, a novel, SH3 domain-containing focal adhesion protein. J. Biol. Chem. 272, 23278–23284 (1997)

    CAS  Article  Google Scholar 

  23. Zhen, M. & Jin, Y. The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C elegans. Nature 401, 371–375 (1999)

    ADS  CAS  PubMed  Google Scholar 

  24. Monkley, S. J., Pritchard, C. A. & Critchley, D. R. Analysis of the mammalian talin2 gene TLN2. Biochem. Biophys. Res. Commun. 286, 880–885 (2001)

    CAS  Article  Google Scholar 

  25. Martel, V. et al. Conformation, localization, and integrin binding of talin depend on its interaction with phosphoinositides. J. Biol. Chem. 276, 21217–21227 (2001)

    CAS  Article  Google Scholar 

  26. McNamee, H. P., Ingber, D. E. & Schwartz, M. A. Adhesion to fibronectin stimulates inositol lipid synthesis and enhances PDGF-induced inositol lipid breakdown. J. Cell Biol. 121, 673–678 (1993)

    CAS  Article  Google Scholar 

  27. Kunz, J. et al. The activation loop of phosphatidylinositol phosphate kinases determines signaling specificity. Mol. Cell 5, 1–11 (2000)

    CAS  Article  Google Scholar 

  28. Tolias, K. F. et al. Type Ialpha phosphatidylinositol-4-phosphate 5-kinase mediates Rac-dependent actin assembly. Curr. Biol. 10, 153–156 (2000)

    CAS  Article  Google Scholar 

  29. McPherson, P. S. et al. Interaction of Grb2 via its Src homology 3 domains with synaptic proteins including synapsin I. Proc. Natl Acad. Sci. USA 91, 6486–6490 (1994)

    ADS  CAS  Article  Google Scholar 

  30. Felici, F., Castagnoli, L., Musacchio, A., Jappelli, R. & Cesareni, G. Selection of antibody ligands from a large library of oligopeptides expressed on a multivalent exposition vector. J. Mol. Biol. 222, 301–310 (1991)

    CAS  Article  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Pietro De Camilli.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing