PtdIns(4,5)P2-Mediated Cell Signaling: Emerging Principles and PTEN as a Paradigm for Regulatory Mechanism

  • Arne Gericke
  • Nicholas R. Leslie
  • Mathias Lösche
  • Alonzo H. Ross
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 991)

Abstract

PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) is a relatively common anionic lipid that regulates cellular functions by multiple mechanisms. Hydrolysis of PtdIns(4,5)P2 by phospholipase C yields inositol trisphosphate and diacylglycerol. Phosphorylation by phosphoinositide 3-kinase yields PtdIns(3,4,5)P3, which is a potent signal for survival and proliferation. Also, PtdIns(4,5)P2 can bind directly to integral and peripheral membrane proteins. As an example of regulation by PtdIns(4,5)P2, we discuss phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in detail. PTEN is an important tumor suppressor and hydrolyzes PtdIns(3,4,5)P3. PtdIns(4,5)P2 enhances PTEN association with the plasma membrane and activates its phosphatase activity. This is a critical regulatory mechanism, but a detailed description of this process from a structural point of view is lacking. The disordered lipid bilayer environment hinders structural determinations of membrane-bound PTEN. A new method to analyze membrane-bound protein measures neutron reflectivity for proteins bound to tethered phospholipid membranes. These methods allow determination of the orientation and shape of membrane-bound proteins. In combination with molecular dynamics simulations, these studies will provide crucial structural information that can serve as a foundation for our understanding of PTEN regulation in normal and pathological processes.

Keywords

Phosphoinositide Phosphatidylinositol 4,5-bisphosphate Lipid membrane PTEN Phosphatase 

Notes

Acknowledgments

We thank Marie-Claire Daou for PTEN protein preparation, and Drs. Siddharth Shenoy, Prabhanshu Shekhar, Frank Heinrich, and Hirsh Nanda for conducting the neutron scattering and MD simulation work and for stimulating discussions and Drs. David Vanderah and Gintaras Valincius for a fruitful collaborations on the design and optimization of tethered bilayer sample formats. This work was supported by the NIH (P01 AG032131, R01 GM101647 and R01 NS021716), NSF (CHEM 442288) and the Department of Commerce (70NANB8H8009 and 70NANB11H8139). Beamtime at the NIST Center for Neutron Research and computational resources at the NIH (http://biowulf.nih.gov), the Extreme Science and Engineering Discovery Environment (XSEDE), supported by the NSF (OCI-105357), with computations performed at the NICS (http://www.nics.tennessee.edu/) and the Pittsburgh Supercomputing Center (BIO110004P), are gratefully acknowledged.

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Arne Gericke
    • 1
  • Nicholas R. Leslie
    • 2
  • Mathias Lösche
    • 3
    • 4
    • 5
  • Alonzo H. Ross
    • 6
    • 7
  1. 1.Department of Chemistry and BiochemistryWorcester Polytechnic InstituteWorcesterUSA
  2. 2.Division of Molecular PhysiologyUniversity of DundeeDundeeUK
  3. 3.Department of PhysicsCarnegie Mellon UniversityPittsburghUSA
  4. 4.Department of Biomedical EngineeringCarnegie Mellon UniversityPittsburghUSA
  5. 5.The National Institute of Standards and TechnologyCenter for Neutron ResearchGaithersburgUSA
  6. 6.Department of BiochemistryUniversity of Massachusetts Medical SchoolWorcesterUSA
  7. 7.Department of Molecular PharmacologyUniversity of Massachusetts Medical SchoolWorcesterUSA

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