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Lipid-mediated Protein Signaling pp 85–104Cite as

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

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Part of the book series: Advances in Experimental Medicine and Biology ((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.

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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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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA, 01609, USA

    Arne Gericke

  2. Division of Molecular Physiology, University of Dundee, Dundee, DD1 5EH, UK

    Nicholas R. Leslie

  3. Department of Physics, Carnegie Mellon University, Pittsburgh, PA, 15213, USA

    Mathias Lösche

  4. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA

    Mathias Lösche

  5. The National Institute of Standards and Technology, Center for Neutron Research, Gaithersburg, MD, 20899, USA

    Mathias Lösche

  6. Department of Biochemistry, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Alonzo H. Ross

  7. Department of Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Alonzo H. Ross

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  1. Arne Gericke
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  2. Nicholas R. Leslie
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  3. Mathias Lösche
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  4. Alonzo H. Ross
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Correspondence to Alonzo H. Ross .

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  1. , Biological Sciences, Virginia Tech, Kraft Drive 1981, Blacksburg, 24061, Virginia, USA

    Daniel G.S. Capelluto

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Gericke, A., Leslie, N.R., Lösche, M., Ross, A.H. (2013). PtdIns(4,5)P2-Mediated Cell Signaling: Emerging Principles and PTEN as a Paradigm for Regulatory Mechanism. In: Capelluto, D. (eds) Lipid-mediated Protein Signaling. Advances in Experimental Medicine and Biology, vol 991. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6331-9_6

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