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

Abstract

PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) is a relatively common anionic lipid that regulates cellular functions by multiple mechanisms. Hydrolysis of PI(4,5)P2 by phospholipase C yields inositol trisphosphate and diacylglycerol. Phosphorylation by phosphoinositide 3-kinase yields PI(3,4,5)P3, which is a potent signal for survival and proliferation. Also, PI(4,5)P2 can bind directly to integral and peripheral membrane proteins. As an example of regulation by PI(4,5)P2, we discuss phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in detail. PTEN is an important tumor suppressor and hydrolyzes PI(3,4,5)P3. PI(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.

Engineering ePTEN, an enhanced PTEN with increased tumor suppressor activities

“…It has been proposed that these cationic residues interact with anionic phospholipids, such as PIP2, and are masked by the inhibitory tail domain (10,12,16,21). In addition, amino acid residues 13-15 are thought to function as a nuclear localization signal (13,22,23).…”

“…The PIP2-binding domain is located in the N terminus (amino acid residues 6-15) and has been suggested to be important for membrane association and nuclear localization (10,13,22). By individually mutating four positively charged residues, we separated the residues necessary for membrane association from nuclear localization.…”

“…PTEN comprises an N-terminal "PIP2-binding" motif, globular catalytic and C2 domains, and a C-terminal tail (8)(9)(10). Positively charged residues in the PIP2-binding and C2 domains have been proposed to recruit PTEN to the plasma membrane through associations with negatively charged head groups of membrane lipids (11)(12)(13).…”

Characterization of the S. cerevisiae inp51 mutant links phosphatidylinositol 4,5-bisphosphate levels with lipid content, membrane fluidity and cold growth

“…1) [41]. PI(4,5)P 2 is a relatively common phospholipid, that plays key regulatory roles in a number of essential cellular processes [29,64], including ion channel modulation [101], cytoskeletal regulation [88,112], endocytosis of plasma membrane proteins [103] and membrane identity [38]. Interestingly, heat stress, a condition that increases membrane fluidity, elevates PI(4,5)P 2 levels and induces the signaling through the CWI pathway [66].…”

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

“…In turn, PIP 3 is generated by PI3K-mediated phosphorylation of PIP 2 in response to activation of receptor tyrosine kinases (2,16). Activation of Akt is opposed by PTEN, which dephosphorylates PIP 3 and consequently blocks Akt activation (8,21). PTEN deletion in mice results in EC hyperproliferation and disordered angiogenesis (23).…”