Phosphatidylinositol 4,5-bisphosphate: targeted production and signaling

Abstract

Phosphatidylinositol 4,5-bisphosphate (PI4,5P(2)) is a key lipid signaling molecule that regulates a vast array of biological activities. PI4,5P(2) can act directly as a messenger or can be utilized as a precursor to generate other messengers: inositol trisphosphate, diacylglycerol, or phosphatidylinositol 3,4,5-trisphosphate. PI4,5P(2) interacts with hundreds of different effector proteins. The enormous diversity of PI4,5P(2) effector proteins and the spatio-temporal control of PI4,5P(2) generation allow PI4,5P(2) signaling to control a broad spectrum of cellular functions. PI4,5P(2) is synthesized by phosphatidylinositol phosphate kinases (PIPKs). The array of PIPKs in cells enables their targeting to specific subcellular compartments through interactions with targeting factors that are often PI4,5P(2) effectors. These interactions are a mechanism to define spatial and temporal PI4,5P(2) synthesis and the specificity of PI4,5P(2) signaling. In turn, the regulation of PI4,5P(2) effectors at specific cellular compartments has implications for understanding how PI4,5P(2) controls cellular processes and its role in diseases.

Figure 1

Overview of PI4,5P₂ functions in the cytosol and plasma membrane. PI4,5P₂ is a polyphosphoinositide that is phosphorylated on the 4^th and 5^th hydroxyl group on the myo-inositol ring and is in the greatest concentration on the plasma membrane but is found on most cellular membrane compartments and in the nucleus. PI4,5P₂ is utilized by PI3K or PLC to generate second messengers: PI3,4,5P₃, DAG and IP₃. The generation of PI4,5P₂ in a spatio-temporal manner is the basis for PI4,5P₂-regulation of diverse cellular events, including endocytosis, exocytosis, vesicle trafficking and cell migration.

Figure 2

The localized production of PI4,5P₂ modulates specific PI4,5P₂ effectors. Extracellular signals and regulators regulate the interaction of PIPKs with targeting factors that recruit PIPKs to specific sub-cellular compartments. By generating PI4,5P₂ on site, PIPKs establish a local PI4,5P₂ pool to modulate the function of local PI4,5P₂ effectors necessary for site-specific biological activities.

Figure 3

PI4,5P₂ modulates E-cadherin trafficking. PIPKIγ interacts with both E-cadherin and AP complexes. Through this dual interaction, PIPKIγ acts as a scaffold between AP complexes and E-cadherin to facilitate E-cadherin endocytosis and trafficking to the basolateral membrane. In addition, AP complexes are a PI4,5P₂ effectors. The localized generation of PI4,5P₂ via PIPKIγ activates AP complexes. PIPKIγ also modulates exocyst-mediated E-cadherin trafficking. PIPKIγ generates local PI4,5P₂ pools on the basolateral membrane via interacting with E-cadherin, which direct the targeting of exocyst. The direct interaction between exocyst and PIPKIγ further facilitates the recruitment of exocyst to adherens junctions, where exocyst-bound lateral cargoes, such as E-cadherin, can be delivered.

Figure 4

PIPKIγ regulates the assembly of E-cadherin into adherens junctions in polarized epithelial cells. Stimuli, such as growth factors, can promote disassembly and phosphorylation of adherens junction components. PIPKIγ can promote nuclear translocation of β-catenin, leading to enhanced transcriptional activity. In migrating tumor cells, which have lost E-cadherin expression (after EMT), PIPKIγi2 coordinates with exocyst complex and talin to mediate polarized delivery of integrins at the leading edge membrane. PI4,5P₂ generation by PIPKIγi2 in plasma membrane or in recycling endosomes near the plasma membrane facilitates the assembly of the exocyst complex and talin. The coordinated activity of PIPKIγi2 and the exocyst complex in concert with talin at the leading edge promotes the polarized recruitment and trafficking of integrin molecules. Loss of PIPKIγi2, the exocyst complex or talin impairs the polarized recruitment/trafficking of integrins required for cell migration.