Phosphatidylinositol Phosphate Kinases Put PI4,5P 2 in Its Place

Abstract

Phosphatidylinositol 4,5 bisphosphate (PI4,5P(2)) is a critical second messenger that regulates a myriad of diverse cellular activities including modulation of the actin cytoskeleton, vesicle trafficking, focal adhesion formation, and nuclear events. In order to effectively regulate these disparate cellular events, synthesis of PI4,5P(2) by phosphatidylinositol phosphate kinases (PIP kinases) must be both spatially and temporally regulated. Two subfamilies of PIP kinases, types I and II, allow the generation of PI4,5P(2) from independent pools of substrate, PI(4)P and PI(5)P respectively. In turn, type I and II PIP kinases show different subcellular localization and thus are involved in distinct signaling pathways. Additionally, several type I isoforms, and their splice variants, have now been shown to be differentially localized throughout the cell and to be involved in the synthesis of PI4,5P(2) at distinct sites. These findings implicate PIP kinases as the major regulators of PI4,5P(2)-mediated events, making them key signaling enzymes in a variety of processes. Understanding the mechanisms regulating spatial and temporal synthesis of PI4,5P(2) by PIP kinases is vital for understanding these processes as a whole. This review examines both structural and regulatory features that modulate activity, localization, and substrate usage of PIPKs.

PIP2-Mediated HCN3 Channel Gating Is Crucial for Rhythmic Burst Firing in Thalamic Intergeniculate Leaflet Neurons

“…Membrane phospholipids can directly influence the function of many channels, including HCN1, 2 and 4 (Pian et al, 2007;Suh and Hille, 2008); therefore, we first investigated whether endogenous PIP 2 modulated HCN channel gating in IGL neurons. At micromolar concentrations, wortmannin blocks type III phosphatidylinositol 4-kinase (PI4K III) (Nakanishi et al, 1995), thereby inhibiting the final step in the biosynthetic pathway for PIP 2 (Doughman et al, 2003;Balla and Balla, 2006;Sasaki et al, 2009). Brain slices were preincubated at 30°C in ACSF containing 15 M wortmannin or 0.1% DMSO (the vehicle as control) for ϳ45 min before recording.…”

“…Among the ligands that can influence HCN gating, the best understood is cAMP; however, the regulation of cellular physiology by I h in IGL neurons is not mediated by this nucleotide. PIP 2 is also an important modulator that regulates various cellular activities including ion channel function (Doughman et al, 2003;Suh and Hille, 2008). Incubation with wortmannin, which leads to depletion of endogenous PIP 2 pools, resulted in a marked hyperpolarizing shift in voltage-dependent activation of both native and recombinant HCN3 channels (Fig.…”

PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway

“…Three major PI5KI isoforms (␣, ␤, and ␥) have been identified. [12][13][14][15] Increasing evidences indicate that PI5KIs, providing spatially and functionally distinct PIP2 pools, guarantee the regulation of specific cellular events: PI5KI␥, for instance, is required for focal adhesion and synaptic vesicle trafficking, 16,17 PI5KI␤ for constitutive receptor endocytosis, 18 whereas PI5KI␣ acts in the regulation of processes dependent on local changes of actin dynamics, such as membrane ruffling and phagocytosis. 19,20 In this report, we took advantage of the fusion protein consisting of GFP and the pleckstrin homology (PH) domain of PLC␦1, that is known to bind PIP2 with high affinity and specificity, [21][22][23] to monitor the dynamics and function of PIP2 during the cytotoxic event.…”

Type Iγ PIP Kinase Is a Novel Uropod Component that Regulates Rear Retraction during Neutrophil Chemotaxis

“…One mechanism by which PtdIns(4,5)P 2 is generated is through type I phosphatidylinositol phosphate kinases (PIPKI), which produce PtdIns(4,5)P 2 through the phosphorylation of the fifth hydroxyl of phosphatidylinositol (4)-phosphate (PI4P) (Doughman et al, 2003). The PIPKI family includes three isoforms: ␣, ␤, and ␥.…”

“…Furthermore, PIPKI␥ mRNA is alternatively spliced to form PIPKI␥635 and PIPKI␥661, which differ by a 26-amino acid C-terminal extension. Previous work has shown that the PIPKI family of lipid kinases display distinct subcellular distributions in fibroblasts (Di Paolo et al, 2002;Ling et al, 2002;Doughman et al, 2003). PIPKI␣ targets to the leading edge of cells where it regulates membrane ruffling (Doughman et al, 2003), whereas PIPKI␥661 targets to focal adhesions and may regulate integrin-mediated adhesions during cell migration via an interaction with the cytoskeletal protein talin (Di Paolo et al, 2002;Ling et al, 2002).…”