Phosphoinositides – The Seven Species: Conversion and Cellular Roles

Abstract

Phosphoinositides are phospholipids that contain a phosphorylated inositol head group. The position and number of phosphate groups varies, which results in seven phosphoinositide species. A large family of enzymes have evolved to specifically modify phosphoinositides. Phosphoinositide kinases and phosphatases modify the phosphorylation state of the inositol head group, whereas phospholipases hydrolyse phosphoinositides to release the soluble head group into the cytosol. The combined action of these enzymes produces the phosphoinositide signature of a cell, where certain membrane compartments are enriched or depleted of specific phosphoinositides. The cellular response of a certain phosphoinositide signature is mediated by phosphoinositide effectors. These effectors contain phosphoinositide recognition domains, which guide the effector to the appropriate location and in many cases also modulate their activity. Phosphoinositides play crucial roles in many cellular processes, including cell signalling, cytoskeletal rearrangements, vesicle transport and control of ion channels. Key Concepts: Phosphoinositides are phospholipids that contain a negatively charged phosphoinositol head group. Phosphoinositides are modified by phosphoinositide kinases, phosphatases and phospholipases. Specific phosphoinositides are enriched in different membrane compartments. Specific phosphoinositide recognition modules are linked to effectors. Tight regulation of generation and depletion of phosphoinositides allows spatio‐temporal control of complex cellular processes. PI3KI and PTEN, which control PtdIns(3,4,5)P 3 levels, belong to the most frequently mutated genes in cancer.

Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

“…Surprisingly, NCT-504 also robustly increased PI(3,5)P2 levels, and to a lesser extent increased levels of PI3P ( Figure 2B and E ). We did not observe an effect on PI(4,5)P2 levels ( Figure 2F ), which is consistent with other reports indicating that the cellular levels of this lipid are mostly generated from PI4P via type I PI4P 5-kinases ( Lietha, 2011 ). Kinetic measurement of PI levels showed that NCT-504 causes an increase in PI5P, PI(3,5)P2 and PI3P levels along with a decrease in PI4P, progressively over 12 hr ( Figure 2—figure supplement 2 ).…”

“…Note that other PI levels were not tested in the dPI4PK Drosophila mutant. We hypothesized that elevation of PI5P might further impact the equilibrium between various PI species ( Lietha, 2011 ; Emerling et al, 2014 ; Balla, 2013 ). To test this hypothesis, we exposed wild type mouse embryonic fibroblasts to nontoxic concentrations of NCT-504 (10 μM) for 12 hr, and then evaluated the levels of PI by HPLC ( Figure 2 ; toxicity assay in Figure 2—figure supplement 1 ).…”

“…The protein is predominantly localized in several tissues, including the brain ( Sasaki et al, 2009 ; Rameh et al, 1997 ; Clarke et al, 2008 ; Clarke et al, 2009 ). Enzymatically, PIP4Kγ phosphorylates phosphatidylinositol-5-phosphate [PI5P] to produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] ( Lietha, 2011 ). The biological function of PIP4Kγ is not completely understood, although recent reports suggest a role in the modulation of vesicle trafficking ( Clarke et al, 2008 ), and mTOR signaling ( Mackey et al, 2014 ).…”

Molecular recognition with boronic acids—applications in chemical biology

“…Receptor 13 is a useful tool for exploring PIP 2 -dependent cellular processes, many of which are linked to diseases including cancer [74], diabetes [14] and Lowe syndrome [45]. This work has identified PIP 2 as a potential drug target in the diagnosis and treatment of these disorders.…”

Role of PIKfyve in macrophage and neutrophil immune response

“…These lipids recruit a unique set of effector proteins, which have PI recognition domains. Upon binding, the effector proteins are either guided to the appropriate location inside the cell or their activity is being modulated (Lietha, 2011).…”