The ubiquitous phosphoinositides

Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy, neuropathy and ciliopathy).

Current Biology, 2001

The membrane phospholipid phosphatidylinositol is the precursor of a family of lipid second-messengers, known as phosphoinositides, which differ in the phosphorylation status of their inositol group. A major advance in understanding phosphoinositide signalling has been the identification of a number of highly conserved modular protein domains whose function appears to be to bind various phosphoinositides. Such 'cut and paste' modules are found in a diverse array of multidomain proteins and recruit their host protein to specific regions in cells via interactions with phosphoinositides. Here, with particular reference to proteins involved in membrane traffic pathways, we discuss recent advances in our understanding of phosphoinositide-binding domains.

EMBO reports, 2007

Phosphoinositides (PIs) have long been known to have important roles in cell signalling. During the past decade, it has become clear that these lipids also act as constitutive signals that aid in defining organelle identity, and are short-lived recruiters and regulators of cytoskeletal and membrane dynamics. Recent studies have provided important clues as to how regulated activation of PI-metabolizing enzymes and recruitment of their binding proteins might cooperate in targeting distinct pools of PIs to different cell physiological functions.

Advances in Biological Regulation, 2014

Biological & Pharmaceutical Bulletin, 2007

Subcellular Biochemistry, 2006

FEBS Letters, 2007

Phosphoinositides serve as important spatio-temporal regulators of intracellular trafficking and cell signalling events. In addition to their recognition by specific phosphoinositide binding domains present within cytoplasmic adaptor proteins or membrane integral channels and transporters phosphoinositides may affect membrane transport by eliciting conformational changes within proteins or by regulating enzymatic activities. During adaptor-mediated membrane traffic phosphoinositides form part of coincidence detection systems that aid in targeting pools of specific phosphoinositides to select intracellular transport pathways. In this review, we discuss potential mechanisms for conferring selectivity onto the phosphoinositide code as well as possible avenues for future research.

Developmental Cell, 2011

Polyphosphoinositides are lipid signaling molecules generated from phosphatidylinositol (PtdIns) with critical roles in vesicular trafficking and signaling. It is poorly understood where PtdIns is located within cells and how it moves around between membranes. Here we identify a hitherto-unrecognized highly mobile membrane compartment as the site of PtdIns synthesis and a likely source of PtdIns of all membranes. We show that the PtdIns-synthesizing enzyme PIS associates with a rapidly moving compartment of ER origin that makes ample contacts with other membranes. In contrast, CDP-diacylglycerol synthases that provide PIS with its substrate reside in the tubular ER. Expression of a PtdInsspecific bacterial PLC generates diacylglycerol also in rapidly moving cytoplasmic objects. We propose a model in which PtdIns is synthesized in a highly mobile lipid distribution platform and is delivered to other membranes during multiple contacts by yet-to-be-defined lipid transfer mechanisms.

Trends in Biochemical Sciences, 1998

Plant Signaling & Behavior, 2008

by phosphorylation of the inositol-ring in the lipid-head group; the action of specific lipid kinases gives rise to a family of structurally-related PIs, in plants representing PtdIns-mono-, and -bisphosphates. Specific PIs, such as phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ), can influence more than one physiological process, raising the question as to how interactions with alternative protein partners are coordinated. Previous studies have proposed that PIs are organized by spatiotemporal compartmentation into distinct functional pools, however, mechanisms for the generation and maintenance of such pools have not been presented. Several recent studies now indicate that not only the distinctive inositolpolyphosphate head groups may be relevant for PI function but also the associated fatty acyl-moieties, which may be involved in sorting of PI precursors into distinct pools. This mini-review aims at highlighting recent evidence that PI acylgroups exert relevant effects on signaling.