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‚Äźtemporal control of complex cellular processes.

  • PI3KI and PTEN, which control PtdIns(3,4,5)P3 levels, belong to the most frequently mutated genes in cancer.

Keywords: phosphoinositides; phosphoinositide kinase; phosphoinositide phosphatase; phospholipase; PH domain; PX domain; FERM domain; signalling; cytoskeleton; vesicular trafficking

Figure 1.

The seven phosphoinositides and their conversion. (a) Stereochemical representation of the seven dmyo‐phosphatidylinositol phosphate species with the three modifiable phosphates at the D3, D4 and D5 position shown as blue, yellow and red spheres, respectively. R and R′ can be saturated (often palmitoyl) or unsaturated (often oleoyl) acyl chains. Total carbon length of R and R′ are in the range of 16–24. (b) The seven phosphoinositides and the converting enzyme reactions are depicted. Kinase reactions are indicated by solid black arrows, phosphatase reactions as solid grey arrows and the PLC reaction is indicated as dashed black arrow. The enzymes catalysing the reactions are indicated in black (kinases and PLC) and grey (phosphatases).

Figure 2.

Localisation of phosphoinositides in the cell. The major phosphoinositide species in the plasma membrane is PtdIns(4,5)P2. Golgi membranes are enriched in PtdIns(4)P. PtdIns(4)P arriving from the Golgi to the plasma membrane is converted to PtdIns(4,5)P2 by PIP5Ks. Endocytosed vesicles are delivered to early endosomes, where the major phosphoinositide is PtdIns(3)P. Early endosomes sort endocytosed material to be recycled to the plasma membrane or to enter the lysosomal pathway through multivesicular bodies. For simplicity, only major phosphoinositide components are indicated.

Figure 3.

Domain structure of important phosphoinositide modifying enzymes. Class I PI3K (PI3K I) is composed of a p110 catalytic and a p85 regulatory subunit. In PLC‐γ, the catalytic domain (PLC‐X and PLC‐Y) and the second PH domain (PH part I and PH part II) are each divided into two parts and separated in sequence, but their 3D structure fold together into globular domains. The numbers next to the domain structures indicate the length of the polypeptide chain of the human enzyme. The reactions catalysed by the enzymes are indicated. Abbreviations: C2, conserved region‐2 of PKC; GAP, GTPase activating protein; iSH2, intervening domain (not an SH2 domain); Ptase, phosphatise; RBD, Ras‐binding domain and SH, Src homology.

Figure 4.

Crystal structures of phosphoinositide‐binding domains. Crystal structures of the (a) PH domain of Akt bound to Ins(1,3,4,5)P4 (pdb: 1h10), (b) the PX domain of p40phox bound to PtdIns(3)P (pdb: 1h6h) and (c) the FERM domain of radixin bound to Ins(1,4,5)P3 (pdb: 1gc6) are shown. Proteins are depicted as ribbons with a transparent surface. Crystal structures were obtained with inositol head groups ((a) and (c)) or soluble short chain lipid (b). Missing parts of the phosphoinositide lipids are schematically completed with brown strokes. N‐ and C‐termini of the domains are indicated.

Figure 5.

PtdIns(3,4,5)P3 in growth factor signalling. Activated growth factor receptors dimerise, which leads to autophosphorylation of their intracellular kinase domains. The adaptor protein Grb2 and the GTP exchange factor SOS (Son of Sevenless) are recruited to activated growth factor receptors. SOS activates the small GTPase Ras, which in turn activates class I PI3K (PI3KI), which consist of a p110 catalytic and a p85 regulatory subunit. Activated PI3KI converts PtdIns(4,5)P2 in the plasma membrane to PtdIns(3,4,5)P3. The serine/threonine protein kinases PKB/Akt and PDK1 interact with PtdIns(3,4,5)P3 through their PH domains, which results in their translocation to the plasma membrane. PDK1 phosphorylates and fully activates PKB/Akt. Phosphorylated PKB/Akt dissociates from the plasma membrane and phosphorylates a number of cytosolic targets, which provides signals for proliferation, growth, survival and metabolic changes. The PI3KI‐PKB/Akt signalling pathway can be switched off by the tumour suppressor PTEN, which reduces PtdIns(3,4,5)P3 levels in the plasma membrane. Ras also transduces canonical proliferative growth factor signals through MAP kinases.

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Further Reading

Kutateladze TG (2010) Translation of the phosphoinositide code by PI effectors. Nature Chemical Biology 6: 507–513.

Sasaki T, Takasuga S, Sasaki J et al. (2009) Mammalian phosphoinositide kinases and phosphatases. Progress in Lipid Research 48: 307–343.

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Lietha, Daniel(Feb 2011) Phosphoinositides – The Seven Species: Conversion and Cellular Roles. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023177]