Phosphoinositides – The Seven Species: Conversion and Cellular Roles


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.



Akiyama C, Shinozaki‐Narikawa N, Kitazawa T et al. (2005) Phosphatidylinositol‐4‐phosphate 5‐kinase gamma is associated with cell‐cell junction in A431 epithelial cells. Cell Biology International 29: 514–520.

Bondeva T, Pirola L, Bulgarelli‐Leva G et al. (1998) Bifurcation of lipid and protein kinase signals of PI3Kgamma to the protein kinases PKB and MAPK. Science 282: 293–296.

Boronenkov IV, Loijens JC, Umeda M and Anderson RA (1998) Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre‐mRNA processing factors. Molecular Biology of the Cell 9: 3547–3560.

van den Bout I and Divecha N (2009) PIP5K‐driven PtdIns(4,5)P2 synthesis: regulation and cellular functions. Journal of Cell Science 122: 3837–3850.

Bunney TD and Katan M (2010) Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nature Reviews Cancer 10: 342–352.

Cantley LC (2002) The phosphoinositide 3‐kinase pathway. Science 296: 1655–1657.

Courtney KD, Corcoran RB and Engelman JA (2010) The PI3K pathway as drug target in human cancer. Journal of Clinical Oncology 28: 1075–1083.

Delmas P and Brown DA (2005) Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nature Reviews Neuroscience 6: 850–862.

Di Paolo G, Pellegrini L, Letinic K et al. (2002) Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin. Nature 420: 85–89.

Elliott PR, Goult BT, Kopp PM et al. (2010) The structure of the talin head reveals a novel extended conformation of the FERM domain. Structure 18: 1289–1299.

Fukami K, Furuhashi K, Inagaki M et al. (1992) Requirement of phosphatidylinositol 4,5‐bisphosphate for alpha‐actinin function. Nature 359: 150–152.

Gaidarov I and Keen JH (1999) Phosphoinositide‐AP‐2 interactions required for targeting to plasma membrane clathrin‐coated pits. Journal of Cell Biology 146: 755–764.

Gilmore AP and Burridge K (1996) Regulation of vinculin binding to talin and actin by phosphatidyl‐inositol‐4‐5‐bisphosphate. Nature 381: 531–535.

Goksoy E, Ma YQ, Wang X et al. (2008) Structural basis for the autoinhibition of talin in regulating integrin activation. Molecular Cell 31: 124–133.

Hamada K, Shimizu T, Matsui T, Tsukita S and Hakoshima T (2000) Structural basis of the membrane‐targeting and unmasking mechanisms of the radixin FERM domain. EMBO Journal 19: 4449–4462.

Janmey PA and Stossel TP (1987) Modulation of gelsolin function by phosphatidylinositol 4,5‐bisphosphate. Nature 325: 362–364.

Keniry M and Parsons R (2008) The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 27: 5477–5485.

Lassing I and Lindberg U (1985) Specific interaction between phosphatidylinositol 4,5‐bisphosphate and profilactin. Nature 314: 472–474.

Ling K, Doughman RL, Firestone AJ, Bunce MW and Anderson RA (2002) Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 420: 89–93.

Malkova S, Stahelin RV, Pingali SV, Cho W and Schlossman ML (2006) Orientation and penetration depth of monolayer‐bound p40phox‐PX. Biochemistry 45: 13566–13575.

Manning BD and Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129: 1261–1274.

Noh DY, Shin SH and Rhee SG (1995) Phosphoinositide‐specific phospholipase C and mitogenic signaling. Biochimica et Biophysica Acta 1242: 99–113.

Papayannopoulos V, Co C, Prehoda KE et al. (2005) A polybasic motif allows N‐WASP to act as a sensor of PIP(2) density. Molecular Cell 17: 181–191.

Pearson MA, Reczek D, Bretscher A and Karplus PA (2000) Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 101: 259–270.

Poulin B, Sekiya F and Rhee SG (2005) Intramolecular interaction between phosphorylated tyrosine‐783 and the C‐terminal Src homology 2 domain activates phospholipase C‐gamma1. Proceedings of the National Academy of Sciences of the USA 102: 4276–4281.

Prasad NK (2009) SHIP2 phosphoinositol phosphatase positively regulates EGFR‐Akt pathway, CXCR4 expression, and cell migration in MDA‐MB‐231 breast cancer cells. International Journal of Oncology 34: 97–105.

Prasad NK, Tandon M, Badve S, Snyder PW and Nakshatri H (2008) Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover. Carcinogenesis 29: 25–34.

Rao VD, Misra S, Boronenkov IV, Anderson RA and Hurley JH (1998) Structure of type II beta phosphatidylinositol phosphate kinase: a protein kinase fold flattened for interfacial phosphorylation. Cell 94: 829–839.

Sala G, Dituri F, Raimondi C et al. (2008) Phospholipase Cgamma1 is required for metastasis development and progression. Cancer Research 68: 10187–10196.

Saltel F, Mortier E, Hytonen VP et al. (2009) New PI(4,5)P2‐ and membrane proximal integrin‐binding motifs in the talin head control beta3‐integrin clustering. Journal of Cell Biology 187: 715–731.

Takei K, Yoshida Y and Yamada H (2005) Regulatory mechanisms of dynamin‐dependent endocytosis. Journal of Biochemistry 137: 243–247.

Yonezawa N, Homma Y, Yahara I, Sakai H and Nishida E (1991) A short sequence responsible for both phosphoinositide binding and actin binding activities of cofilin. Journal of Biological Chemistry 266: 17218–17221.

York JD, Odom AR, Murphy R, Ives EB and Wente SR (1999) A phospholipase C‐dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285: 96–100.

Zhao L and Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27: 5486–5496.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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