Phosphatidylinositol 3,4-bisphosphate

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Chemical structure of sn-1-stearoyl-2-arachidonoyl phosphatidylinositol (3,4)-bisphosphate Phosphatidylinositol-3,4-bisphosphate.svg
Chemical structure of sn-1-stearoyl-2-arachidonoyl phosphatidylinositol (3,4)-bisphosphate

Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2) is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways. [1]

Of all the phospholipids found within the membrane, inositol phospholipids make up less than 10%. [2] Phosphoinositide’s (PI’s), also known as phosphatidylinositol phosphates, are synthesized in the cell's endoplasmic reticulum by the protein phosphatidylinositol synthase (PIS). [3] [4] [5] PI’s are highly compartmentalized; their main components include a glycerol backbone, two fatty acid chains enriched with stearic acid and arachidonic acid, and an inositol ring whose phosphate groups' regulation differs between organelles depending on the specific PI and PIP kinases and PIP phosphatases present in the organelle. [6] [7] [8] These kinases and phosphatases conduct phosphorylation and dephosphorylation at the inositol sugar head groups 3’, 4’, and 5’ positions, producing differing phosphoinositides, including PtdIns(3,4)P2. [9] [1] PI kinases catalyze phosphate groups binding while PI phosphatases remove phosphate groups at the three positions on the PI inositol ring, giving seven different combinations of PI’s. [10] [11]

PtdIns(3,4)P2 is dephophosphorylated by the phosphatase INPP4B on the 4' position of the inositol ring and by the TPTE (transmembrane phosphatases with tensin homology) family of phosphatases on the 3 position of the inositol ring.

The PH domain in a number of proteins binds to PtdIns(3,4)P2 including the PH domain in PKB. The generation of PtdIns(3,4)P2 at the plasma membrane upon the activation of class I PI 3-kinases and SHIP phosphatases causes these proteins to translocate to the plasma membrane, thereby affecting their activity.

Class I and II phosphoinositide 3-kinases (PI3Ks) synthesize PtdIns(3,4)P2 by phosphorylating the phosphoinositide PI4P’s 3' -OH position. [12] [13] Phosphatases SHIP1 and SH2-containing inositol 5’-polyphosphatases (SHIP2) produce PtdIns(3,4)P2 through desphosphorylation of PtdIns(3,4,5)P3’s 5’ inositol ring position. [14] [15] In addition to these positive regulators at the plasma membrane (PM), 3-phosphatase tensin homolog (PTEN) acts as a negative regulator of PtdIns(3,4)P2 production by depleting PtdIns(3,4,5)P3 levels at the PM through dephosphorylation of PtdIns(3,4,5)P3’s 3’ inositol ring position, giving rise to PtdIns(4,5)P2. [16] [17] Inositol polyphosphate 4-phosphatase isozymes, INPP4A and INPP4B, also act as negative PtdIns(3,4)P2 regulators, though through a more direct interaction- by hydrolyzing PtdIns(3,4)P2’s 4-phosphate, producing PI3P. [18] [19] [20] PtdIns(3,4)P2 has been indicated to be critical for AKT (Protein kinase B, PKB) activation within the PI3K pathway through the PI’s regulation by the SHIP1 and 2 phosphatases. Akt is recruited and subsequently activated through its PH domains interaction with PtdIns(3,4)P2 and PtdIns(3,4,5)P3 both of which have shown to have high affinity with the Akt PH domain. [21] Once bound to the PM through its interaction with PtdIns(3,4)P2 and PtdIns(3,4,5)P3, Akt is activated through release of its auto-inhibitory interaction between the PH and kinase domains. [22] Following this release, T308 in the proteins activation loop and S437 in the proteins hydrophobic domain are phosphorylated by Phosphoinositide-dependent kinase-1 (PDK1) [23] and mechanistic target of Rapamycin Complex 2 (mTORC2), [24] respectively. Test tube experiments have shown that the essential recruitment of PDK1 for Akt activation at the PM can be driven through interactions with both PtdIns(3,4)P2 and PtdIns(3,4,5)P3. [25]

It was originally presumed that 5-phosphatases dephosphorylation of PI(3,4,5)P3 would be anti-tumoral, similar to tumor suppressor PTEN. Yet the 5-phosphatase SHIP proteins synthesis of PI(3,4)P2 has been linked to tumor cell survival due to the lipid’s binding and subsequent activation of Akt. [26] Akt activation causes downstream metabolism alterations, apoptosis suppression and a rise in cell proliferation. [27] This pathway and its effects have shown up in 50% of cancers. [28] In conjunction, investigators have shown a rise in PI(3,4)P2 levels and mutation of 4-phosphatase INPP4B has shown mammary epithelial transformation. [29]

Recently, PtdIns(3,4)P2 has been shown to play an important role in vesicle maturation during clathrin-mediated endocytosis (CME). [30] [31] PtdIns(4)P synthesizing phosphatases SHIP2 and synaptojanin are recruited to clathrin structures at the beginning of the CME process. [32] [33] This production of PtdIns(4)P subsequently leads to PtdIns(3,4)P2 synthesis through PI3K-C2α11, and the newly synthesized PtdIns(3,4)P2 then recruits SNX9 and SNX18 PX-BAR domain proteins which narrow the nascent vesicles neck to eventually be cut and released by dynamin, forming vesicles. [34] [35]

PI(3,4)P2 plays another possible role at the PM, promoting cytoskeletal rearrangements through actin regulatory proteins like Lamellipodin. [36] [37] Lamellipodin is recruited to the PM where it is believed to interact with PI(3,4)P2 through its PH domain. Once at the PM, it can regulate lamellipodia actin networks and cell migration by interacting with actin-binding proteins like Ena/VASP. [38] [39] [40]

Related Research Articles

<span class="mw-page-title-main">Phosphatidylinositol</span> Chemical compound

Phosphatidylinositol consists of a family of lipids made of a phosphate group, two fatty acid chains, and one inositol molecule. They represent a class of the phosphatidylglycerides. Typically phosphatidylinositols form a minor component on the cytosolic side of eukaryotic cell membranes. The phosphate group gives the molecules a negative charge at physiological pH.

<span class="mw-page-title-main">Protein kinase B</span> Set of three serine/threonine-specific protein kinases

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

<span class="mw-page-title-main">Inositol phosphate</span>

Inositol phosphates are a group of mono- to hexaphosphorylated inositols. Each form of inositol phosphate is distinguished by the number and position of the phosphate group on the inositol ring.

<i>PTEN</i> (gene) Tumor suppressor gene

Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate cancer. Genes corresponding to PTEN (orthologs) have been identified in most mammals for which complete genome data are available.

<span class="mw-page-title-main">Phosphatidylinositol (3,4,5)-trisphosphate</span> Chemical compound

Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid that resides on the plasma membrane.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Phosphatidylinositol 3-phosphate</span> Chemical compound

Phosphatidylinositol 3-phosphate (PtdIns3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosphoinositide 3-kinases activity on phosphatidylinositol.

<span class="mw-page-title-main">P110δ</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the PIK3CD gene.

<span class="mw-page-title-main">Phosphatidylinositol 3,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 3,5-bisphosphate is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P levels, and more than 100-fold lower than the abundant PtdIns4P and PtdIns(4,5)P2. PtdIns(3,5)P2 was first reported to occur in mouse fibroblasts and budding yeast S. cerevisiae in 1997. In S. cerevisiae PtdIns(3,5)P2 levels increase dramatically during hyperosmotic shock. The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes.

Phosphatidylinositol phosphate kinases (PIPK) are kinases that phosphorylate the phosphoinositides PtdInsP and PtdInsP2 that are derivatives of phosphatidylinositol (PtdIns). It has been found that PtdIns is only phosphorylated on three (3,4,5) of its five hydroxyl groups, possibly because D-2 and D-6 hydroxyl groups cannot be phosphorylated because of steric hindrance. All 7 combinations of phosphorylated PtdIns have been found in animals, all except PtdIns(3,4,5)P3 have been found in plants.

<span class="mw-page-title-main">PX domain</span>

The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.

<span class="mw-page-title-main">PIKFYVE</span> Protein-coding gene in the species Homo sapiens

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

Bisphosphate may refer to:

Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation and many other cellular functions. Generally, phosphoinositides transduce signals by recruiting specific phosphoinositide-binding proteins to intracellular membranes.

Lewis C. Cantley is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer and diabetes mellitus. He is currently Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. He was formerly a professor in the Departments of Systems Biology and Medicine at Harvard Medical School, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center, in Boston, Massachusetts. In 2016, he was elected Chairman of the Board for the Hope Funds for Cancer Research.

Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase is an enzyme with systematic name 1-phosphatidyl-1D-myo-inositol-3,4,5-trisphosphate 5-phosphohydrolase, that has two isoforms: SHIP1 and SHIP2 (INPPL1).

Leonard (Len) R Stephens FRS is a molecular biologist, senior group leader and associate director at the Babraham Institute.

Phillip (Phill) Thomas Hawkins FRS is a molecular biologist, senior group leader at the Babraham Institute.

References

  1. ↑ Dimitrios Karathanassis; Robert V. Stahelin; Jerónimo Bravo; Olga Perisic; Christine M Pacold; Wonhwa Cho; Roger L Williams (2002). "Binding of the PX domain of p47phox to phosphatidylinositol 3,4-bisphosphate and phosphatidic acid is masked by an intramolecular interaction". EMBO Journal. 21 (19): 5057–5068. doi:10.1093/emboj/cdf519. PMC   129041 . PMID   12356722.
  2. ↑ Alberts, B., Johnson, A., Lewis, J., Morgan, D., Raff, M., Roberts, K., & Walters, P. (2015). Molecular biology of the cell (Sixth ed.). New York, NY: Garland Science.
  3. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
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  5. ↑ Epand RM. Recognition of polyunsaturated acyl chains by enzymes acting on membrane lipids. Biochim Biophys Acta. (2012) 1818:957–62. 10.1016/j.bbamem.2011.07.018
  6. ↑ Agranoff BW, Bradley R M, Brady RO. The enzymatic synthesis of inositol phosphatide. J Biol Chem. (1958) 233:1077–83.
  7. ↑ Epand RM. Recognition of polyunsaturated acyl chains by enzymes acting on membrane lipids. Biochim Biophys Acta. (2012) 1818:957–62. 10.1016/j.bbamem.2011.07.018
  8. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
  9. ↑ Alberts, B., Johnson, A., Lewis, J., Morgan, D., Raff, M., Roberts, K., & Walters, P. (2015). Molecular biology of the cell (Sixth ed.). New York, NY: Garland Science.
  10. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
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  12. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
  13. ↑ Balla T. Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev. (2013) 93:1019–137. 10.1152/physrev.00028.2012
  14. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
  15. ↑ Fernandes S, Iyer S, Kerr WG. Role of SHIP1 in cancer and mucosal inflammation. Ann NY Acad Sci. (2013) 1280:6–10. 10.1111/nyas.12038
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  18. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
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  20. ↑ Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, et al. . Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. (2009) 16:115–25. 10.1016/j.ccr.2009.06.006
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  22. ↑ Ebner M, Lučić I, Leonard TA, Yudushkin I. PI(3,4,5)P3 Engagement Restricts Akt Activity to Cellular Membranes. Mol Cell. 2017;65(3):416-431.e6.
  23. ↑ Alessi DR, James SR, Downes CP, Holmes AB, Gaffney P, Reese CB, et al. Characterization of a 3- phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Current Biology. 1997;7(4).
  24. ↑ Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex. Science. 2005;307(5712):1098–101.
  25. ↑ Alessi DR, James SR, Downes CP, Holmes AB, Gaffney P, Reese CB, et al. Characterization of a 3- phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Current Biology. 1997;7(4).
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  27. ↑ Ebner M, Lučić I, Leonard TA, Yudushkin I. PI(3,4,5)P3 Engagement Restricts Akt Activity to Cellular Membranes. Mol Cell. 2017;65(3):416-431.e6.
  28. ↑ Ebner M, Lučić I, Leonard TA, Yudushkin I. PI(3,4,5)P3 Engagement Restricts Akt Activity to Cellular Membranes. Mol Cell. 2017;65(3):416-431.e6.
  29. ↑ Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, et al. . Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. (2009) 16:115–25. 10.1016/j.ccr.2009.06.006
  30. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
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  32. ↑ Gozzelino, L., De Santis, M. C., Gulluni, F., Hirsch, E., & Martini, M. (2020). PI(3,4)P2 Signaling in Cancer and Metabolism. Frontiers in oncology, 10, 360. https://doi.org/10.3389/fonc.2020.00360
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