PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

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Homo sapiens
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Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase.
Literature References
PubMed ID Title Journal Year
17200115 Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity

Rocher, G, Letourneux, C, Porteu, F, Lenormand, P

J. Biol. Chem. 2007
25495341 The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site

Irvine, RF, Clarke, JH, Burke, JE, Giudici, ML, Marugan, J, Maloney, DJ, Williams, RL

Biochem. J. 2015
19896968 Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases

Wang, M, Irvine, RF, Clarke, JH

Adv Enzyme Regul 2010
17245604 Phospholipase D signaling: orchestration by PIP2 and small GTPases

Schmidt, M, Oude Weernink, PA, López de Jesús, M

Naunyn Schmiedebergs Arch Pharmacol 2007
9367159 A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate

Rameh, LE, Cantley, LC, Duckworth, BC, Tolias, KF

Nature 1997
15464023 Regulation and cellular roles of phosphoinositide 5-kinases

Schmidt, M, Jakobs, KH, Oude Weernink, PA

Eur J Pharmacol 2004
18753295 Localization of phosphatidylinositol phosphate kinase IIgamma in kidney to a membrane trafficking compartment within specialized cells of the nephron

Irvine, RF, Emson, PC, Clarke, JH

Am J Physiol Renal Physiol 2008
16979564 A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis

Jalink, K, Heck, AJ, Mohammed, S, Halstead, JR, Meeuws, S, Divecha, N, D'Santos, CS, Snel, MH, van Rheenen, J

Curr Biol 2006
12422219 Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin

Cestra, G, Pellegrini, L, Di Paolo, G, Zoncu, R, Letinic, K, Wenk, MR, Voronov, S, De Camilli, P, Guo, J, Chang, S

Nature 2002
19805105 A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane

Cheong, I, Mandelker, D, Zhu, J, Schmidt-Kittler, O, Kinzler, KW, Vogelstein, B, Amzel, LM, Gabelli, SB, Huang, CH

Proc. Natl. Acad. Sci. U.S.A. 2009
21827948 Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110?

Vadas, O, Burke, JE, Finegan, T, Williams, RL, Perisic, O, Berndt, A

Structure 2011
16456541 B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK

Rocher, G, Porteu, F, Letourneux, C

EMBO J 2006
9211928 Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules

Thum, O, Majerus, PW, Parker, GJ, Boronenkov, IV, Zhang, X, Prestwich, GD, Anderson, RA, Loijens, JC, Chen, J, Norris, FA

J Biol Chem 1997
19576174 PtdIns5P protects Akt from dephosphorylation through PP2A inhibition

Leslie, N, Ramel, D, Chicanne, G, Gaits-Iacovoni, F, Lagarrigue, F, Tronchère, H, Payrastre, B, Dupuis-Coronas, S

Biochem. Biophys. Res. Commun. 2009
23758345 Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization

Irvine, RF, Clarke, JH

Biochem. J. 2013
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