Reactome | PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

Stable Identifier

R-HSA-6811558

Type

Pathway

Species

Homo sapiens

Locations in the PathwayBrowser

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Summation

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
19576174	PtdIns5P protects Akt from dephosphorylation through PP2A inhibition Ramel, D, Lagarrigue, F, Dupuis-Coronas, S, Chicanne, G, Leslie, N, Gaits-Iacovoni, F, Payrastre, B, Tronch�re, H	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 Clarke, JH, Irvine, RF	Biochem. J.	2013
9211928	Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules Zhang, X, Loijens, JC, Boronenkov, IV, Parker, GJ, Norris, FA, Chen, J, Thum, O, Prestwich, GD, Majerus, PW, Anderson, RA	J Biol Chem	1997
16456541	B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK Letourneux, C, Rocher, G, Porteu, F	EMBO J	2006
21827948	Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110? Burke, JE, Vadas, O, Berndt, A, Finegan, T, Perisic, O, Williams, RL	Structure	2011
19805105	A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane Mandelker, D, Gabelli, SB, Schmidt-Kittler, O, Zhu, J, Cheong, I, Huang, CH, Kinzler, KW, Vogelstein, B, Amzel, LM	Proc. Natl. Acad. Sci. U.S.A.	2009
12422219	Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin Di Paolo, G, Pellegrini, L, Letinic, K, Cestra, G, Zoncu, R, Voronov, S, Chang, S, Guo, J, Wenk, MR, De Camilli, P	Nature	2002
16979564	A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis Halstead, JR, van Rheenen, J, Snel, MH, Meeuws, S, Mohammed, S, D'Santos, CS, Heck, AJ, Jalink, K, Divecha, N	Curr Biol	2006
18753295	Localization of phosphatidylinositol phosphate kinase IIgamma in kidney to a membrane trafficking compartment within specialized cells of the nephron Clarke, JH, Emson, PC, Irvine, RF	Am J Physiol Renal Physiol	2008
15464023	Regulation and cellular roles of phosphoinositide 5-kinases Oude Weernink, PA, Schmidt, M, Jakobs, KH	Eur J Pharmacol	2004
9367159	A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate Rameh, LE, Tolias, KF, Duckworth, BC, Cantley, LC	Nature	1997
17245604	Phospholipase D signaling: orchestration by PIP2 and small GTPases Oude Weernink, PA, L�pez de Jes�s, M, Schmidt, M	Naunyn Schmiedebergs Arch Pharmacol	2007
19896968	Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases Clarke, JH, Wang, M, Irvine, RF	Adv Enzyme Regul	2010
25495341	The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site Clarke, JH, Giudici, ML, Burke, JE, Williams, RL, Maloney, DJ, Marugan, J, Irvine, RF	Biochem. J.	2015
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, Lenormand, P, Porteu, F	J. Biol. Chem.	2007