PIP3 activates AKT signaling (Homo sapiens)

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483, 60, 797, 24, 34, 3552, 6322, 4127, 561, 5, 9, 15, 32...4661, 6545, 47, 5461, 657243, 44, 73313, 79396540, 423, 60, 7911, 36603, 796374266033, 57624, 8, 10, 13, 19...2, 6, 14, 16, 18...12, 25, 71PDPK1PIP2 TNRC6 p-S-AKTPIP3 p-S473-AKT1 E17K mutantPIP2 p-S-AKTPIP3 miR-26A Endonucleolytic RISC PI3K InhibitorsPI3K PDPK1PIP3 miR-26A Nonendonucleolytic RISC AKTPIP3 p-S473-AKT1 E17K mutantPIP2 miR-26A PTEN mRNAmiR-26A RISC PTENMg2+ AKTPIP3 AKTPIP3THEM4/TRIB3 TORC2 complex miR-26A Endonucleolytic Minimal RISC nucleoplasmcytosolp-S-AKTPDPK1PIP3 AKT inhibitorsAKT miR-26A Nonendonucleolytic Minimal RISC AKT inhibitors PDPK1PIP3 Nonendonucleolytic Argonaute PHLPP miR-26A RISC PHLPP AKT1 E17K mutantPIP2 THEM4/TRIB3 PDPK1p-S473-AKT1 E17K mutantPIP2 PDPK1PIP2 ATPAKT1S1ADPp-S939,T1462-TSC2PDPK1 ADPGSK3PHLPP1 PTEN mRNAPIPTEN mRNA TNRC6A PIADPTNRC6B p-S473-AKT1 E17K mutant ATPPDPK1PIP3ADPMLST8 p-T-CDKN1A/BMK2206 PDPK1 EIF2C3 p-S15,S356-RPS6KB2Active AKTPIPTEN MutantsMOV10 p-T-AKTActive AKTIntrinsic Pathway for ApoptosisPIPIADPADPMDM2p-S-AKTPDPK1PIP3ATPATPmiR-26A2 MAPKAP1 p-S196-CASP9p-S351-NR4A1THEM4/TRIB3H2OATPPiH2ONR4A1AKT inhibitorsPiMTOR TORC2 complexPHLPP2 Mg2+ ATPCREB1EIF2C1 ADPADPAKT1 E17K mutantPIP2EIF2C4 p-T308,S473-AKT1 E17K mutantmiR-26A1 PIp-T23-CHUKADPTNRC6C p-S-AKTPIP3PI3K inhibitorsPDPK1PIP2AKTEIF2C2 PI3K InhibitorsPI3KAKT inhibitorsAKTTriciribine CHUKATPActivatorPI3KActivatorPI3K/PI3K mutantsPTEN mRNAmiR-26A RISCCASP9PDPK1 Forkhead box transcription factorPIATPPIAKT1 E17K mutantBADRICTOR p-S473-AKT1 E17K mutantPIP2Mn2+ PDPK1 AKT1 E17K mutant PTENMg2+RPS6KB2PDPK1PHLPP Phospho-Forkhead box transcription factorAKTPIP3AKTPIP3THEM4/TRIB3H2Op-S9/21-GSK3TRIB3 THEM4 p-S99-BADPTEN p-S183,T246-AKT1S1ADPATPATPp-S473-AKT1 E17K mutant PI3K mutantsp-S133-CREB1PIAKT/AKT1 E17K mutantPDPK1p-S473-AKT1 E17K mutantPIP2miR-26A RISCATPPIperifosine p-S166,S188-MDM2TSC2PIATPCDKN1A/B717, 30, 7879793579357934794, 8, 10, 19, 23...


Description

Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1257604

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  374. Palamidessi A, Frittoli E, Garré M, Faretta M, Mione M, Testa I, Diaspro A, Lanzetti L, Scita G, Di Fiore PP.; ''Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration.''; PubMed Europe PMC Scholia
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History

View all...
CompareRevisionActionTimeUserComment
114764view16:25, 25 January 2021ReactomeTeamReactome version 75
113208view11:27, 2 November 2020ReactomeTeamReactome version 74
112432view15:37, 9 October 2020ReactomeTeamReactome version 73
101336view11:22, 1 November 2018ReactomeTeamreactome version 66
100874view20:56, 31 October 2018ReactomeTeamreactome version 65
100415view19:30, 31 October 2018ReactomeTeamreactome version 64
99964view16:14, 31 October 2018ReactomeTeamreactome version 63
99519view14:47, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99161view12:41, 31 October 2018ReactomeTeamreactome version 62
93830view13:39, 16 August 2017ReactomeTeamreactome version 61
93382view11:22, 9 August 2017ReactomeTeamreactome version 61
88094view09:28, 26 July 2016RyanmillerOntology Term : 'kinase mediated signaling pathway' added !
88093view09:25, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86468view09:18, 11 July 2016ReactomeTeamreactome version 56
83247view10:30, 18 November 2015ReactomeTeamVersion54
81352view12:52, 21 August 2015ReactomeTeamVersion53
76821view08:04, 17 July 2014ReactomeTeamFixed remaining interactions
76525view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75858view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75558view10:35, 10 June 2014ReactomeTeamReactome 48 Update
74913view13:44, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74557view08:35, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT

PIP3

THEM4/TRIB3		ComplexREACT_12823 (Reactome)
AKT PIP3ComplexREACT_147984 (Reactome)
AKT inhibitors AKTComplexREACT_148070 (Reactome)
AKT inhibitorsMetaboliteREACT_148563 (Reactome)
AKT/AKT1 E17K mutantProteinREACT_147936 (Reactome)
AKT1 E17K mutant PIP2ComplexREACT_148412 (Reactome)
AKT1 E17K mutant ProteinP31749 (Uniprot-TrEMBL)
AKT1 E17K mutantProteinP31749 (Uniprot-TrEMBL)
AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
AKTProteinREACT_12946 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activator PI3K/PI3K mutantsComplexREACT_148475 (Reactome)
Activator PI3KComplexREACT_148170 (Reactome)
Active AKTProteinREACT_13116 (Reactome)
Active AKTProteinREACT_13319 (Reactome)
BADProteinQ92934 (Uniprot-TrEMBL)
CASP9ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
CDKN1A/BProteinREACT_13380 (Reactome)
CHUKProteinO15111 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C2 ProteinQ9UKV8 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
Forkhead box transcription factorProteinREACT_13013 (Reactome)
GSK3ProteinREACT_13050 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
Intrinsic Pathway for ApoptosisPathwayREACT_964 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MK2206 MetaboliteCHEBI:716367 (ChEBI)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mn2+ MetaboliteCHEBI:18291 (ChEBI)
NR4A1ProteinP22736 (Uniprot-TrEMBL)
PDPK1 PIP2ComplexREACT_148508 (Reactome)
PDPK1 PIP3ComplexREACT_148385 (Reactome)
PDPK1

p-S473-AKT1 E17K mutant

PIP2		ComplexREACT_148312 (Reactome)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PHLPP ComplexREACT_13329 (Reactome)
PHLPP1 ProteinO60346 (Uniprot-TrEMBL)
PHLPP2 ProteinQ6ZVD8 (Uniprot-TrEMBL)
PI3K Inhibitors PI3KComplexREACT_148204 (Reactome)
PI3K inhibitorsMetaboliteREACT_148311 (Reactome) PI3K inhibitors bind the catalytic subunit of PIK3CA, blocking its phosphoinositide kinase activity.
PI3K mutantsComplexREACT_148388 (Reactome)
PIMetaboliteCHEBI:16618 (ChEBI)
PIMetaboliteCHEBI:18348 (ChEBI)
PTEN Mg2+ComplexREACT_12877 (Reactome)
PTEN MutantsProteinREACT_148130 (Reactome)
PTEN ProteinP60484 (Uniprot-TrEMBL)
PTEN mRNA miR-26A RISCComplexREACT_147972 (Reactome)
PTEN mRNA ProteinENST00000371953 (ENSEMBL)
PTEN mRNARnaENST00000371953 (ENSEMBL)
Phospho-Forkhead box transcription factorProteinREACT_13209 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RICTOR ProteinQ6R327 (Uniprot-TrEMBL)
RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
THEM4 ProteinQ5T1C6 (Uniprot-TrEMBL)
THEM4/TRIB3ProteinREACT_148496 (Reactome)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TORC2 complexComplexREACT_13222 (Reactome)
TRIB3 ProteinQ96RU7 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
Triciribine MetaboliteCHEBI:65310 (ChEBI)
miR-26A RISCComplexREACT_148347 (Reactome)
miR-26A1 ProteinMI0000083 (miRBase)
miR-26A2 ProteinMI0000750 (miRBase)
p-S-AKT

PDPK1

PIP3		ComplexREACT_148335 (Reactome)
p-S-AKT PIP3ComplexREACT_148552 (Reactome)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S15,S356-RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
p-S166,S188-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S183,T246-AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
p-S196-CASP9ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
p-S351-NR4A1ProteinP22736 (Uniprot-TrEMBL)
p-S473-AKT1 E17K mutant PIP2ComplexREACT_148525 (Reactome)
p-S473-AKT1 E17K mutant ProteinP31749 (Uniprot-TrEMBL)
p-S9/21-GSK3ProteinREACT_13164 (Reactome)
p-S939,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-S99-BADProteinQ92934 (Uniprot-TrEMBL)
p-T-AKTProteinREACT_12669 (Reactome)
p-T-CDKN1A/BProteinREACT_12999 (Reactome)
p-T23-CHUKProteinO15111 (Uniprot-TrEMBL)
p-T308,S473-AKT1 E17K mutantProteinP31749 (Uniprot-TrEMBL)
perifosine MetaboliteCHEBI:428891 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_12383 (Reactome)
ADPArrowREACT_12391 (Reactome)
ADPArrowREACT_12395 (Reactome)
ADPArrowREACT_12420 (Reactome)
ADPArrowREACT_12461 (Reactome)
ADPArrowREACT_12485 (Reactome)
ADPArrowREACT_12532 (Reactome)
ADPArrowREACT_12537 (Reactome)
ADPArrowREACT_12549 (Reactome)
ADPArrowREACT_12565 (Reactome)
ADPArrowREACT_12572 (Reactome)
ADPArrowREACT_12584 (Reactome)
ADPArrowREACT_12597 (Reactome)
ADPArrowREACT_12614 (Reactome)
ADPArrowREACT_147781 (Reactome)
ADPArrowREACT_147846 (Reactome)
ADPArrowREACT_147858 (Reactome)
ADPArrowREACT_147862 (Reactome)
AKT

PIP3

THEM4/TRIB3		TBarREACT_12391 (Reactome)
AKT PIP3REACT_12391 (Reactome)
AKT PIP3REACT_12567 (Reactome)
AKT inhibitorsREACT_147895 (Reactome)
AKT/AKT1 E17K mutantREACT_147895 (Reactome)
AKT1 E17K mutant PIP2REACT_147858 (Reactome)
AKT1 E17K mutantREACT_147896 (Reactome)
AKT1S1REACT_12383 (Reactome)
AKTREACT_147886 (Reactome)
ATPREACT_12383 (Reactome)
ATPREACT_12391 (Reactome)
ATPREACT_12395 (Reactome)
ATPREACT_12420 (Reactome)
ATPREACT_12461 (Reactome)
ATPREACT_12485 (Reactome)
ATPREACT_12532 (Reactome)
ATPREACT_12537 (Reactome)
ATPREACT_12549 (Reactome)
ATPREACT_12565 (Reactome)
ATPREACT_12572 (Reactome)
ATPREACT_12584 (Reactome)
ATPREACT_12597 (Reactome)
ATPREACT_12614 (Reactome)
ATPREACT_147781 (Reactome)
ATPREACT_147846 (Reactome)
ATPREACT_147858 (Reactome)
ATPREACT_147862 (Reactome)
Activator PI3K/PI3K mutantsREACT_147854 (Reactome)
Activator PI3Kmim-catalysisREACT_147781 (Reactome)
Active AKTArrowREACT_12584 (Reactome)
Active AKTREACT_12403 (Reactome)
Active AKTmim-catalysisREACT_12383 (Reactome)
Active AKTmim-catalysisREACT_12395 (Reactome)
Active AKTmim-catalysisREACT_12420 (Reactome)
Active AKTmim-catalysisREACT_12461 (Reactome)
Active AKTmim-catalysisREACT_12485 (Reactome)
Active AKTmim-catalysisREACT_12532 (Reactome)
Active AKTmim-catalysisREACT_12537 (Reactome)
Active AKTmim-catalysisREACT_12549 (Reactome)
Active AKTmim-catalysisREACT_12565 (Reactome)
Active AKTmim-catalysisREACT_12572 (Reactome)
Active AKTmim-catalysisREACT_12597 (Reactome)
Active AKTmim-catalysisREACT_12614 (Reactome)
BADREACT_12565 (Reactome)
CASP9REACT_12395 (Reactome)
CDKN1A/BREACT_12420 (Reactome)
CHUKREACT_12461 (Reactome)
CREB1REACT_12597 (Reactome)
Forkhead box transcription factorREACT_12572 (Reactome)
GSK3REACT_12549 (Reactome)
H2OREACT_12403 (Reactome)
H2OREACT_12542 (Reactome)
H2OREACT_147756 (Reactome)
MDM2REACT_12537 (Reactome)
NR4A1REACT_12614 (Reactome)
PDPK1 PIP2ArrowREACT_147862 (Reactome)
PDPK1 PIP2REACT_147790 (Reactome)
PDPK1 PIP3ArrowREACT_12584 (Reactome)
PDPK1 PIP3REACT_147711 (Reactome)
PDPK1

p-S473-AKT1 E17K mutant

PIP2		REACT_147862 (Reactome)
PDPK1

p-S473-AKT1 E17K mutant

PIP2		mim-catalysisREACT_147862 (Reactome)
PDPK1REACT_147701 (Reactome)
PDPK1REACT_147873 (Reactome)
PHLPP mim-catalysisREACT_12403 (Reactome)
PI3K inhibitorsREACT_147854 (Reactome)
PI3K mutantsmim-catalysisREACT_147846 (Reactome)
PIArrowREACT_12542 (Reactome)
PIArrowREACT_147781 (Reactome)
PIArrowREACT_147846 (Reactome)
PIREACT_12542 (Reactome)
PIREACT_147701 (Reactome)
PIREACT_147756 (Reactome)
PIREACT_147781 (Reactome)
PIREACT_147846 (Reactome)
PIREACT_147873 (Reactome)
PIREACT_147886 (Reactome)
PIREACT_147896 (Reactome)
PTEN Mg2+mim-catalysisREACT_12542 (Reactome)
PTEN Mutantsmim-catalysisREACT_147756 (Reactome)
PTEN mRNA miR-26A RISCTBarREACT_147819 (Reactome)
PTEN mRNAREACT_147761 (Reactome)
Phospho-Forkhead box transcription factorArrowREACT_12572 (Reactome)
PiArrowREACT_12403 (Reactome)
PiArrowREACT_12542 (Reactome)
REACT_12383 (Reactome) PRAS40 (proline-rich Akt/PKB substrate 40 kDa) is a substrate of AKT, the phosphorylation of which leads to the binding of this protein to 14-3-3. PRAS40 binds to mTOR complexes, mediating AKT signals to mTOR. Interaction of PRAS40 with the mTOR kinase domain is induced under conditions that inhibit mTOR signalling, such as growth factor deprivation. Binding of PRAS40 inhibits mTOR. PRAS40 phosphorylation by AKT and association with the cytosolic anchor protein 14-3-3, lead to mTOR stimulation (Vander Haar E, et al, 2007). Although it was originally identified in the context of insulin signalling, it was later shown that PRAS40 may also play a role in nerve growth factor-mediated neuroprotection (Saito A, et al, 2004).
REACT_12391 (Reactome) Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.
Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005).
REACT_12395 (Reactome) AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it.
REACT_12403 (Reactome) The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT.
REACT_12420 (Reactome) Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
REACT_12461 (Reactome) AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival.
REACT_12485 (Reactome) Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT.
REACT_12532 (Reactome) AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a TSC1-TSC2 protein complex that is a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.
The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.
REACT_12537 (Reactome) AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of ubiquitin-protein ligase E3 MDM2 promotes nuclear localization and inhibits interaction between MDM2 and p19ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001).
REACT_12542 (Reactome) The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Maehema et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase. The role of other phosphoinositide phosphatases (INPP5D, INPPL1, INPP5K, PTPRQ, INPP4B) in the negative regulation of PI3K/AKT signaling will be described in future editions of Reactome.
REACT_12549 (Reactome) GSK3 (glycogen synthase kinase-3) participates in the Wnt signaling pathway. It is implicated in the hormonal control of several regulatory proteins including glycogen synthase, and the transcription factors MYB and JUN. GSK3 phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. GSK3 is inhibited when phosphorylated by AKT1.
REACT_12558 (Reactome) AKT, phosphorylated at threonine (AKT1 308; AKT2 309; AKT3 305) and serine (AKT1 473; AKT2 474; AKT3 472) translocates to the nucleus, reaching a maximum after 15 min and returning to a basal level after 45 min of NGF stimulation. Control of the amount of nuclear AKT is achieved through the action of the phosphatase PP2A.
REACT_12565 (Reactome) Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004).
REACT_12567 (Reactome) The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003).
REACT_12572 (Reactome) Cell survival and growth are also promoted by AKT phosphorylation of Forkhead box (FOX) transcription factors, most notably FoxO1, FoxO3a and FoxO4. Once phosphorylated by AKT, these factors are removed from the nucleus, associate with 14-3-3 proteins, and are retained in the cytoplasm, thus producing a change in their transcriptional activity. For instance, unphosphorylated FoxO3a in the nucleus triggers apoptosis, most likely by inducing the expression of critical genes, such as the Fas ligand gene. In another example, AKT phosphorylation of FOXO4 prevents FOXO4-mediated upregulation of p27Kip1.
REACT_12584 (Reactome) Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005).
REACT_12597 (Reactome) AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival.
REACT_12614 (Reactome) AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362).
REACT_147701 (Reactome) PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999).
REACT_147711 (Reactome) Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005)
REACT_147756 (Reactome) One of the functions of PTEN is to act as a phosphoinositide phosphatase that catalyzes dephosphorylation of PIP3 into PIP2. PTEN thus reduces the amount of available PIP3, counteracting PI3K activity and downregulating AKT signaling. PTEN is frequently targeted by loss of function mutations in cancer and in familial cancer syndromes known as PTHS (PTEN hamartoma tumor syndromes, a collection of diseases including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease). Some PTEN loss-of-function variants are also found in autism spectrum disorder patients. For a recent review of PTEN involvement in cancer, please refer to Hollander et al. 2011.

The majority of missense mutations that impair phosphoinositide phosphatase activity of PTEN cluster in exon 5 of PTEN gene and result in substitution of amino acid residues in the catalytic cleft of the phosphatase domain. Arginine at position 130 is the most frequently substituted PTEN residue in cancer. R130 of human PTEN is the last arginine residue in the conserved H-C-K/R-A-G-K-G-R sequence (corresponding to HCXXGXXR motif of protein tyrosine phosphatases) in the catalytic cleft of the PTEN phosphatase domain and is essential for catalysis (Barford et al. 1994, Lee et al. 1999). PTEN R130 substitution mutants show markedly decreased phosphoinositide phosphatase activity (Han et al. 2000, Koul et al. 2002) and are frequently found in endometrial carcinoma (Kong et al. 1997, Konopka et al. 2007). The cysteine residue at position 124 (C124) of human PTEN, in the conserved H-C-K/R-A-G-K-G-R sequence, 'attacks' the phosphate group of a substrate and forms a thio-phosphate intermediate during the dephosphorylation reaction (Guan and Dixon 1991, Barford et al. 1994, Lee et al. 1999). Therefore, substitution of this critical C124 abolishes PTEN phosphatase activity (Han et al. 2000, Koul et al. 2002). Substitution of histidine H123 in the conserved H-C-K/R-A-G-K-G-R sequence also impairs PTEN phosphatase activity (Lee et al. 1999).

Missense mutations also target amino acid residues in the N-terminal phosphatase domain that are outside the catalytic cleft. Substitution of histidine at position 93 affects the conserved WPD loop of the phosphatase domain of PTEN, and PTEN H93 mutants show low phosphoinositide phosphatase activity (Lee et al. 1999). Serine residue S170 and histidine residue H173 participate in the formation of hydrogen bonds between the N-terminal phosphatase domain of PTEN and the C-terminal membrane-binding C2 domain (Lee et al. 1999). H173, and to a lesser extent S170, are targeted by missense mutations in cancer, and substitution mutants have impaired phosphoinositide phosphatase activity (Han et al. 2000).

Missense mutations also occur in the C2 domain of PTEN. The C2 domain is implicated in membrane binding and localization of PTEN, but also in PTEN roles unrelated to its phosphoinositide phosphatase function (Raftopoulou et al. 2004). Since the roles of these C2 domain PTEN mutants in cancer have not been clarified, these variants will be annotated when more information becomes available.

Besides missense mutations, nonsense mutations that result in PTEN protein truncation are also frequently found in cancer samples. The three residues most frequently targeted by nonsense mutations are R130, R233 and R335. While R130* mutation directly affects the phosphatase domain of PTEN, R233* and R335* affect the C2 domain. It is has not yet been elucidated whether R233* and R335* affect PTEN membrane localization or impair PTEN function in some other way.

In cancer, PTEN is also frequently inactivated by genomic deletions and loss of heterozygosity (LOH) affecting chromosome band 10q23 or by epigenetic silencing (reviewed by Hollander et al. 2011).
REACT_147761 (Reactome) MIR26A microRNAs, miR-26A1 and miR-26A2, transcribed from genes on chromosome 3 and 12, respectively, bind PTEN mRNA (Huse et al. 2009).

The MIR26A2 locus is frequently amplified in glioma tumors that retained one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to downregulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and prevent loss of heterozigosity at the PTEN locus in a mouse PTEN +/- glioma model, based on a monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
REACT_147781 (Reactome) A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.

In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
REACT_147790 (Reactome) A portion of PDPK1 (PDK1) is anchored to the plasma membrane in the absence of PI3K activity through PIP2 binding (Currie et al. 1999). This PIP2-bound PDPK1 is able to bind and phosphorylate PIP2-bound AKT E17K mutants (Carpten et al. 2007, Landgraf et al. 2008) phosphorylated on serine residue S473.
REACT_147819 (Reactome) PTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing the remaining PTEN protein expression (Huse et al. 2009).
REACT_147846 (Reactome) Constitutively active PI3K complex produces PIP3 in the absence of growth stimuli, resulting in aberrant activation of downstream AKT signaling that positively regulates cell growth and survival. The PIK3CA gene, encoding the catalytic subunit of PI3K (p110alpha), is one of the most frequently mutated oncogenes in cancer. Hotspot mutations are found in the helical domain and kinase domain of PIK3CA, with the most frequent mutations being E545K substitution in the helical domain and H1047R substitution in the kinase domain.
The oncogenic PIK3CA mutants annotated here preserve their ability to bind PIK3R1 (p85alpha) regulatory subunit, but are constitutively active either because the inhibitory interactions with PIK3R1 are relieved, or because the conformation of the catalytic domain is changed. Missense mutations that result in substitution of amino acids at positions 542, 545 or 546 of PI3K disrupt an inhibitory interaction between the helical domain of PIK3CA and the nSH2 domain of PIK3R1. The effect of substitution of glutamic acid residue at position 545 has been studied in detail in PIK3CA E545K mutant, where glutamic acid is replaced with lysine (Miled et al. 2007, Huang et al. 2007, Zhao et al. 2005). The gain-of-function has been experimentally confirmed for PIK3CA E545A mutant (Horn et al. 2008), while PIK3CA E545G, PIK3CA E545Q and PIK3CA E545V mutants are assumed to behave similarly. The structural and functional consequences of glutamic acid to lysine substitution at position 542, in PIK3CA E542K mutant, have been established (Miled et al. 2007, Horn et al. 2008) and are extrapolated to PIK3CA E542Q and PIK3CA E542V mutants. A less frequent substitution of glutamine residue at position 546 follows the same mechanism, as shown for PIK3CA Q546K mutant (Miled et al. 2007) and extrapolated to PIK3CA Q546E, PIK3CA Q546H, PIK3CA Q546L, PIK3CA Q546P and PIK3CA Q546R mutants.
In the kinase domain of PIK3CA, substitution of histidine residue at position 1047 or methionine residue at position 1043, detected in PIK3CA H1047R, PIK3CA H1047L, PIK3CA H1047Y, PIK3CA M1043I, PIK3CA M1043T and PIK3CA M1043V mutants, is predicted to change the conformation of the activation loop (Huang et al. 2007) and was shown to confer constitutive activity, in the absence of growth factors, to PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants (Zhao et al. 2005, Horn et al. 2008). The catalytic activity of PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants may be further increased by binding of PIK3R1 regulatory subunit to phosphopeptides generated by activated receptor tyrosine kinases (Hon et al. 2011). PIK3CA H1047Y, PIK3CA M1043T and PIK3CA M1043V mutants are expected to behave similarly.
The arginine residue at position 38 of PIK3CA (R38) is located at a contact site between the ABD and kinase domains of PIK3CA. Substitution of this arginine residue with histidine in PIK3CA R38H mutant is likely to disrupt the interaction between the ABD domain and the kinase domain, causing a conformational change of the kinase domain that leads to increased enzymatic activity (Huang et al. 2007). PIK3CA R38H mutant shows reduced PIK3R1 binding and modestly increased catalytic activity (measured indirectly, via AKT1 phosphorylation) under serum starved conditions (Zhao et al. 2005). PIK3CA R38C, PIK3CA R38G and PIK3CA R38S mutants are expected to behave similarly.
Mutations in other conserved domains of PIK3CA, such as membrane-binding C2 domain (Mandelker et al. 2009), have not been annotated as their mechanism of action needs to be further elucidated.
Although less common than mutations in PIK3CA, mutations in PIK3R1, encoding the regulatory subunit of PI3K (p85alpha) have been recently described. Mutations mapping to iSH2 and nSH2 domains, the two domains of PIK3R1 involved in the inhibition of PIK3CA, which were shown to result in constitutive activity of PIK3R1 complex, are annotated here. An experimentally studied nSH2 domain mutant is PIK3R1 G376R (Sun et al. 2010). PIK3R1 iSH2 domain mutants, affected by amino acid substitutions and small inframe deletions, PIK3R1 D560Y (Jaiswal et al. 2009), PIK3R1 N564D (Jaiswal et al. 2009), PIK3R1 N564K (Sun et al. 2010), PIK3R1 H450_E451del (Urick et al. 2011), PIK3R1 K459del (Urick et al. 2011), PIK3R1 R574_T576del (Urick et al. 2011) and PIK3R1 Y463_L466del (Urick et al. 2011), were all shown to bind PIK3CA and confer constitutive activity to PI3K complex. PIK3R1 D560H, PIK3R1 R574I and PIK3R1 R574T mutants are expected to behave similarly to functionally characterized D560 and R574 substitution mutants.
Co-occurrence of PIK3CA and PIK3R1 mutations has been documented in some tumors, but since it is rare and the exact clinical combinations of PIK3CA and PIK3R1 mutants have not been studied, complexes of PIK3CA mutants with PIK3R1 mutants are not shown (Urick et al. 2011).
Although rare, perturbations in genes encoding other isoforms of PI3K subunits have also been reported in cancers. Mutations in PIK3R2, encoding PI3K regulatory subunit isoform p85beta, are found infrequently in endometrial cancers, but have not been functionally studied (Cheung et al. 2011). They are not shown in this context. PIK3CB, encoding PI3K catalytic subunit isoform p110beta, can be overexpressed in cancer, mainly due to genomic gain. Several studies have shown that PTEN deficient cancer cell lines depend on PIK3CB (p110beta) for AKT activation and sustained growth (Wee et al. 2008, Jiang et al. 2010, Chen et al. 2011). PIK3CB activation synergizes with PTEN loss in mouse prostate cancer model (Jia et al. 2008). Mutations in PIK3CB are very rare, have not been functionally studied, and are therefore not shown. Structural studies indicate that, in comparison with PIK3CA (p110alpha), PIK3CB (p110beta) and PIK3CD (p110delta) form additional inhibitory contacts with the regulatory subunit p85alpha, and are therefore probably less prone to mutational activation (Burke et al. 2011).
For more information, please refer to recent reviews by Liu et al. 2009 and Vogt et al. 2009.
REACT_147854 (Reactome) A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009.
REACT_147858 (Reactome) PIP2-binding AKT1 E17K mutants are anchored to the plasma membrane in the absence of PI3K activity and are constitutively phosphorylated on serine S473, presumably by the TORC2 complex (Carpten et al. 2007, Landgraf et al. 2008).
REACT_147862 (Reactome) PIP2-bound AKT1 E17K mutant is constitutively phosphorylated on threonine residue T308 (Carpten et al. 2007, Landgraf et al. 2008), presumably by PIP2-bound PDPK1 (Currie et al. 1999).
REACT_147873 (Reactome) PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999).
REACT_147886 (Reactome) PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied.
REACT_147895 (Reactome) AKT inhibitors bind AKT and prevent its association with the membrane, thereby blocking AKT activation (Kondapaka et al. 2003, Yap et al. 2011, Berndt et al. 2010). AKT inhibitors annotated here target all AKT isoforms (AKT1, AKT2 and AKT3). None of the annotated inhibitors are AKT E17K mutant specific and none of them have been approved for clinical use. For a recent review, please refer to Liu et al. 2009.
REACT_147896 (Reactome) Substitution of glutamic acid with lysine at position 17 of AKT1 results in constitutive plasma membrane localization of AKT1, independent of PI3K activity and PIP3 generation (Carpten et al. 2007). This constitutive plasma membrane targeting of AKT1 E17K mutant is due to an increased affinity for PIP2 (Landgraf et al. 2008).
RPS6KB2REACT_12485 (Reactome)
THEM4/TRIB3REACT_12567 (Reactome)
TORC2 complexmim-catalysisREACT_12391 (Reactome)
TORC2 complexmim-catalysisREACT_147858 (Reactome)
TSC2REACT_12532 (Reactome)
miR-26A RISCREACT_147761 (Reactome)
p-S-AKT

PDPK1

PIP3		REACT_12584 (Reactome)
p-S-AKT

PDPK1

PIP3		mim-catalysisREACT_12584 (Reactome)
p-S-AKT PIP3ArrowREACT_12391 (Reactome)
p-S-AKT PIP3REACT_147711 (Reactome)
p-S133-CREB1ArrowREACT_12597 (Reactome)
p-S15,S356-RPS6KB2ArrowREACT_12485 (Reactome)
p-S166,S188-MDM2ArrowREACT_12537 (Reactome)
p-S183,T246-AKT1S1ArrowREACT_12383 (Reactome)
p-S196-CASP9ArrowREACT_12395 (Reactome)
p-S351-NR4A1ArrowREACT_12614 (Reactome)
p-S473-AKT1 E17K mutant PIP2ArrowREACT_147858 (Reactome)
p-S473-AKT1 E17K mutant PIP2REACT_147790 (Reactome)
p-S9/21-GSK3ArrowREACT_12549 (Reactome)
p-S939,T1462-TSC2ArrowREACT_12532 (Reactome)
p-S99-BADArrowREACT_12565 (Reactome)
p-T-AKTArrowREACT_12403 (Reactome)
p-T-CDKN1A/BArrowREACT_12420 (Reactome)
p-T23-CHUKArrowREACT_12461 (Reactome)
p-T308,S473-AKT1 E17K mutantArrowREACT_147862 (Reactome)
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