Pathway Human Homo sapiens

PTEN Regulation

R-HSA-6807070 in Reactome release 97: under PIP3 activates AKT signaling, with 127 genes placed in it by the mapping files and 4 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-6807070 (mouse), R-RNO-6807070 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-6807070.4
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2017-06-12
Last updated: 2019-03-25
Events inside: 4, counted from the record

PTEN is regulated at the level of gene transcription, mRNA translation, localization and protein stability.

Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).

MicroRNAs miR-26A1, miR-26A2, miR-22, miR-25, miR-302, miR-214, miR-17-5p, miR-19 and miR-205 bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Huse et al. 2009, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Cai et al. 2013). In addition, coding and non-coding RNAs can prevent microRNAs from binding to PTEN mRNA. These RNAs are termed competing endogenous RNAs or ceRNAs. Transcripts of the pseudogene PTENP1 and mRNAs transcribed from SERINC1, VAPA and CNOT6L genes exhibit this activity (Poliseno, Salmena, Zhang et al. 2010, Tay et al. 2011, Tay et al. 2014).

PTEN can translocate from the cytosol to the nucleus after undergoing monoubiquitination. PTEN's ability to localize to the nucleus contributes to its tumor suppressive role (Trotman et al. 2007). The ubiquitin protease USP7 (HAUSP) targets monoubiquitinated PTEN in the nucleus, resulting in PTEN deubiquitination and nuclear exclusion. PML, via an unknown mechanism that involves USP7- and PML-interacting protein DAXX, inhibits USP7-mediated deubiquitination of PTEN, thus promoting PTEN nuclear localization. Disruption of PML function in acute promyelocytic leukemia, through a chromosomal translocation that results in expression of a fusion protein PML-RARA, leads to aberrant PTEN localization (Song et al. 2008).

Several ubiquitin ligases, including NEDD4, WWP2, STUB1 (CHIP), RNF146, XIAP and MKRN1, polyubiquitinate PTEN and target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Ahmed et al. 2011, Maddika et al. 2011, Lee et al. 2015, Li et al. 2015). The ubiquitin proteases USP13 and OTUD3, frequently down-regulated in breast cancer, remove polyubiquitin chains from PTEN, thus preventing its degradation and increasing its half-life (Zhang et al. 2013, Yuan et al. 2015). The catalytic activity of PTEN is negatively regulated by PREX2 binding (Fine et al. 2009, Hodakoski et al. 2014) and TRIM27-mediated ubiquitination (Lee et al. 2013), most likely through altered PTEN conformation.

In addition to ubiquitination, PTEN also undergoes SUMOylation (Gonzalez-Santamaria et al. 2012, Da Silva Ferrada et al. 2013, Lang et al. 2015, Leslie et al. 2016). SUMOylation of the C2 domain of PTEN may regulate PTEN association with the plasma membrane (Shenoy et al. 2012) as well as nuclear localization of PTEN (Bassi et al. 2013, Collaud et al. 2016). PIASx-alpha, a splicing isorom of E3 SUMO-protein ligase PIAS2 has been implicated in PTEN SUMOylation (Wang et al. 2014). SUMOylation of PTEN may be regulated by activated AKT (Lin et al. 2016). Reactions describing PTEN SUMOylation will be annotated when mechanistic details become available.

Phosphorylation affects the stability and activity of PTEN. FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336, which increases PTEN half-life by inhibiting NEDD4-mediated polyubiquitination and subsequent degradation of PTEN. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).

PTEN localization and activity are affected by acetylation of its lysine residues (Okumura et al. 2006, Ikenoue et al. 2008, Meng et al. 2016). PTEN can undergo oxidation, which affects its function, but the mechanism is poorly understood (Tan et al. 2015, Shen et al. 2015, Verrastro et al. 2016).

Literature Reactome attaches

Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1Genes Dev., 2006, vol. 20, p. 1308-20PubMed 16702404
The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivoGenes Dev., 2009, vol. 23, p. 1327-37PubMed 19487573
Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorshipProc. Natl. Acad. Sci. U.S.A., 2010, vol. 107, p. 2183-8PubMed 20080666
Ubiquitination regulates PTEN nuclear import and tumor suppressionCell, 2007, vol. 128, p. 141-56PubMed 17218261
The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML networkNature, 2008, vol. 455, p. 813-7PubMed 18716620
NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENCell, 2007, vol. 128, p. 129-39PubMed 17218260
The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradationJ. Biol. Chem., 2012, vol. 287, p. 15996-6006

Reactome's record lists 14 orthologous events, R-MMU-6807070 (Mus musculus), R-RNO-6807070 (Rattus norvegicus) among the species this site serves, and 12 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"PTEN Regulation". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-6807070 with StableID: R-HSA-6807070.4 (accessed 2026-10-01 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 127 genes in this human pathway; showing 1 to 100, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 2
Gene	Authority id	Mapping file id	Evidence codes
GeneADRM1	AuthorityHGNC:15759	Mapping file id11047 NCBI file	EvidenceTAS
GeneAGO1	AuthorityHGNC:3262	Mapping file id26523 NCBI file	EvidenceTAS
GeneAGO2	AuthorityHGNC:3263	Mapping file id27161 NCBI file	EvidenceTAS
GeneAGO3	AuthorityHGNC:18421	Mapping file id192669 NCBI file	EvidenceTAS
GeneAGO4	AuthorityHGNC:18424	Mapping file id192670 NCBI file	EvidenceTAS
GeneAKT1	AuthorityHGNC:391	Mapping file id207 NCBI file	EvidenceTAS
GeneAKT2	AuthorityHGNC:392	Mapping file id208 NCBI file	EvidenceTAS
GeneAKT3	AuthorityHGNC:393	Mapping file id10000 NCBI file	EvidenceTAS
GeneATF2	AuthorityHGNC:784	Mapping file id1386 NCBI file	EvidenceIEA, TAS
GeneATN1	AuthorityHGNC:3033	Mapping file id1822 NCBI file	EvidenceIEA
GeneBMI1	AuthorityHGNC:1066	Mapping file id648 NCBI file	EvidenceIEA, TAS
GeneCBX2	AuthorityHGNC:1552	Mapping file id84733 NCBI file	EvidenceIEA, TAS
GeneCBX4	AuthorityHGNC:1554	Mapping file id8535 NCBI file	EvidenceIEA, TAS
GeneCBX6	AuthorityHGNC:1556	Mapping file id23466 NCBI file	EvidenceIEA, TAS
GeneCBX8	AuthorityHGNC:15962	Mapping file id57332 NCBI file	EvidenceIEA, TAS
GeneCHD3	AuthorityHGNC:1918	Mapping file id1107 NCBI file	EvidenceIEA, TAS
GeneCHD4	AuthorityHGNC:1919	Mapping file id1108 NCBI file	EvidenceIEA, TAS
GeneCOMMD3-BMI1	AuthorityHGNC:48326	Mapping file id100532731 NCBI file	EvidenceIEA, TAS
GeneCSNK2A1	AuthorityHGNC:2457	Mapping file id1457 NCBI file	EvidenceTAS
GeneCSNK2A2	AuthorityHGNC:2459	Mapping file id1459 NCBI file	EvidenceTAS
GeneCSNK2B	AuthorityHGNC:2460	Mapping file id1460 NCBI file	EvidenceTAS
GeneEED	AuthorityHGNC:3188	Mapping file id8726 NCBI file	EvidenceIEA, TAS
GeneEGR1	AuthorityHGNC:3238	Mapping file id1958 NCBI file	EvidenceIEA, TAS
GeneEZH2	AuthorityHGNC:3527	Mapping file id2146 NCBI file	EvidenceIEA, TAS
GeneFRK	AuthorityHGNC:3955	Mapping file id2444 NCBI file	EvidenceTAS
GeneGATAD2A	AuthorityHGNC:29989	Mapping file id54815 NCBI file	EvidenceIEA, TAS
GeneGATAD2B	AuthorityHGNC:30778	Mapping file id57459 NCBI file	EvidenceIEA, TAS
GeneHDAC1	AuthorityHGNC:4852	Mapping file id3065 NCBI file	EvidenceIEA, TAS
GeneHDAC2	AuthorityHGNC:4853	Mapping file id3066 NCBI file	EvidenceIEA, TAS
GeneHDAC3	AuthorityHGNC:4854	Mapping file id8841 NCBI file	EvidenceIEA
GeneHDAC5	AuthorityHGNC:14068	Mapping file id10014 NCBI file	EvidenceIEA
GeneHDAC7	AuthorityHGNC:14067	Mapping file id51564 NCBI file	EvidenceIEA
GeneJUN	AuthorityHGNC:6204	Mapping file id3725 NCBI file	EvidenceIEA, TAS
GeneKDM1A	AuthorityHGNC:29079	Mapping file id23028 NCBI file	EvidenceIEA
GeneLAMTOR1	AuthorityHGNC:26068	Mapping file id55004 NCBI file	EvidenceTAS
GeneLAMTOR2	AuthorityHGNC:29796	Mapping file id28956 NCBI file	EvidenceTAS
GeneLAMTOR3	AuthorityHGNC:15606	Mapping file id8649 NCBI file	EvidenceTAS
GeneLAMTOR4	AuthorityHGNC:33772	Mapping file id389541 NCBI file	EvidenceTAS
GeneLAMTOR5	AuthorityHGNC:17955	Mapping file id10542 NCBI file	EvidenceTAS
GeneMAF1	AuthorityHGNC:24966	Mapping file id84232 NCBI file	EvidenceIEA, TAS
GeneMAPK1	AuthorityHGNC:6871	Mapping file id5594 NCBI file	EvidenceTAS
GeneMAPK3	AuthorityHGNC:6877	Mapping file id5595 NCBI file	EvidenceTAS
GeneMBD3	AuthorityHGNC:6918	Mapping file id53615 NCBI file	EvidenceIEA, TAS
GeneMECOM	AuthorityHGNC:3498	Mapping file id2122 NCBI file	EvidenceIEA, TAS
GeneMKRN1	AuthorityHGNC:7112	Mapping file id23608 NCBI file	EvidenceTAS
GeneMLST8	AuthorityHGNC:24825	Mapping file id64223 NCBI file	EvidenceTAS
GeneMOV10	AuthorityHGNC:7200	Mapping file id4343 NCBI file	EvidenceTAS
GeneMTA1	AuthorityHGNC:7410	Mapping file id9112 NCBI file	EvidenceIEA, TAS
GeneMTA2	AuthorityHGNC:7411	Mapping file id9219 NCBI file	EvidenceIEA, TAS
GeneMTA3	AuthorityHGNC:23784	Mapping file id57504 NCBI file	EvidenceIEA, TAS
GeneMTOR	AuthorityHGNC:3942	Mapping file id2475 NCBI file	EvidenceTAS
GeneNEDD4	AuthorityHGNC:7727	Mapping file id4734 NCBI file	EvidenceTAS
GeneNR2E1	AuthorityHGNC:7973	Mapping file id7101 NCBI file	EvidenceIEA
GeneOTUD3	AuthorityHGNC:29038	Mapping file id23252 NCBI file	EvidenceTAS
GenePHC1	AuthorityHGNC:3182	Mapping file id1911 NCBI file	EvidenceIEA, TAS
GenePHC2	AuthorityHGNC:3183	Mapping file id1912 NCBI file	EvidenceIEA, TAS
GenePHC3	AuthorityHGNC:15682	Mapping file id80012 NCBI file	EvidenceIEA, TAS
GenePML	AuthorityHGNC:9113	Mapping file id5371 NCBI file	EvidenceTAS
GenePPARG	AuthorityHGNC:9236	Mapping file id5468 NCBI file	EvidenceIEA, TAS
GenePREX2	AuthorityHGNC:22950	Mapping file id80243 NCBI file	EvidenceTAS
GenePSMA1	AuthorityHGNC:9530	Mapping file id5682 NCBI file	EvidenceTAS
GenePSMA2	AuthorityHGNC:9531	Mapping file id5683 NCBI file	EvidenceTAS
GenePSMA3	AuthorityHGNC:9532	Mapping file id5684 NCBI file	EvidenceTAS
GenePSMA4	AuthorityHGNC:9533	Mapping file id5685 NCBI file	EvidenceTAS
GenePSMA5	AuthorityHGNC:9534	Mapping file id5686 NCBI file	EvidenceTAS
GenePSMA6	AuthorityHGNC:9535	Mapping file id5687 NCBI file	EvidenceTAS
GenePSMA7	AuthorityHGNC:9536	Mapping file id5688 NCBI file	EvidenceTAS
GenePSMB1	AuthorityHGNC:9537	Mapping file id5689 NCBI file	EvidenceTAS
GenePSMB2	AuthorityHGNC:9539	Mapping file id5690 NCBI file	EvidenceTAS
GenePSMB3	AuthorityHGNC:9540	Mapping file id5691 NCBI file	EvidenceTAS
GenePSMB4	AuthorityHGNC:9541	Mapping file id5692 NCBI file	EvidenceTAS
GenePSMB5	AuthorityHGNC:9542	Mapping file id5693 NCBI file	EvidenceTAS
GenePSMB6	AuthorityHGNC:9543	Mapping file id5694 NCBI file	EvidenceTAS
GenePSMB7	AuthorityHGNC:9544	Mapping file id5695 NCBI file	EvidenceTAS
GenePSMC1	AuthorityHGNC:9547	Mapping file id5700 NCBI file	EvidenceTAS
GenePSMC2	AuthorityHGNC:9548	Mapping file id5701 NCBI file	EvidenceTAS
GenePSMC3	AuthorityHGNC:9549	Mapping file id5702 NCBI file	EvidenceTAS
GenePSMC4	AuthorityHGNC:9551	Mapping file id5704 NCBI file	EvidenceTAS
GenePSMC5	AuthorityHGNC:9552	Mapping file id5705 NCBI file	EvidenceTAS
GenePSMC6	AuthorityHGNC:9553	Mapping file id5706 NCBI file	EvidenceTAS
GenePSMD1	AuthorityHGNC:9554	Mapping file id5707 NCBI file	EvidenceTAS
GenePSMD11	AuthorityHGNC:9556	Mapping file id5717 NCBI file	EvidenceTAS
GenePSMD12	AuthorityHGNC:9557	Mapping file id5718 NCBI file	EvidenceTAS
GenePSMD13	AuthorityHGNC:9558	Mapping file id5719 NCBI file	EvidenceTAS
GenePSMD14	AuthorityHGNC:16889	Mapping file id10213 NCBI file	EvidenceTAS
GenePSMD2	AuthorityHGNC:9559	Mapping file id5708 NCBI file	EvidenceTAS
GenePSMD3	AuthorityHGNC:9560	Mapping file id5709 NCBI file	EvidenceTAS
GenePSMD6	AuthorityHGNC:9564	Mapping file id9861 NCBI file	EvidenceTAS
GenePSMD7	AuthorityHGNC:9565	Mapping file id5713 NCBI file	EvidenceTAS
GenePSMD8	AuthorityHGNC:9566	Mapping file id5714 NCBI file	EvidenceTAS
GenePTEN	AuthorityHGNC:9588	Mapping file id5728 NCBI file	EvidenceTAS
GeneRBBP4	AuthorityHGNC:9887	Mapping file id5928 NCBI file	EvidenceIEA, TAS
GeneRBBP7	AuthorityHGNC:9890	Mapping file id5931 NCBI file	EvidenceIEA, TAS
GeneRCOR1	AuthorityHGNC:17441	Mapping file id23186 NCBI file	EvidenceIEA
GeneREST	AuthorityHGNC:9966	Mapping file id5978 NCBI file	EvidenceIEA
GeneRHEB	AuthorityHGNC:10011	Mapping file id6009 NCBI file	EvidenceTAS
GeneRING1	AuthorityHGNC:10018	Mapping file id6015 NCBI file	EvidenceIEA, TAS
GeneRNF146	AuthorityHGNC:21336	Mapping file id81847 NCBI file	EvidenceTAS
GeneRNF2	AuthorityHGNC:10061	Mapping file id6045 NCBI file	EvidenceIEA, TAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

PIP3 activates AKT signalingR-HSA-1257604266 genes

Children

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.