PHLPP1

Summary

PHLPP1 (PH domain and leucine rich repeat protein phosphatase 1, HGNC:20610) is a protein-coding gene on chromosome 18q21.33, encoding PH domain leucine-rich repeat-containing protein phosphatase 1 (O60346). Protein phosphatase involved in regulation of Akt and PKC signaling.

This gene encodes a member of the serine/threonine phosphatase family. The encoded protein promotes apoptosis by dephosphorylating and inactivating the serine/threonine kinase Akt, and functions as a tumor suppressor in multiple types of cancer. Increased expression of this gene may also play a role in obesity and type 2 diabetes by interfering with Akt-mediated insulin signaling.

Source: NCBI Gene 23239 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 335 total — 3 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_194449

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20610
Approved symbol	PHLPP1
Name	PH domain and leucine rich repeat protein phosphatase 1
Location	18q21.33
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0606, SCOP, PPM3A
Ensembl gene	ENSG00000081913
Ensembl biotype	protein_coding
OMIM	609396
Entrez	23239

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding_CDS_not_defined, 3 protein_coding

ENST00000262719, ENST00000487409, ENST00000497351, ENST00000588452, ENST00000588953, ENST00000591106, ENST00000591386, ENST00000937482

RefSeq mRNA: 1 — MANE Select: NM_194449 NM_194449

CCDS: CCDS45881

Canonical transcript exons

ENST00000262719 — 17 exons

Exon	Start	End
ENSE00000807322	62945109	62945271
ENSE00000807324	62941718	62941918
ENSE00000807328	62905224	62905284
ENSE00000807332	62895781	62896011
ENSE00000950323	62902964	62903166
ENSE00001011894	62972514	62972708
ENSE00001011896	62958629	62958759
ENSE00001011899	62963368	62963472
ENSE00001011901	62975397	62975625
ENSE00001142318	62895011	62895157
ENSE00001234525	62715541	62717259
ENSE00001542362	62978262	62980433
ENSE00003490833	62914913	62915008
ENSE00003496989	62838784	62838909
ENSE00003539784	62830035	62830231
ENSE00003688037	62860435	62860601
ENSE00003691051	62919959	62920114

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1046 / max 325.6449, expressed in 1599 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170544	3.8084	770
170543	2.1205	949
170541	1.9799	865
170545	1.8916	430
170540	0.4446	177
170542	0.2599	115
170547	0.1716	47
170539	0.1356	57
208578	0.1120	40
170546	0.0804	15

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	97.61	gold quality
ventricular zone	UBERON:0003053	96.91	gold quality
medial globus pallidus	UBERON:0002477	96.39	gold quality
globus pallidus	UBERON:0001875	95.95	gold quality
middle frontal gyrus	UBERON:0002702	95.90	gold quality
inferior vagus X ganglion	UBERON:0005363	95.00	gold quality
cranial nerve II	UBERON:0000941	94.37	gold quality
ganglionic eminence	UBERON:0004023	93.39	gold quality
buccal mucosa cell	CL:0002336	93.22	gold quality
CA1 field of hippocampus	UBERON:0003881	92.87	gold quality
lateral globus pallidus	UBERON:0002476	92.78	gold quality
subthalamic nucleus	UBERON:0001906	91.74	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.54	gold quality
medulla oblongata	UBERON:0001896	91.25	gold quality
putamen	UBERON:0001874	90.59	gold quality
postcentral gyrus	UBERON:0002581	90.42	gold quality
ventral tegmental area	UBERON:0002691	90.42	gold quality
superior vestibular nucleus	UBERON:0007227	90.28	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.18	gold quality
parietal lobe	UBERON:0001872	90.17	gold quality
inferior olivary complex	UBERON:0002127	90.03	gold quality
adrenal tissue	UBERON:0018303	89.81	gold quality
caudate nucleus	UBERON:0001873	89.67	gold quality
amygdala	UBERON:0001876	89.45	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.25	gold quality
Ammon’s horn	UBERON:0001954	89.18	gold quality
spinal cord	UBERON:0002240	89.13	gold quality
frontal pole	UBERON:0002795	89.05	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.97	gold quality
temporal lobe	UBERON:0001871	88.93	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	113.63
E-HCAD-25	yes	50.79
E-ANND-3	yes	6.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1

miRNA regulators (miRDB)

132 targeting PHLPP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394

Literature-anchored findings (GeneRIF, showing 40)

• Mechanism to selectively terminate Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms. (PMID:17386267)
• PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation. (PMID:18162466)
• Study focuses on the function of PHLPP1 and PHLPP2 in modulating signaling by Akt and PKC. (PMID:18511290)
• Loss of PHLPP expression is associated with colon cancer. (PMID:19079341)
• Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells (PMID:19261608)
• In the striatum, reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing (PMID:19745829)
• demonstrate a key role for beta-TrCP in controlling the level of PHLPP1, and activation of Akt negatively regulates this degradation process. (PMID:19797085)
• The PHLPP1 dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. (PMID:20513427)
• Aberrantly expressed UCH-L1 boosts signaling through the Akt pathway by downregulating the antagonistic phosphatase PHLPP1, an event that requires its de-ubiquitinase activity (PMID:20574456)
• Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells. (PMID:20861921)
• a compensatory feedback regulation in which the activation of Akt is inhibited by up-regulation of PHLPP through mTOR, and this mTOR-dependent expression of PHLPP subsequently determines the rapamycin sensitivity of cancer cells. (PMID:21177869)
• the cellular localization of beta-TrCP1 is altered in glioblastoma, resulting in dysregulation of PHLPP1 and other substrates such as beta-catenin. (PMID:21454620)
• Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity. (PMID:21461637)
• Knockdown of Scribble (Scrib) results in redistribution of PHLPP1 from the membrane to the cytoplasm and an increase in Akt phosphorylation. (PMID:21701506)
• show for the first time a significant disruption of all three members of the PTEN-NHERF1-PHLPP1 tumor suppressor network in high-grade tumors, correlating with Akt activation and patient’s abysmal survival (PMID:21804599)
• codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2 (PMID:21840483)
• Knockdown of PHLPP1 or PHLPP2 resulted in an increase in S6K1 phosphorylation. (PMID:21986499)
• PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for pancreatic ductal adenocarcinoma. (PMID:22044669)
• PHLPP as a novel tumor suppressor. (PMID:22144674)
• PHLPP1 and PHLPP2 have an effect on retinal rod CNG channel sensitivity. (PMID:22183406)
• Loss of PHLPP1 is associated with chronic lymphocytic leukemia. (PMID:22237780)
• Studies suggest that the effects of PHLPP1 deletion on prostate carcinogenesis may be explained by the strong dependence of prostate cancer on phosphoinositide 3-kinase (PI3K)/Akt signalling. (PMID:22340730)
• USP46-mediated stabilization of PHLPP and the subsequent inhibition of Akt. (PMID:22391563)
• a novel USP1-PHLPP1-Akt signaling axis, and decreased USP1 level in lung cancer cells may play an important role in lung cancer progress. (PMID:22426999)
• AG490 time-dependently down-regulated the protein expression of PHLPP and induced apoptosis of K562 cells (PMID:22931649)
• we found that SGT1 was able to regulate the stability of PHLPP1, which is the direct phosphatase for Akt ser473 phosphorylation (PMID:23440515)
• Data indicate that binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential recruitment of these proteins to membranes containing tocopherols. (PMID:23512990)
• This study reveals functional and mechanistic links between miRNA-224 and the tumor suppressors PHLPP1 and PHLPP2 in the pathogenesis of colorectal cancer (PMID:23846336)
• The overall survival time and relapse-free survival time in PHLPP1-positive gastric cancer patients were significantly longer than in PHLPP1-negative patients. (PMID:24037758)
• A hypoxia-induced decrease of PHLPP expression is attenuated by knocking down HIF1alpha but not HIF2alpha. (PMID:24061475)
• Suppression of PHLPP1 by DNA methylation contributes to melanoma development and progression. (PMID:24121273)
• our results reveal WDR48 and USP12 as novel PHLPP1 regulators and potential suppressors of tumor cell survival. (PMID:24145035)
• PHLPP1 is a binding protein for Mst1 and it modulates the Hippo pathway by dephosphorylating Mst1 at the inhibitory Thr(387) of Mst1. (PMID:24393845)
• biochemical characterization of phosphatase domain of PHLPP1 and PHLPP2;PHLPP1 and PHLPP2 have similar in vitro activities and respond comparably to the presence of metallic ions; metallic ions affect structural stability of the domain;identified 3 residues likely involved in metal coordination and 2 that may be important for structural integrity (PMID:24892992)
• miR-141 and its targets PHLPP1 and PHLPP2 play critical roles in NSCLC tumorigenesis (PMID:24945731)
• PHLPP1, along with miR-522, promoted tumor cell growth in glioblastoma cells. (PMID:25776496)
• Aberrant expression of PHLPP1 and PHLPP2 correlates with poor prognosis in patients with hypopharyngeal squamous cell carcinoma (PMID:25793736)
• Results showed that PHLPP1 and PHLPP2 gene expression are down-regulated in esophageal squamous cell carcinoma. Their promotor is a target for mir-224. (PMID:26245343)
• Data show that both serine/threonine phosphatases PHLPP and dephosphorylated the physiological substrates of Akt1 and Akt3 with similar efficiencies. (PMID:26427440)
• high levels of PHLPP might reflect a less aggressive lung adenocarcinoma phenotype and predict better survival in patients with lung adenocarcinoma. (PMID:26463718)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	phlpp1	ENSDARG00000078694
mus_musculus	Phlpp1	ENSMUSG00000044340
rattus_norvegicus	Phlpp1	ENSRNOG00000002821

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

PH domain leucine-rich repeat-containing protein phosphatase 1 — O60346 (reviewed: O60346)

Alternative names: Pleckstrin homology domain-containing family E member 1, Suprachiasmatic nucleus circadian oscillatory protein

All UniProt accessions (2): O60346, K7EP91

UniProt curated annotations — full annotation on UniProt →

Function. Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on ‘Ser-473’ of AKT2 and AKT3, ‘Ser-660’ of PRKCB and ‘Ser-657’ of PRKCA. Isoform 2 seems to have a major role in regulating Akt signaling in hippocampal neurons. Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of ‘Ser-473’ of Akt triggers apoptosis and suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Dephosphorylates STK4 on ‘Thr-387’ leading to STK4 activation and apoptosis. Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation. Inhibits cancer cell proliferation and may act as a tumor suppressor. Dephosphorylates RAF1 inhibiting its kinase activity. May act as a negative regulator of K-Ras signaling in membrane rafts. Involved in the hippocampus-dependent long-term memory formation. Involved in circadian control by regulating the consolidation of circadian periodicity after resetting. Involved in development and function of regulatory T-cells.

Subunit / interactions. Interacts with the nucleotide free form of K-Ras (KRAS) via its LRR repeats. Interacts with AKT2, AKT3, PRKCB isoform beta-II, STK4, RPS6KB1, RAF1. Isoform 1 (predominantly) and isoform 2 interact with BRAP. Interacts with FKBP5; FKBP5 acts as a scaffold for PHLPP1 and Akt. Interacts with SCRIB; SCRIB acts as a scaffold for PHLPP1 and Akt. Interacts with NHERF1; NHERF1 scaffolds a heterotrimeric complex with PTEN at the plasma membrane. Interacts with WDR48 and USP12.

Subcellular location. Cytoplasm. Membrane. Nucleus Cell membrane.

Tissue specificity. In colorectal cancer tissue, expression is highest in the surface epithelium of normal colonic mucosa adjacent to the cancer tissue but is largely excluded from the crypt bases. Expression is lost or significantly decreased in 78% of tested tumors (at protein level). Ubiquitously expressed in non-cancerous tissues.

Activity regulation. Insensitive to okadaic acid. Deubiquitination by WDR48-USP12 complex positively regulates PHLPP1 stability.

Domain organisation. The PH domain is required for interaction with PRKCB and its dephosphorylation.

Isoforms (2)

UniProt ID	Names	Canonical?
O60346-1	1, beta	yes
O60346-2	2, alpha

RefSeq proteins (1): NP_919431* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR001849	PH_domain	Domain
IPR001932	PPM-type_phosphatase-like_dom	Domain
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036457	PPM-type-like_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family
IPR055071	RA_PHLPP-like	Domain

Pfam: PF00169, PF00481, PF13516, PF13855, PF23010

Catalyzed reactions (Rhea), 2 shown:

• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (51 total): repeat 21, region of interest 7, compositionally biased region 7, sequence conflict 6, modified residue 3, domain 2, chain 1, short sequence motif 1, splice variant 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60346-F1	66.08	0.34

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 1, 317, 412

Mutagenesis-validated functional residues (1):

Position	Phenotype
1715–1717	loss of function in vivo, but does not abolishes intrinsic phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-199418	Negative regulation of the PI3K/AKT network

MSigDB gene sets: 253 (showing top): GOBP_CIRCADIAN_RHYTHM, FREAC2_01, TAATAAT_MIR126, GOBP_TOLERANCE_INDUCTION, TTTGTAG_MIR520D, GOBP_REGULATION_OF_TOLERANCE_INDUCTION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, IRF7_01, FOSTER_TOLERANT_MACROPHAGE_DN, FREAC3_01, MCLACHLAN_DENTAL_CARIES_DN, GOBP_NEGATIVE_REGULATION_OF_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, GOBP_JNK_CASCADE, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION

GO Biological Process (10): regulation of T cell anergy (GO:0002667), apoptotic process (GO:0006915), entrainment of circadian clock (GO:0009649), intracellular signal transduction (GO:0035556), regulation of apoptotic process (GO:0042981), regulation of MAPK cascade (GO:0043408), regulation of JNK cascade (GO:0046328), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), regulation of p38MAPK cascade (GO:1900744), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491)

GO Molecular Function (5): protein serine/threonine phosphatase activity (GO:0004722), metal ion binding (GO:0046872), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PIP3 activates AKT signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
regulation of MAPK cascade	2
regulation of T cell tolerance induction	1
T cell anergy	1
regulation of lymphocyte anergy	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to external stimulus	1
regulation of circadian rhythm	1
signal transduction	1
apoptotic process	1
regulation of programmed cell death	1
MAPK cascade	1
regulation of intracellular signal transduction	1
JNK cascade	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
negative regulation of intracellular signal transduction	1
p38MAPK cascade	1
intracellular signaling cassette	1
phosphoprotein phosphatase activity	1
cation binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2084 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHLPP1	AKT1	P31749	995
PHLPP1	FKBP4	Q02790	992
PHLPP1	FKBP5	Q13451	992
PHLPP1	AKT2	P31751	949
PHLPP1	AKT3	Q9Y243	936
PHLPP1	PLEK2	Q9NYT0	788
PHLPP1	PLEK	P08567	786
PHLPP1	PDP1	Q9P0J1	770
PHLPP1	PTEN	P60484	767
PHLPP1	USP12	O75317	722
PHLPP1	TBC1D4	O60343	702
PHLPP1	CD200	P41217	687
PHLPP1	TBC1D7	Q9P0N9	676
PHLPP1	GSK3A	P49840	656
PHLPP1	WDR48	Q8TAF3	628

IntAct

58 interactions, top by confidence:

A	B	Type	Score
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
USP1	PHLPP1	psi-mi:“MI:0914”(association)	0.740
USP46	PHLPP1	psi-mi:“MI:0914”(association)	0.740
WDR20	PHLPP1	psi-mi:“MI:0914”(association)	0.670
PHLPP1	SCRIB	psi-mi:“MI:0915”(physical association)	0.670
PRKCB	PHLPP1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.600
PHLPP1	PRKCB	psi-mi:“MI:0915”(physical association)	0.600
PRKCB	PHLPP1	psi-mi:“MI:0915”(physical association)	0.600
USP12	PHLPP1	psi-mi:“MI:0914”(association)	0.570
PHLPP1	USP12	psi-mi:“MI:0914”(association)	0.570
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
SKP2	DPYSL4	psi-mi:“MI:0914”(association)	0.530
NHERF1	PHLPP1	psi-mi:“MI:0915”(physical association)	0.520
PHLPP1	BRAP	psi-mi:“MI:0403”(colocalization)	0.440
BRAP	PHLPP1	psi-mi:“MI:0915”(physical association)	0.440
PHLPP1	Rps6kb1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
PHLPP1	ITGB1	psi-mi:“MI:0915”(physical association)	0.400
Scrib	PHLPP1	psi-mi:“MI:0915”(physical association)	0.400
NEFL	PHLPP1	psi-mi:“MI:0915”(physical association)	0.370
RPS6KB1	PHLPP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (406): AKT1 (Biochemical Activity), AKT1 (Affinity Capture-Western), USP12 (Affinity Capture-Western), WDR48 (Affinity Capture-Western), WDR20 (Affinity Capture-Western), PHLPP1 (Biochemical Activity), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NFE2, A0FI79, A1A5B6, A4D2P6, D7PF45, F1LXF1, O15357, O60346, O75808, P11274, P49796, P52734, P53349, P59672, P70268, P78524, P98174, Q0QWG9, Q13233, Q13905, Q16825, Q3MII6, Q50H33, Q5RDA9, Q62925, Q63433, Q6NS60, Q6P549, Q6PDJ6, Q6WVG3, Q7Z5H3, Q8BL80, Q8BUP8, Q8N2R8, Q8TF61, Q8VHK2, Q8WXD9, Q924W7, Q92625, Q96CX2

Diamond homologs: A5PJZ2, A6K136, A8MPX8, O04719, O60346, O64583, P40371, P49595, P49597, P49598, Q0D673, Q0JAA0, Q2PC20, Q2QWE3, Q4PSE8, Q53Q11, Q5R522, Q5SGD2, Q65XK7, Q6EN45, Q6L4R7, Q6L5C4, Q6L5H6, Q6ZVD8, Q7XQU7, Q7XR06, Q8BVT6, Q8BXN7, Q8CHE4, Q8LAY8, Q8N3J5, Q93YW5, Q9FIF5, Q9LDA7, Q9LME4, Q9LNW3, Q9S9Z7, Q9WTR8, Q9XEE8, Q9ZW21

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
PHLPP1	down-regulates	AKT	dephosphorylation
PHLPP1	unknown	AKT2	dephosphorylation
PHLPP1	down-regulates	AKT2	dephosphorylation
GSK3B	down-regulates	PHLPP1	phosphorylation
PHLPP1	up-regulates	STK4	binding
PHLPP1	“down-regulates quantity”	PRKCA	dephosphorylation
PHLPP1	“down-regulates quantity”	PRKCB	dephosphorylation
PHLPP1	“down-regulates activity”	RPS6KB1	dephosphorylation
PHLPP1	“down-regulates quantity by destabilization”	PRKCB	dephosphorylation
PHLPP1	“down-regulates activity”	AKT1	dephosphorylation
PHLPP1	“down-regulates activity”	AKT2	dephosphorylation
PHLPP1	“up-regulates activity”	STK4	dephosphorylation
PHLPP1	“down-regulates activity”	AKT3	dephosphorylation
PHLPP1	“down-regulates activity”	AKT	dephosphorylation
PHLPP1	down-regulates	AKT1	dephosphorylation
CSNK1A1	“down-regulates quantity by destabilization”	PHLPP1	phosphorylation
GSK3B	“down-regulates quantity by destabilization”	PHLPP1	phosphorylation
PHLPP1	“down-regulates activity”	RAF1	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

335 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	289
Likely benign	20
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1526622	GRCh37/hg19 18q21.2-23(chr18:52675201-78014123)	Pathogenic
1526628	GRCh37/hg19 18q21.32-23(chr18:58305972-78014123)	Pathogenic
3062374	GRCh37/hg19 18q21.2-23(chr18:48766173-78014123)x1	Pathogenic

SpliceAI

4768 predictions. Top by Δscore:

Variant	Effect	Δscore
18:62830028:A:AG	acceptor_gain	1.0000
18:62830030:TTCA:T	acceptor_loss	1.0000
18:62830033:A:AG	acceptor_gain	1.0000
18:62830033:AG:A	acceptor_gain	1.0000
18:62830033:AGG:A	acceptor_loss	1.0000
18:62830034:G:GA	acceptor_gain	1.0000
18:62830034:GG:G	acceptor_gain	1.0000
18:62830034:GGA:G	acceptor_gain	1.0000
18:62830034:GGAA:G	acceptor_gain	1.0000
18:62830034:GGAAA:G	acceptor_gain	1.0000
18:62830198:A:T	donor_gain	1.0000
18:62830225:TGGAA:T	donor_gain	1.0000
18:62830226:GGAAA:G	donor_gain	1.0000
18:62830230:AA:A	donor_gain	1.0000
18:62830231:AG:A	donor_loss	1.0000
18:62830232:G:GG	donor_gain	1.0000
18:62830233:TAA:T	donor_loss	1.0000
18:62838779:TATA:T	acceptor_loss	1.0000
18:62838781:TA:T	acceptor_loss	1.0000
18:62838783:G:GA	acceptor_loss	1.0000
18:62838783:GGTA:G	acceptor_gain	1.0000
18:62838908:AGG:A	donor_loss	1.0000
18:62838911:T:A	donor_loss	1.0000
18:62860599:AAGG:A	donor_loss	1.0000
18:62860600:AGGTA:A	donor_loss	1.0000
18:62860602:G:GA	donor_loss	1.0000
18:62860603:T:G	donor_loss	1.0000
18:62873497:T:TA	acceptor_gain	1.0000
18:62895006:AATAG:A	acceptor_gain	1.0000
18:62895158:G:GG	donor_gain	1.0000

AlphaMissense

11152 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:62830092:T:A	V545D	1.000
18:62830094:C:A	R546S	1.000
18:62830095:G:C	R546P	1.000
18:62830127:T:A	W557R	1.000
18:62830127:T:C	W557R	1.000
18:62830129:G:C	W557C	1.000
18:62830129:G:T	W557C	1.000
18:62830164:T:C	L569P	1.000
18:62838889:T:A	W627R	1.000
18:62838889:T:C	W627R	1.000
18:62716344:T:C	C221R	0.999
18:62717149:C:A	P489Q	0.999
18:62717251:T:C	F523S	0.999
18:62830097:A:G	K547E	0.999
18:62830098:A:T	K547I	0.999
18:62830099:A:C	K547N	0.999
18:62830099:A:T	K547N	0.999
18:62830128:G:C	W557S	0.999
18:62830136:C:A	R560S	0.999
18:62830137:G:C	R560P	0.999
18:62830170:T:A	V571E	0.999
18:62830212:T:C	L585P	0.999
18:62838890:G:C	W627S	0.999
18:62860529:T:C	L665P	0.999
18:62860545:C:A	N670K	0.999
18:62860545:C:G	N670K	0.999
18:62895031:T:C	L696P	0.999
18:62895037:T:C	L698P	0.999
18:62941823:C:A	N1022K	0.999
18:62941823:C:G	N1022K	0.999

dbSNP variants (sampled 300 via entrez): RS1000004110 (18:62729761 A>G), RS1000012276 (18:62833144 G>A), RS1000014501 (18:62725666 G>A,T), RS1000048266 (18:62804261 C>T), RS1000054182 (18:62847093 C>A,T), RS1000063317 (18:62832786 TGA>T), RS1000067789 (18:62946791 C>T), RS1000073180 (18:62885827 T>C), RS1000081439 (18:62848613 G>A), RS1000106360 (18:62766462 C>T), RS1000115129 (18:62852809 A>G), RS1000125762 (18:62724186 A>G,T), RS1000131476 (18:62882399 G>C), RS1000151738 (18:62942511 A>G), RS1000161587 (18:62761149 G>A)

Disease associations

OMIM: gene MIM:609396 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): attention deficit-hyperactivity disorder (MONDO:0007743)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003473_6	Aggressiveness in attention deficit hyperactivity disorder	9.000000e-06
GCST008156_13	Hip circumference adjusted for BMI	2.000000e-07
GCST90002400_250	Plateletcrit	1.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0007985	platelet crit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3414405 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.16	Kd	690	nM	CHEMBL3414669
6.16	Kd	690	nM	CHEMBL3414688
6.14	Kd	720	nM	CHEMBL3414686

PubChem BioAssay actives

3 with measured affinity, of 30 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R)-2,7,8-trimethyl-2-(4-methylpentyl)-3,4-dihydrochromen-6-ol	1200633: Binding affinity to GST-tagged PH domain of PHLPP1 (unknown origin) by surface Plasmon resonance spectroscopy	kd	0.6900	uM
8-bromo-2-methyl-2-(4-methylpentyl)-3,4-dihydrochromene-6-sulfonamide	1200633: Binding affinity to GST-tagged PH domain of PHLPP1 (unknown origin) by surface Plasmon resonance spectroscopy	kd	0.6900	uM
2,7,8-trimethyl-2-(4-methylpentyl)-3,4-dihydrochromene-6-sulfonamide	1200633: Binding affinity to GST-tagged PH domain of PHLPP1 (unknown origin) by surface Plasmon resonance spectroscopy	kd	0.7200	uM

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	3
Valproic Acid	decreases expression, increases methylation	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
ciglitazone	affects binding, increases expression	1
arsenic trichloride	decreases expression, increases expression, increases reaction, affects binding	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation	1
Phthalic Acids	decreases methylation	1
Polychlorinated Biphenyls	affects expression	1
Potassium Dichromate	decreases expression	1
Rotenone	affects reaction, decreases phosphorylation, decreases expression, decreases reaction, increases cleavage (+1 more)	1
Silicon Dioxide	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3419784	Binding	Inhibition of PHLPP1-mediated reduction in phosphorylation of Akt at Ser473 in human LNCAP cells after 24 hrs by Western blot analysis	Exploitation of the ability of γ-tocopherol to facilitate membrane co-localization of Akt and PHLPP1 to develop PHLPP1-targeted Akt inhibitors. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8MJ	Abcam HCT 116 PHLPP1 KO	Cancer cell line	Male
CVCL_B9AA	Abcam MCF-7 PHLPP1 KO	Cancer cell line	Female
CVCL_B9PQ	Abcam A-549 PHLPP1 KO	Cancer cell line	Male
CVCL_TD31	HAP1 PHLPP1 (-) 1	Cancer cell line	Male
CVCL_TD32	HAP1 PHLPP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	PHASE4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	PHASE4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	PHASE4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	PHASE4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	PHASE4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	PHASE4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	PHASE4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	PHASE4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	PHASE4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	PHASE4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	PHASE4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	PHASE4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	PHASE4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	PHASE4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	PHASE4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder
NCT00299234	PHASE4	TERMINATED	Atomoxetine for Children With Acquired Attentional Disorders Following Completion of Chemotherapy for ALL
NCT00302406	PHASE4	COMPLETED	Naturalistic Substitution of Concerta in Adult Subject With ADHD Receiving Immediate Release Methylphenidate
NCT00305370	PHASE4	COMPLETED	Aripiprazole Associated With Methylphenidate in Children and Adolescents With Bipolar Disorder and ADHD
NCT00381758	PHASE4	COMPLETED	The COMACS Study: A Comparison of Methylphenidates in an Analog Classroom Setting
NCT00406354	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany
NCT00434213	PHASE4	COMPLETED	Characterization of Dermal Reactions in Pediatric Patients With ADHD Using DAYTRANA
NCT00468143	PHASE4	COMPLETED	A Within-Subject Cross-Over Comparison Between Immediate Release and Extended Release Adderall
NCT00471354	PHASE4	COMPLETED	A Study for Patients With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine
NCT00483106	PHASE4	COMPLETED	Clinical and Pharmacogenetic Study of Attention Deficit With Hyperactivity Disorder (ADHD)
NCT00485849	PHASE4	COMPLETED	A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD
NCT00485875	PHASE4	COMPLETED	Safety and Efficacy of Switching From a Stimulant Medication to Atomoxetine in Children and Adolescents With ADHD
NCT00486122	PHASE4	COMPLETED	Evaluation of Continuous Symptom Treatment of ADHD
NCT00500071	PHASE4	COMPLETED	Dose-Optimization Study Evaluating the Efficacy, Safety and Tolerability of Vyvanse (Lisdexamfetamine Dimesylate) in Children Aged 6-12 Diagnosed With ADHD
NCT00506727	PHASE4	COMPLETED	Analog Classroom Study Comparison of ADDERALL XR With STRATTERA in Children Aged 6-12 With ADHD
NCT00510276	PHASE4	COMPLETED	Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) With Atomoxetine in Young Adults and Its Effects on Functional Outcomes
NCT00517504	PHASE4	COMPLETED	Methylphenidate Study in Young Children With Developmental Disorders
NCT00517647	PHASE4	COMPLETED	Atomoxetine Pilot Study in Preschool Children With ADHD
NCT00518232	PHASE4	COMPLETED	A Study to Determine Effective and Tolerable Titration Scheme for OROS-Methylphenidate in Children With Attention-deficit Hyperactivity Disorder
NCT00530257	PHASE4	COMPLETED	Study of the Effects of Osmotic-Release Oral System (OROS) Methylphenidate (Concerta) on Attention and Memory
NCT00536419	PHASE4	UNKNOWN	Impact of Attention Deficit/Hyperactivity Disorder and Substance Use Disorder on Motorcycle Traffic Accidents
NCT00546910	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00552266	PHASE4	UNKNOWN	Methylphenidate in ADHD With Trichotillomania
NCT00564954	PHASE4	COMPLETED	A Study of Dex-methylphenidate Extended Release in Children (6-12 Years) With Attention-Deficit/Hyperactivity Disorder (ADHD)