PHLPP2

Summary

PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2, HGNC:29149) is a protein-coding gene on chromosome 16q22.2, encoding PH domain leucine-rich repeat-containing protein phosphatase 2 (Q6ZVD8). Protein phosphatase involved in regulation of Akt and PKC signaling.

Predicted to enable metal ion binding activity and phosphoprotein phosphatase activity. Predicted to be involved in intracellular signal transduction. Located in several cellular components, including cilium; intercellular bridge; and mitotic spindle.

Source: NCBI Gene 23035 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 207 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015020

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29149
Approved symbol	PHLPP2
Name	PH domain and leucine rich repeat protein phosphatase 2
Location	16q22.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0931, PPM3B
Ensembl gene	ENSG00000040199
Ensembl biotype	protein_coding
OMIM	611066
Entrez	23035

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000393524, ENST00000538126, ENST00000564884, ENST00000567016, ENST00000568004, ENST00000568954, ENST00000574977, ENST00000891456, ENST00000891457, ENST00000914408, ENST00000943438, ENST00000943439

RefSeq mRNA: 2 — MANE Select: NM_015020 NM_001289003, NM_015020

CCDS: CCDS32479, CCDS73910

Canonical transcript exons

ENST00000568954 — 19 exons

Exon	Start	End
ENSE00001171882	71667178	71667333
ENSE00001368132	71655240	71655434
ENSE00001375321	71676447	71676649
ENSE00001382151	71672262	71672322
ENSE00001385296	71678755	71678985
ENSE00001386411	71663899	71664099
ENSE00001387676	71669275	71669370
ENSE00001389833	71652790	71653021
ENSE00002605591	71644924	71650044
ENSE00002619449	71724329	71724701
ENSE00003482554	71656571	71656681
ENSE00003493448	71658653	71658815
ENSE00003535768	71681751	71681905
ENSE00003562235	71690519	71690709
ENSE00003621420	71714512	71714801
ENSE00003638616	71702598	71702731
ENSE00003640440	71684476	71684601
ENSE00003653256	71658233	71658363
ENSE00003677019	71679389	71679535

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 97.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1498 / max 84.5287, expressed in 1739 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158031	8.5886	1731
158030	0.5593	271
158032	0.0019	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	97.08	gold quality
jejunal mucosa	UBERON:0000399	95.52	gold quality
colonic mucosa	UBERON:0000317	90.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.15	gold quality
middle temporal gyrus	UBERON:0002771	88.96	gold quality
pigmented layer of retina	UBERON:0001782	88.70	gold quality
germinal epithelium of ovary	UBERON:0001304	87.60	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.14	gold quality
duodenum	UBERON:0002114	86.07	gold quality
mucosa of transverse colon	UBERON:0004991	85.41	gold quality
postcentral gyrus	UBERON:0002581	84.73	gold quality
superior frontal gyrus	UBERON:0002661	84.35	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.01	gold quality
rectum	UBERON:0001052	83.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.09	gold quality
orbitofrontal cortex	UBERON:0004167	82.95	gold quality
parietal pleura	UBERON:0002400	82.58	gold quality
entorhinal cortex	UBERON:0002728	82.34	gold quality
endothelial cell	CL:0000115	82.04	gold quality
parietal lobe	UBERON:0001872	82.02	gold quality
transverse colon	UBERON:0001157	80.79	gold quality
endometrium epithelium	UBERON:0004811	80.41	gold quality
small intestine	UBERON:0002108	80.40	gold quality
Brodmann (1909) area 10	UBERON:0013541	80.11	gold quality
cerebellum	UBERON:0002037	79.95	gold quality
intestine	UBERON:0000160	79.89	gold quality
cerebellar cortex	UBERON:0002129	79.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.83	gold quality
cerebellar hemisphere	UBERON:0002245	79.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.82	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	4.53
E-MTAB-7303	no	257.19
E-ANND-3	no	6.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

133 targeting PHLPP2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• A functional polymorphism that impairs the activity of PHLPP2 and correlates with elevated Akt phosphorylation and increased PKC levels, was identified. (PMID:19324870)
• The PHLPP2 dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. (PMID:20513427)
• Knockdown of PHLPP1 or PHLPP2 resulted in an increase in S6K1 phosphorylation. (PMID:21986499)
• PHLPP1 and PHLPP2 have an effect on retinal rod CNG channel sensitivity. (PMID:22183406)
• Diacylglycerol signaling limits Akt activation through diacylglycerol kinase delta and PHLPP2. (PMID:23184957)
• IGF-1 may exert its proliferative effects by negatively regulating the PTEN/PHLPP2 signaling pathway in CM cells. (PMID:23715723)
• 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)
• Low PHLPP2 expression is associated with malignant phenotypes in non-small cell lung cancer. (PMID:23856247)
• Results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-kappaB signaling. (PMID:24553260)
• 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)
• Data show that miR-372 modulated the expression of phosphoprotein phosphatase PHLPP2 by directly targeting its 3’-untranslated region (3’-UTR) and that miR-372 expression was inversely correlated with PHLPP2 expression in glioma samples. (PMID:25160587)
• Aberrant expression of PHLPP1 and PHLPP2 correlates with poor prognosis in patients with hypopharyngeal squamous cell carcinoma (PMID:25793736)
• miR-135a promotes cell proliferation in bladder cancer by targeting PHLPP2 and FOXO1, and is performed as an onco- (PMID:25888950)
• Our studies not only first time identify PHLPP2 downregulation by lung carcinogen B[a]P/B[a]PDE, but also elucidate a novel molecular mechanisms underlying lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. (PMID:25977341)
• 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)
• Suggest that direct PHLPP2 downregulation is required for miR-32-induced cell proliferation of breast cancer cells. (PMID:26276160)
• Data show that both serine/threonine phosphatases PHLPP and dephosphorylated the physiological substrates of Akt1 and Akt3 with similar efficiencies. (PMID:26427440)
• Cheliensisin A (Chel A)treatment led to PH domain and Leucine rich repeat Protein Phosphatases (PHLPP2) protein degradation and subsequently increased in c-Jun phosphorylation, which could be attenuated by inhibition of autophagy mediated by Beclin 1. (PMID:27556506)
• results identify a novel role of PHLPP in regulating aPKC and cell polarity. (PMID:27760826)
• miR-3117 contributes to the proliferation of HepG2 by targeting PHLPPL. (PMID:27822662)
• two PHLPP isozymes, PHLPP1 and PHLPP2, were identified in a search for phosphatases that dephosphorylate Akt, and thus suppress growth factor signaling. (PMID:27913677)
• Overexpression of PHLPP2 without its 3’UTR attenuated the effects of miR-181a on cell proliferation and apoptosis in keloid fibroblast cells. (PMID:27915346)
• Low PHLPP2 expression is associated with luminal breast cancer. (PMID:28224609)
• Results show that MiR-27a directly targets PHLPP2 by binding to its 3’-UTR to inhibit its expression, and that downregulation of PHLPP2 could rescue the effect of anti-miR-27a in gastric cancer cells. (PMID:28327189)
• miR-938 promoted CRC cell proliferation by inhibiting PHLPP2 (PMID:28433657)
• TMCO1 recruited the PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) to dephosphorylate pAKT1(serine 473) (S473). Mutagenesis at S60 of the TMCO1 protein released TMCO1-induced cell-cycle arrest and restored the AKT pathway in BFTC905 cells. Stable TMCO1 (wild-type) overexpression suppressed, whereas T33A and S60A mutants recovered, tumor size in xenograft mice. (PMID:28972042)
• MiR-141-3p targets PHLPP2 at its 3’-untranslated region. (PMID:29738771)
• PHLPP2 stabilization by p27 mediates its inhibition of bladder cancer invasion by promoting autophagic degradation of MMP2 protein. (PMID:29930380)
• miR135a may protect human umbilical vein endothelial cell from mechanical stretch - induced injury by inhibiting PHLPP2 to activate PI3k/Akt signaling pathway. (PMID:30045018)
• DualLuciferase activity assay demonstrated that the tumor suppressor PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) was a target of miR125b, which inhibited PHLPP2 and directly bound to the 3’untranslated region of PHLPP2, resulting in elevated Akt signaling. (PMID:30226579)
• miR493 acted as a onco-miR in prostate cancer cells and promoted cell proliferation via inhibiting tumor suppresser PHLPP2 expression and activating Akt signaling pathway. (PMID:30868840)
• Identification and development of long non-coding RNA-associated regulatory network in colorectal cancer. (PMID:31144439)
• Results found PHLPP2 expression level frequently downregulated in non-small cell lung cancer (NSCLC) patients and associated with the presence of lymph node metastasis. Importantly, PHLPP2 was found to be an independent indicator of prognosis for overall and disease-free survival suggesting it as a robust clinical marker for NSCLC survival. (PMID:31571378)
• Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy. (PMID:32116109)
• MiR-493 Induces Cytotoxic Autophagy in Prostate Cancer Cells through Regulation on PHLPP2. (PMID:32188381)
• PTEN and PHLPP crosstalk in cancer cells and in TGFbeta-activated stem cells. (PMID:32294598)
• miR-15a-5p targets PHLPP2 in gastric cancer cells to modulate platinum resistance and is a suitable serum biomarker for oxaliplatin resistance. (PMID:32567934)
• PHLPP2 is regulated by competing endogenous RNA network in pathogenesis of colon cancer. (PMID:32633726)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Phlpp2	ENSMUSG00000031732
rattus_norvegicus	Phlpp2	ENSRNOG00000016108

Paralogs (31): LRRC7 (ENSG00000033122), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), 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 2 — Q6ZVD8 (reviewed: Q6ZVD8)

Alternative names: PH domain leucine-rich repeat-containing protein phosphatase-like

All UniProt accessions (4): H3BMS5, H3BS75, I3L187, Q6ZVD8

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 AKT1, ‘Ser-660’ of PRKCB isoform beta-II and ‘Ser-657’ of PRKCA. 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 decreases cell proliferation. Also controls the phosphorylation of AKT3. 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. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Dephosphorylates RAF1 inhibiting its kinase activity.

Subunit / interactions. Interacts with AKT1, AKT3 and PRKCB isoform beta-II. Interacts with STK4, RPS6KB1, RAF1. Interacts with FKBP5; FKBP5 acts as a scaffold for PHLPP2 and Akt. Interacts with NHERF1; NHERF1 scaffolds a heterotrimeric complex with PTEN.

Subcellular location. Cytoplasm. Membrane. Nucleus.

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 80% of tested tumors (at protein level).

Activity regulation. Inhibited by AKT1, AKT2 and AKT3. Activated by oleic acid and arachidonic acid.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6ZVD8-1	1	yes
Q6ZVD8-2	2
Q6ZVD8-3	3

RefSeq proteins (2): NP_001275932, NP_055835* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR001932	PPM-type_phosphatase-like_dom	Domain
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
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: PF00481, PF00560, 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 (46 total): repeat 22, sequence conflict 7, mutagenesis site 5, compositionally biased region 3, splice variant 3, domain 2, region of interest 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZVD8-F1	75.11	0.47

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 (1): 1210

Mutagenesis-validated functional residues (5):

Position	Phenotype
783	decreases activity.
806	decreases activity.
808	abolishes activity.
989	decreases activity.
1024	decreases 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: 179 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GCM_MAP4K4, AAGCAAT_MIR137, chr16q22, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, AAGCCAT_MIR135A_MIR135B, GOBP_FOREBRAIN_DEVELOPMENT, ACCAATC_MIR509, GOBP_HIPPOCAMPUS_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, ACATTCC_MIR1_MIR206, GOBP_HEAD_DEVELOPMENT, SABATES_COLORECTAL_ADENOMA_DN, GOCC_NEURON_PROJECTION

GO Biological Process (2): hippocampus development (GO:0021766), intracellular signal transduction (GO:0035556)

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 (9): photoreceptor inner segment (GO:0001917), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cilium (GO:0005929), photoreceptor outer segment membrane (GO:0042622), intercellular bridge (GO:0045171), mitotic spindle (GO:0072686), 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	5
intracellular anatomical structure	2
pallium development	1
limbic system development	1
anatomical structure development	1
signal transduction	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
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
photoreceptor outer segment	1
ciliary membrane	1
spindle	1

Protein interactions and networks

STRING

1526 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHLPP2	AKT3	Q9Y243	964
PHLPP2	AKT2	P31751	870
PHLPP2	AKT1	P31749	829
PHLPP2	PTEN	P60484	725
PHLPP2	PLEK2	Q9NYT0	691
PHLPP2	PLEK	P08567	685
PHLPP2	NHERF1	O14745	683
PHLPP2	USP12	O75317	656
PHLPP2	GSK3A	P49840	651
PHLPP2	USP46	P62068	646
PHLPP2	PHLPP1	O60346	572
PHLPP2	WDR48	Q8TAF3	572
PHLPP2	MDM2	Q00987	548
PHLPP2	PDP1	Q9P0J1	547
PHLPP2	MAPK3	P27361	538

IntAct

26 interactions, top by confidence:

A	B	Type	Score
PTEN	NHERF1	psi-mi:“MI:0915”(physical association)	0.830
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
PHLPP2	NHERF1	psi-mi:“MI:0915”(physical association)	0.760
PHLPP2	NHERF1	psi-mi:“MI:0407”(direct interaction)	0.760
NHERF1	PHLPP2	psi-mi:“MI:0915”(physical association)	0.760
PHLPP2	NHERF1	psi-mi:“MI:0914”(association)	0.760
USP46	PHLPP1	psi-mi:“MI:0914”(association)	0.740
AKT1	THEM4	psi-mi:“MI:0914”(association)	0.730
WDR20	PHLPP1	psi-mi:“MI:0914”(association)	0.670
USP12	PHLPP1	psi-mi:“MI:0914”(association)	0.570
PHLPP1	USP12	psi-mi:“MI:0914”(association)	0.570
DNAAF11	CHEK1	psi-mi:“MI:0914”(association)	0.530
PRKCB	PHLPP2	psi-mi:“MI:0915”(physical association)	0.520
PHLPP2	PRKCB	psi-mi:“MI:0915”(physical association)	0.520
PHLPP2	RPS11	psi-mi:“MI:0915”(physical association)	0.400
PHLPP2	Scrib	psi-mi:“MI:0915”(physical association)	0.400
RPS6KB1	PHLPP1	psi-mi:“MI:0914”(association)	0.350
PHLPP2	GRN	psi-mi:“MI:0914”(association)	0.350
USP46	PJA2	psi-mi:“MI:0914”(association)	0.350
WDR48	UNC13B	psi-mi:“MI:0914”(association)	0.350
USP46	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (69): USP12 (Affinity Capture-Western), WDR48 (Affinity Capture-Western), WDR20 (Affinity Capture-Western), PHLPP2 (Affinity Capture-MS), PHLPP2 (Affinity Capture-MS), PHLPP2 (Affinity Capture-MS), PHLPP2 (Far Western), SLC9A3R1 (Far Western), PHLPP2 (Reconstituted Complex), PHLPP2 (Affinity Capture-Western), PHLPP2 (Affinity Capture-MS), DMWD (Affinity Capture-MS), SLC9A3R1 (Affinity Capture-MS), SLC9A3R2 (Affinity Capture-MS), SNX27 (Affinity Capture-MS)

ESM2 similar proteins: A6QLV3, A7SFP1, A8XWW4, B0W6M9, B3LWU3, B3P3E8, B4IBI9, B4JTV9, B4LXW1, B4N9T4, B4PU77, B4QVR7, B5DX45, B6CZ61, B9F655, O35125, O88520, Q1L8Y7, Q22875, Q32KP2, Q4R3P6, Q4V8I7, Q53EV4, Q5F4C4, Q5FVI3, Q5GIG6, Q5M8G4, Q5RAV5, Q5RFE9, Q5ZLN0, Q6AYI5, Q6DHL5, Q6GPJ5, Q6INV3, Q6P1C6, Q6UXM1, Q6ZVD8, Q7SXW3, Q7Z4L9, Q80VQ1

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

12 interactions.

A	Effect	B	Mechanism
PHLPP2	down-regulates	AKT	dephosphorylation
PHLPP2	“down-regulates quantity”	PRKCB	dephosphorylation
PHLPP2	“down-regulates quantity”	PRKCA	dephosphorylation
PHLPP2	“down-regulates activity”	AKT3	dephosphorylation
PHLPP2	“down-regulates activity”	RPS6KB1	dephosphorylation
PHLPP2	“down-regulates quantity by destabilization”	PRKCB	dephosphorylation
PHLPP2	“down-regulates activity”	AKT1	dephosphorylation
PHLPP2	“down-regulates activity”	AKT2	dephosphorylation
PHLPP2	“up-regulates activity”	STK4	dephosphorylation
PHLPP2	“down-regulates activity”	AKT	dephosphorylation
PHLPP2	down-regulates	AKT1	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	182
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3633 predictions. Top by Δscore:

Variant	Effect	Δscore
16:71652789:CCT:C	donor_gain	1.0000
16:71653028:A:T	acceptor_gain	1.0000
16:71655235:CTTA:C	donor_loss	1.0000
16:71655236:TTA:T	donor_loss	1.0000
16:71655239:C:CT	donor_loss	1.0000
16:71655430:ACAGC:A	acceptor_gain	1.0000
16:71655431:CAGC:C	acceptor_gain	1.0000
16:71655431:CAGCC:C	acceptor_gain	1.0000
16:71655432:AGC:A	acceptor_gain	1.0000
16:71655433:GC:G	acceptor_gain	1.0000
16:71655434:CCTA:C	acceptor_gain	1.0000
16:71655435:C:CC	acceptor_gain	1.0000
16:71655440:A:AC	acceptor_gain	1.0000
16:71655440:A:C	acceptor_gain	1.0000
16:71655447:CA:C	acceptor_gain	1.0000
16:71655448:A:AC	acceptor_gain	1.0000
16:71655448:A:C	acceptor_gain	1.0000
16:71658228:CCTA:C	donor_loss	1.0000
16:71658230:TAC:T	donor_loss	1.0000
16:71658231:A:AC	donor_gain	1.0000
16:71658232:C:CC	donor_gain	1.0000
16:71658232:C:CG	donor_loss	1.0000
16:71658360:CAAA:C	acceptor_gain	1.0000
16:71658362:AA:A	acceptor_gain	1.0000
16:71658364:C:CC	acceptor_gain	1.0000
16:71667172:ACTT:A	donor_loss	1.0000
16:71667173:CTT:C	donor_loss	1.0000
16:71667174:TTAC:T	donor_loss	1.0000
16:71667175:TA:T	donor_loss	1.0000
16:71667176:A:AC	donor_gain	1.0000

AlphaMissense

8671 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:71658343:G:C	N723K	1.000
16:71658343:G:T	N723K	1.000
16:71658783:A:G	L673P	1.000
16:71679515:A:G	L304P	1.000
16:71681795:G:C	N282K	1.000
16:71681795:G:T	N282K	1.000
16:71681811:A:G	L277P	1.000
16:71684496:A:G	W239R	1.000
16:71684496:A:T	W239R	1.000
16:71690580:A:T	V183D	1.000
16:71690586:A:G	L181P	1.000
16:71690623:A:G	W169R	1.000
16:71690623:A:T	W169R	1.000
16:71690649:C:G	R160P	1.000
16:71650002:C:G	G954R	0.999
16:71650010:C:G	R951P	0.999
16:71652911:C:A	G899V	0.999
16:71653004:C:T	G868D	0.999
16:71655333:A:G	L831P	0.999
16:71655369:A:G	F819S	0.999
16:71655375:C:T	G817D	0.999
16:71658274:A:C	N746K	0.999
16:71658274:A:T	N746K	0.999
16:71658284:A:G	L743P	0.999
16:71658290:A:G	L741P	0.999
16:71658344:T:A	N723I	0.999
16:71658353:A:G	L720P	0.999
16:71658698:G:C	N701K	0.999
16:71658698:G:T	N701K	0.999
16:71658699:T:A	N701I	0.999

dbSNP variants (sampled 300 via entrez): RS1000013061 (16:71725559 G>A), RS1000017270 (16:71688743 T>C), RS1000028171 (16:71651071 G>T), RS1000044317 (16:71650685 C>A,T), RS1000048241 (16:71688321 T>A,G), RS1000141575 (16:71648792 A>C), RS1000142108 (16:71700490 T>C), RS1000270252 (16:71709648 G>A,T), RS1000296076 (16:71668579 T>C,G), RS1000307660 (16:71709301 G>C), RS1000406673 (16:71660619 T>C), RS1000432959 (16:71662819 T>A,C), RS1000448141 (16:71725795 G>A,T), RS1000470221 (16:71666557 A>C), RS1000498859 (16:71721140 C>T)

Disease associations

OMIM: gene MIM:611066 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002606_4	Prostate cancer	3.000000e-08
GCST003262_262	Post bronchodilator FEV1	2.000000e-06
GCST003262_266	Post bronchodilator FEV1	3.000000e-06
GCST003262_269	Post bronchodilator FEV1	2.000000e-06
GCST003262_270	Post bronchodilator FEV1	2.000000e-06
GCST003262_539	Post bronchodilator FEV1	2.000000e-06
GCST003262_540	Post bronchodilator FEV1	2.000000e-06
GCST007979_1	Postoperative acute renal failure after cardiac surgery	4.000000e-08
GCST009240_116	Serum metabolite levels (CMS)	2.000000e-22
GCST009242_57	Serum metabolite levels	1.000000e-14
GCST010002_114	Refractive error	4.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0009951	response to surgery
EFO:0009955	post-operative acute kidney injury

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1275209 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 14 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1270562	SALAZOSULFATHIAZOLE	2
CHEMBL377353	SALAZOSULFAMIDE	2	14

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

ChEMBL bioactivities

12 potent at pChembl≥5 of 31 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.43	IC50	3750	nM	CHEMBL1270266
5.40	IC50	4000	nM	CHEMBL1271272
5.40	IC50	4000	nM	CHEMBL1269845
5.40	IC50	4000	nM	CHEMBL471225
5.30	IC50	5000	nM	CHEMBL1269022
5.30	IC50	5000	nM	CHEMBL611747
5.16	IC50	7000	nM	CHEMBL1269954
5.00	IC50	1e+04	nM	CHEMBL487046
5.00	IC50	1e+04	nM	CHEMBL512908
5.00	IC50	1e+04	nM	CHEMBL1270061
5.00	IC50	1e+04	nM	CHEMBL1270169
5.00	IC50	1e+04	nM	CHEMBL1269665

PubChem BioAssay actives

12 with measured affinity, of 32 total; 12 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
5-[[4-[(2,4-diamino-5-methylphenyl)diazenyl]phenyl]diazenyl]-2-hydroxybenzoic acid	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	3.7500	uM
1-[(4-methoxyanilino)methyl]naphthalen-2-ol	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	4.0000	uM
1-amino-9,10-dioxo-4-(3-sulfamoylanilino)anthracene-2-sulfonic acid	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	4.0000	uM
6-methoxy-N-(2-piperidin-2-ylethyl)quinolin-8-amine	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	4.0000	uM
2-(dimethylamino)ethyl 4-aminobenzoate	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	5.0000	uM
1,3-bis(1H-indazol-6-yl)thiourea	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	5.0000	uM
4-[(3-hydroxy-2-pyridinyl)diazenyl]benzenesulfonamide	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	7.0000	uM
5-[3-pyridin-2-yl-6-(5-sulfofuran-2-yl)-1,2,4-triazin-5-yl]furan-2-sulfonic acid	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	10.0000	uM
4-[[4-(dimethylamino)phenyl]-(4-nitrophenyl)methyl]-N,N-dimethylaniline	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	10.0000	uM
2-(3,4,5-trihydroxy-6-oxoxanthen-9-yl)cyclohexane-1-carboxylic acid	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	10.0000	uM
2,3-dinitrofluoren-9-one	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	10.0000	uM
5-[[4-[[2,4-diamino-5-methyl-3-[(4-methyl-2-sulfophenyl)diazenyl]phenyl]diazenyl]phenyl]diazenyl]-2-hydroxybenzoic acid	525943: Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
sodium arsenite	affects binding, increases reaction, decreases expression, increases methylation, affects cotreatment (+2 more)	2
Acetaminophen	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
arecoline hydrobromide	decreases phosphorylation, increases abundance, increases expression, affects reaction	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
arsenite	decreases reaction, affects binding	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Acetaldehyde	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arecoline	increases abundance, increases expression, affects reaction, decreases phosphorylation	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzene	increases expression	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lead	decreases expression	1
Tobacco Smoke Pollution	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1274995	Binding	Inhibition of PHLPP2 phosphatase domain expressed in Escherichia coli at 10 uM	Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TD33	HAP1 PHLPP2 (-) 1	Cancer cell line	Male
CVCL_TD34	HAP1 PHLPP2 (-) 2	Cancer cell line	Male
CVCL_TD35	HAP1 PHLPP2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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