PPM1B

Summary

PPM1B (protein phosphatase, Mg2+/Mn2+ dependent 1B, HGNC:9276) is a protein-coding gene on chromosome 2p21, encoding Protein phosphatase 1B (O75688). Enzyme with a broad specificity.

The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase has been shown to dephosphorylate cyclin-dependent kinases (CDKs), and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to cause cell-growth arrest or cell death. Alternative splicing results in multiple transcript variants encoding different isoforms. Additional transcript variants have been described, but currently do not represent full-length sequences.

Source: NCBI Gene 5495 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 82 total — 1 pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9276
Approved symbol	PPM1B
Name	protein phosphatase, Mg2+/Mn2+ dependent 1B
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	PPC2BETAX, PP2CB, PP2CBETA
Ensembl gene	ENSG00000138032
Ensembl biotype	protein_coding
OMIM	603770
Entrez	5495

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 20 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000282412, ENST00000345249, ENST00000378540, ENST00000378551, ENST00000409432, ENST00000409473, ENST00000409486, ENST00000419807, ENST00000459690, ENST00000487286, ENST00000488866, ENST00000854776, ENST00000854777, ENST00000854778, ENST00000854779, ENST00000854780, ENST00000854781, ENST00000854782, ENST00000854783, ENST00000854784, ENST00000919023, ENST00000919024, ENST00000919025, ENST00000946340, ENST00000946341

RefSeq mRNA: 4 — MANE Select: NM_002706 NM_001033557, NM_002706, NM_177968, NM_177969

CCDS: CCDS1816, CCDS1817, CCDS1818, CCDS46271

Canonical transcript exons

ENST00000282412 — 6 exons

Exon	Start	End
ENSE00001811674	44230413	44231472
ENSE00003460167	44201186	44202045
ENSE00003536333	44209210	44209327
ENSE00003548257	44217967	44218078
ENSE00003790025	44218480	44218537
ENSE00003842199	44168875	44169274

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.6982 / max 535.4932, expressed in 1811 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19989	37.6982	1811

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.29	gold quality
oocyte	CL:0000023	98.37	gold quality
choroid plexus epithelium	UBERON:0003911	97.96	gold quality
pigmented layer of retina	UBERON:0001782	97.63	gold quality
retina	UBERON:0000966	97.61	gold quality
gastrocnemius	UBERON:0001388	97.12	gold quality
muscle of leg	UBERON:0001383	96.93	gold quality
biceps brachii	UBERON:0001507	96.72	gold quality
muscle organ	UBERON:0001630	96.62	gold quality
skeletal muscle organ	UBERON:0014892	96.62	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.58	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.53	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.50	gold quality
skeletal muscle tissue	UBERON:0001134	96.26	gold quality
deltoid	UBERON:0001476	96.15	gold quality
gluteal muscle	UBERON:0002000	96.01	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	95.95	gold quality
vastus lateralis	UBERON:0001379	95.67	gold quality
cranial nerve II	UBERON:0000941	95.43	gold quality
quadriceps femoris	UBERON:0001377	95.41	gold quality
medial globus pallidus	UBERON:0002477	95.39	gold quality
tibialis anterior	UBERON:0001385	95.01	gold quality
globus pallidus	UBERON:0001875	94.88	gold quality
blood vessel layer	UBERON:0004797	94.86	gold quality
popliteal artery	UBERON:0002250	94.79	gold quality
tibial artery	UBERON:0007610	94.78	gold quality
muscle tissue	UBERON:0002385	94.74	gold quality
diaphragm	UBERON:0001103	94.58	gold quality
bone marrow	UBERON:0002371	94.52	gold quality
putamen	UBERON:0001874	94.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.27
E-MTAB-4850	no	434.05
E-MTAB-6142	no	52.48

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

80 targeting PPM1B, 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-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889

Literature-anchored findings (GeneRIF, showing 23)

• e catalytic mechanism of DmGPx, unlike that of selenocysteine (Sec)GPxs, involves formation of an internal disulfide that is pivotal to the interaction with Trx (PMID:17098255)
• PP2Cbeta down-regulates cytokine-induced NF-kappaB activation by altering IKK activity. (PMID:14585847)
• Overexpression of PPM1A and the related PPM1B greatly reduced Cdk9 T-loop phosphorylation (PMID:18829461)
• Protein phosphatase 1B is mediated dephosphorylation and inactivation of I-kappa B kinase as well as the termination of the Tumor Necrosis Factor-alpha-induced NF-kappaappaB activation. (PMID:18930133)
• results implicate a novel and important role for PP2Cbetal in regulating hPXR activity and CYP3A4 expression by inhibiting or desensitizing signaling pathways that negatively regulate the function of pregnane X receptor in liver cells (PMID:20538721)
• Studies show that Ppm1b plays a multilayered role in regulating the availability and optimal activity of the EKLF protein in erythroid cells. (PMID:22393050)
• PPM1B functions as a TBK1 phosphatase dephosphorylates TBK1 at serine 172 and terminates TBK1-mediated IRF3 activation and IFNbeta gene expression. (PMID:22750291)
• the phosphatase PPM1B as a novel selective modulator of PPARgamma activity. (PMID:23320500)
• Protein kinase A activates NF-kappaB-mediated transcription by destabilization of PP2Cbeta. (PMID:23756813)
• Cadmium reversed PPM1A-induced cell cycle arrest and cadmium insensitive PPM1A mutant rescued cadmium induced cell death. (PMID:23903585)
• Results identify PPM1B as a critical regulator of both p38 MAPK-dependent and independent senescence pathways during normal cellular aging process. (PMID:24674756)
• PPM1B interacts with Groucho 4 and is localized to DNA in a Groucho-dependent manner, and phosphatase activity is required for transcriptional silencing. (PMID:25631048)
• This study has identified PPM1B and miR-186 as potential diagnostic markers in bladder cancer. Promotion of PPM1B and suppression of miR-186 may offer effective therapeutic strategies in the treatment of bladder cancer. (PMID:26494000)
• Results indicate that protein phosphatase 1B (PPM1B) negatively regulates cancer cell motility and invasiveness through dephosphorylating Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1). (PMID:29307615)
• PPM1B plays a negative role in the activation of the p38-RB1-E2F1 pathway and that targeting PPM1B could be useful in certain types of cancer by stimulating chemotherapy-induced cell death. (PMID:29654756)
• TRIM59 promotes tumor growth in hepatocellular carcinoma and regulates the cell cycle by degradation of protein phosphatase 1B. (PMID:31875525)
• Relationship between the Levels of mRNA Expression for Protein Phosphatase 1B and Proteins Involved in Cytoskeleton Remodeling in Squamous Cell Carcinoma of the Larynx and Hypopharynx. (PMID:32915364)
• Protein phosphatase PPM1B inhibits DYRK1A kinase through dephosphorylation of pS258 and reduces toxic tau aggregation. (PMID:33380426)
• [TRIM59 regulates invasion and migration of nasopharyngeal carcinoma cells by targeted modulation of PPM1B]. (PMID:34308852)
• Protein Phosphatase PPM1B Inhibits Gastric Cancer Progression and Serves as a Favorable Prognostic Biomarker. (PMID:35319516)
• Pleckstrin-2-promoted PPM1B degradation plays an important role in transforming growth factor-beta-induced breast cancer cell invasion and metastasis. (PMID:36928924)
• Circ_0090231 knockdown protects vascular smooth muscle cells from ox-LDL-induced proliferation, migration and invasion via miR-942-5p/PPM1B axis during atherosclerosis. (PMID:37515673)
• RBM10 regulates the tumorigenic potential of human cancer cells by modulating PPM1B and YBX1 activities. (PMID:38246397)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppm1ba	ENSDARG00000001888
mus_musculus	Ppm1b	ENSMUSG00000061130
rattus_norvegicus	Ppm1b	ENSRNOG00000030667
drosophila_melanogaster	Pdp	FBGN0029958
drosophila_melanogaster	CG10376	FBGN0032702
caenorhabditis_elegans	pdp-1	WBGENE00022832

Paralogs (16): PPM1F (ENSG00000100034), TAB1 (ENSG00000100324), PPM1A (ENSG00000100614), PPM1H (ENSG00000111110), PPM1G (ENSG00000115241), ILKAP (ENSG00000132323), PPM1J (ENSG00000155367), PPM1L (ENSG00000163590), PPM1K (ENSG00000163644), PPM1M (ENSG00000164088), PDP1 (ENSG00000164951), PPM1D (ENSG00000170836), PDP2 (ENSG00000172840), PPM1E (ENSG00000175175), PP2D1 (ENSG00000183977), PPM1N (ENSG00000213889)

Protein

Protein identifiers

Protein phosphatase 1B — O75688 (reviewed: O75688)

Alternative names: Protein phosphatase 2C isoform beta

All UniProt accessions (3): O75688, B8ZZF0, C9JIR6

UniProt curated annotations — full annotation on UniProt →

Function. Enzyme with a broad specificity. Dephosphorylates CDK2 and CDK6 in vitro. Dephosphorylates PRKAA1 and PRKAA2. Inhibits TBK1-mediated antiviral signaling by dephosphorylating it at ‘Ser-172’. Plays an important role in the termination of TNF-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB.

Subunit / interactions. Monomer. Interacts with PAK6. Interacts with the phosphorylated form of IKBKB/IKKB.

Subcellular location. Cytoplasm. Cytosol. Membrane.

Tissue specificity. Highly expressed in heart and skeletal muscle.

Post-translational modifications. Isgylation negatively regulates its activity. N-myristoylation is essential for the recognition of its substrates for dephosphorylation.

Cofactor. Binds 2 magnesium or manganese ions per subunit.

Similarity. Belongs to the PP2C family.

Isoforms (5)

UniProt ID	Names	Canonical?
O75688-1	Beta-1, Beta-X, PPM1B2	yes
O75688-2	Beta-2, PPM1B1
O75688-3	Beta-X
O75688-4	4
O75688-5	5

RefSeq proteins (4): NP_001028729, NP_002697, NP_808907, NP_808908 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000222	PP2C_BS	Binding_site
IPR001932	PPM-type_phosphatase-like_dom	Domain
IPR012911	PP2C_C	Domain
IPR015655	PP2C	Family
IPR036457	PPM-type-like_dom_sf	Homologous_superfamily
IPR036580	PP2C_C_sf	Homologous_superfamily

Pfam: PF00481, PF07830

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 (49 total): strand 13, helix 8, splice variant 7, binding site 5, turn 4, compositionally biased region 3, cross-link 2, region of interest 2, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2P8E	X-RAY DIFFRACTION	1.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75688-F1	85.52	0.71

Functional residue map

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

Ligand- & substrate-binding residues (5): 61; 243; 286; 60; 60

Post-translational modifications (4): 386, 2, 12, 142

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-9700645	ALK mutants bind TKIs
R-HSA-9725370	Signaling by ALK fusions and activated point mutants

MSigDB gene sets: 387 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, CCAWYNNGAAR_UNKNOWN, GCM_GSPT1, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GCM_ZNF198, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, DITTMER_PTHLH_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (9): protein dephosphorylation (GO:0006470), N-terminal protein myristoylation (GO:0006499), negative regulation of interferon-beta production (GO:0032688), peptidyl-threonine dephosphorylation (GO:0035970), regulation of canonical NF-kappaB signal transduction (GO:0043122), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of defense response to virus (GO:0050687), positive regulation of canonical Wnt signaling pathway (GO:0090263), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223)

GO Molecular Function (8): magnesium ion binding (GO:0000287), protein serine/threonine phosphatase activity (GO:0004722), manganese ion binding (GO:0030145), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), cation binding (GO:0043169), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleolus (GO:0005730), cytosol (GO:0005829), membrane (GO:0016020), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by ALK in cancer	2
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
canonical NF-kappaB signal transduction	2
negative regulation of intracellular signal transduction	2
dephosphorylation	1
protein modification process	1
N-terminal protein lipidation	1
protein myristoylation	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
protein dephosphorylation	1
regulation of intracellular signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of response to biotic stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of defense response to virus	1
defense response to virus	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
metal ion binding	1
phosphoprotein phosphatase activity	1
transition metal ion binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
ion binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2849 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPM1B	PREPL	Q4J6C6	966
PPM1B	CAMKMT	Q7Z624	953
PPM1B	SLC3A1	Q07837	938
PPM1B	PPP2CB	P11082	760
PPM1B	YEATS4	O95619	718
PPM1B	PPP2CA	P05323	532
PPM1B	PRMT5	O14744	520
PPM1B	PPP5C	P53041	518
PPM1B	ARIH1	Q9Y4X5	508
PPM1B	PTPN2	P17706	496
PPM1B	PPM1G	O15355	490
PPM1B	CDK2	P24941	482
PPM1B	STK38	Q15208	479
PPM1B	PREP	P48147	476
PPM1B	CMTR1	Q8N1G2	469

IntAct

136 interactions, top by confidence:

A	B	Type	Score
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
HIP1R	HIP1	psi-mi:“MI:0914”(association)	0.640
LRRC32	SMPD2	psi-mi:“MI:0914”(association)	0.640
PPM1B	ARRB2	psi-mi:“MI:2364”(proximity)	0.600
ISG15	PPM1B	psi-mi:“MI:0195”(covalent binding)	0.560
PPM1B	ISG15	psi-mi:“MI:0195”(covalent binding)	0.560
PPM1B	ERBB3	psi-mi:“MI:0915”(physical association)	0.550
ERBB3	PPM1B	psi-mi:“MI:0915”(physical association)	0.550
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
PPM1A	INPPL1	psi-mi:“MI:0914”(association)	0.530
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
TIMP3	ZZEF1	psi-mi:“MI:0914”(association)	0.530
PVR	ORC4	psi-mi:“MI:0914”(association)	0.530
CERKL	PPM1B	psi-mi:“MI:0914”(association)	0.530
IL25	PPM1B	psi-mi:“MI:0914”(association)	0.530
PPM1B	ARRB1	psi-mi:“MI:0915”(physical association)	0.500
RBM45	HNRNPDL	psi-mi:“MI:0914”(association)	0.460
PPM1B	Smurf2	psi-mi:“MI:0915”(physical association)	0.400
SNX27	PPM1B	psi-mi:“MI:0915”(physical association)	0.400
PPM1B	MARK3	psi-mi:“MI:0915”(physical association)	0.400
PPM1B	AATK	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	ERBB4	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	EGFR	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	KDR	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	RYK	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	ROR1	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	ROR2	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	PTK7	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (277): PPARG (Biochemical Activity), PPM1B (Affinity Capture-MS), PPM1B (Affinity Capture-Western), PPM1B (Affinity Capture-MS), PPM1B (Affinity Capture-MS), PPM1B (Affinity Capture-MS), PPM1B (Affinity Capture-MS), CASK (Co-fractionation), CDK1 (Co-fractionation), LRRK1 (Co-fractionation), MAP4K5 (Co-fractionation), NAA10 (Co-fractionation), PPM1B (Co-fractionation), PPM1B (Co-fractionation), PPM1B (Co-fractionation)

ESM2 similar proteins: A0A3L7I2I8, A3A8W2, A4IF63, A6K136, D2GXS7, D3ZQG6, F7H9X2, O60733, O62829, O62830, O75688, O88483, P20650, P35813, P35814, P35816, P42694, P49443, P93006, P97570, P97819, Q05AL2, Q15750, Q28DF4, Q2PC20, Q3UV70, Q5F361, Q5R522, Q5RA52, Q5SMK6, Q69QZ0, Q69VD9, Q6ING9, Q6NYU2, Q6ZHC8, Q7XJ53, Q7XUC5, Q84JD5, Q8AYC9, Q8BXN7

Diamond homologs: A0A7U2MSD6, A0BLX0, A0BQL0, A0CUB5, A0DSB3, A0DTY1, A3A8Q4, A3A8W2, A3A8W6, A5PJZ2, F1LNI5, G0RT93, O04719, O15355, O15743, O62829, O62830, O75688, O80871, O81716, P20650, P34221, P35813, P35814, P35815, P36993, P38089, P39966, P40371, P49443, P49444, P49593, P49595, P49596, P49597, P49598, P79126, P93006, Q09172, Q09173

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
PPM1B	unknown	CDK9	dephosphorylation
PPM1B	down-regulates	IKBKB	dephosphorylation
PPM1B	“down-regulates activity”	IKBKB	dephosphorylation
PPM1B	“down-regulates activity”	PAX2	dephosphorylation
PKA	“down-regulates quantity by destabilization”	PPM1B	phosphorylation
PPM1B	“down-regulates activity”	MPRIP	dephosphorylation
PPM1B	“up-regulates activity”	PPARG	dephosphorylation
PPM1B	“down-regulates activity”	DYRK1A	dephosphorylation
PPM1B	“down-regulates activity”	CDK2	dephosphorylation
PPM1B	“down-regulates activity”	TBK1	dephosphorylation
PPM1B	“down-regulates activity”	MAP3K7	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 160 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SHC1 events in ERBB2 signaling	5	22.0×	9e-04
Signaling by ERBB2 TMD/JMD mutants	5	22.0×	9e-04
Signaling by ERBB2 KD Mutants	5	19.6×	1e-03
Signaling by high-kinase activity BRAF mutants	5	14.7×	2e-03
PCP/CE pathway	5	13.9×	2e-03
Beta-catenin independent WNT signaling	5	13.6×	2e-03
MAP2K and MAPK activation	5	13.2×	2e-03
Signaling by moderate kinase activity BRAF mutants	5	11.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein phosphorylation	6	11.8×	7e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	12	6.7×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	55
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
684922	GRCh37/hg19 2p21(chr2:44438045-44546016)x1	Pathogenic

SpliceAI

1457 predictions. Top by Δscore:

Variant	Effect	Δscore
2:44174816:G:GG	donor_gain	1.0000
2:44201185:GATTT:G	acceptor_gain	1.0000
2:44209201:A:AG	acceptor_gain	1.0000
2:44209202:A:G	acceptor_gain	1.0000
2:44209206:ACAG:A	acceptor_gain	1.0000
2:44209322:TTGA:T	donor_gain	1.0000
2:44209323:TGAAG:T	donor_loss	1.0000
2:44209325:AAGG:A	donor_loss	1.0000
2:44209328:GTA:G	donor_loss	1.0000
2:44209329:T:A	donor_loss	1.0000
2:44218079:G:GG	donor_gain	1.0000
2:44218474:TTTTA:T	acceptor_loss	1.0000
2:44218476:TTAG:T	acceptor_loss	1.0000
2:44218477:TA:T	acceptor_loss	1.0000
2:44218478:A:AG	acceptor_gain	1.0000
2:44218478:AGG:A	acceptor_loss	1.0000
2:44218479:G:GG	acceptor_gain	1.0000
2:44218479:GGC:G	acceptor_gain	1.0000
2:44218479:GGCGT:G	acceptor_gain	1.0000
2:44218535:GGG:G	donor_gain	1.0000
2:44218536:GG:G	donor_gain	1.0000
2:44218536:GGG:G	donor_gain	1.0000
2:44218537:GG:G	donor_gain	1.0000
2:44218537:GGTAA:G	donor_loss	1.0000
2:44218538:G:GA	donor_loss	1.0000
2:44218538:G:GG	donor_gain	1.0000
2:44218539:TAA:T	donor_loss	1.0000
2:44169212:GGC:G	donor_gain	0.9900
2:44169213:GC:G	donor_gain	0.9900
2:44169214:C:G	donor_gain	0.9900

AlphaMissense

3162 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:44201203:G:C	G2R	1.000
2:44201203:G:T	G2C	1.000
2:44201204:G:A	G2D	1.000
2:44201210:T:C	F4S	1.000
2:44201213:T:C	L5S	1.000
2:44201221:C:A	P8T	1.000
2:44201221:C:T	P8S	1.000
2:44201222:C:A	P8H	1.000
2:44201235:A:C	K12N	1.000
2:44201235:A:T	K12N	1.000
2:44201289:A:C	Q30H	1.000
2:44201289:A:T	Q30H	1.000
2:44201290:G:A	G31R	1.000
2:44201290:G:C	G31R	1.000
2:44201291:G:A	G31E	1.000
2:44201291:G:T	G31V	1.000
2:44201293:T:A	W32R	1.000
2:44201293:T:C	W32R	1.000
2:44201294:G:C	W32S	1.000
2:44201294:G:T	W32L	1.000
2:44201295:G:C	W32C	1.000
2:44201295:G:T	W32C	1.000
2:44201296:A:G	R33G	1.000
2:44201297:G:A	R33K	1.000
2:44201297:G:C	R33T	1.000
2:44201297:G:T	R33I	1.000
2:44201298:A:C	R33S	1.000
2:44201298:A:T	R33S	1.000
2:44201306:T:C	M36T	1.000
2:44201306:T:G	M36R	1.000

dbSNP variants (sampled 300 via entrez): RS1000038824 (2:44179513 G>C), RS1000045112 (2:44213267 A>G,T), RS1000102603 (2:44179050 A>C), RS1000105339 (2:44194720 C>T), RS1000113008 (2:44185635 G>A), RS1000125816 (2:44215332 A>G), RS1000165278 (2:44185358 G>A), RS1000176631 (2:44212782 G>A), RS1000180276 (2:44176669 A>G), RS1000229040 (2:44212617 G>A,T), RS1000234073 (2:44176864 C>T), RS1000246463 (2:44181206 C>G), RS1000341596 (2:44190279 C>G,T), RS1000381404 (2:44185887 T>G), RS1000427141 (2:44186228 C>G)

Disease associations

OMIM: gene MIM:603770 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000135	Hypogonadism
HP:0000358	Posteriorly rotated ears
HP:0000527	Long eyelashes
HP:0000787	Nephrolithiasis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001558	Decreased fetal movement
HP:0001611	Hypernasal speech
HP:0001943	Hypoglycemia
HP:0002007	Frontal bossing
HP:0002342	Moderate intellectual disability
HP:0002901	Hypocalcemia
HP:0003128	Lactic acidosis
HP:0003131	Cystinuria
HP:0005280	Depressed nasal bridge
HP:0200125	Mitochondrial respiratory chain defects

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001956_41	Height	4.000000e-09
GCST007323_95	Risk-taking tendency (4-domain principal component model)	1.000000e-09
GCST007326_102	Number of sexual partners	1.000000e-11
GCST007328_27	Alcohol consumption (drinks per week)	3.000000e-11
GCST007565_100	Morning person	7.000000e-17
GCST007576_298	Chronotype	7.000000e-17
GCST008058_277	Estimated glomerular filtration rate	2.000000e-07
GCST008839_453	Height	2.000000e-17
GCST009391_412	Metabolite levels	6.000000e-06
GCST010002_389	Refractive error	3.000000e-26
GCST012227_1184	Hip circumference adjusted for BMI	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0010387	phosphatidylcholine 38:5 measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2845 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,679 (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
CHEMBL48449	CANTHARIDIN	4	4,679

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

ChEMBL bioactivities

16 potent at pChembl≥5 of 27 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	IC50	0.3	nM	CHEMBL421377
8.52	IC50	3	nM	CHEMBL421377
6.90	IC50	126	nM	OKADAIC ACID
6.37	IC50	430	nM	CANTHARIDIN
6.28	Ki	520	nM	CHEMBL5188453
6.24	IC50	570	nM	DEMETHYL-CANTHARIDIN
6.00	IC50	1000	nM	CHEMBL318253
5.75	IC50	1780	nM	CANTHARIDIN
5.70	IC50	1980	nM	DEMETHYL-CANTHARIDIN
5.55	IC50	2820	nM	CHEMBL100883
5.53	IC50	2960	nM	CHEMBL48076
5.49	IC50	3220	nM	CHEMBL100935
5.33	IC50	4710	nM	CHEMBL47665
5.32	IC50	4820	nM	CHEMBL48010
5.28	IC50	5310	nM	DEMETHYL-CANTHARIDIN
5.25	IC50	5600	nM	CHEMBL101932

PubChem BioAssay actives

16 with measured affinity, of 71 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
(5R,8S,11R,12S,15S,18S,19S,22R)-18-[(1E,3E,5S,6S)-6-methoxy-3,5-dimethyl-7-phenylhepta-1,3-dienyl]-1,5,12,15,19-pentamethyl-2-methylidene-8-(2-methylpropyl)-3,6,9,13,16,20,25-heptaoxo-1,4,7,10,14,17,21-heptazacyclopentacosane-11,22-dicarboxylic acid	164492: Inhibitory concentration against protein phosphatase 1 (PP1) using phosphorylase-a assay	ic50	0.0003	uM
(2R)-3-[(2S,6R,8S,11R)-2-[(E,2R)-4-[(2S,2’R,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5’-oxolane]-2’-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid	164490: Inhibitory concentration against Protein phosphatase 1(10 nM) isolated from rabbit muscle	ic50	0.1260	uM
Cantharidin	164495: Inhibitory activity against protein phosphatase-1 from rabbit skeletal muscle	ic50	0.4300	uM
2-amino-4-[4-(3,4-dihydroxyphenyl)phenyl]benzoic acid	1851304: Binding affinity to PPM1B (unknown origin) expressed in Escherichia coli BL21 assessed as inhibition constant using pNPP as substrate by absorbance based analysis	ki	0.5200	uM
(1R,2R,6S,7R)-4,10-dioxatricyclo[5.2.1.02,6]decane-3,5-dione	164495: Inhibitory activity against protein phosphatase-1 from rabbit skeletal muscle	ic50	0.5700	uM
(2R)-2-[[(2S,3S,4E,6E,8S,9S)-3-acetamido-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoyl]amino]propanoic acid	164492: Inhibitory concentration against protein phosphatase 1 (PP1) using phosphorylase-a assay	ic50	1.0000	uM
(2S)-2-[(3aS,4R,7S,7aR)-1,3-dioxo-3a,4,5,6,7,7a-hexahydro-4,7-epoxyisoindol-2-yl]-3-(1H-imidazol-5-yl)propanoic acid	164499: Inhibitory concentration against protein phosphatase 1 (PP1) was determined	ic50	2.8200	uM
(1S,4R)-3-ethoxycarbonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	164498: Inhibitory activity against recombinant Protein phosphatase 1	ic50	2.9600	uM
(2R)-2-[(3aR,4S,7R,7aS)-1,3-dioxo-3a,4,5,6,7,7a-hexahydro-4,7-epoxyisoindol-2-yl]-3-(1H-imidazol-5-yl)propanoic acid	164499: Inhibitory concentration against protein phosphatase 1 (PP1) was determined	ic50	3.2200	uM
(1S,4R)-3-methoxycarbonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	164498: Inhibitory activity against recombinant Protein phosphatase 1	ic50	4.7100	uM
(1S,4R)-3-propoxycarbonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	164498: Inhibitory activity against recombinant Protein phosphatase 1	ic50	4.8200	uM
2-[[(2S,3S,4E,6E,8S,9S)-3-acetamido-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoyl]amino]acetic acid	164492: Inhibitory concentration against protein phosphatase 1 (PP1) using phosphorylase-a assay	ic50	5.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Cisplatin	decreases expression, increases expression, affects cotreatment	2
Dexamethasone	increases expression, affects cotreatment	2
Valproic Acid	affects expression, decreases methylation	2
Aflatoxin B1	decreases expression, increases methylation	2
Particulate Matter	affects cotreatment, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases methylation	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
methylselenic acid	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4432737	Binding	Time-dependent irreversible inhibition of N-terminal His-tagged PPM1B (unknown origin) expressed in Escherichia coli BL21 (DE3) cells at 80 uM preincubated with enzyme followed by p-nitrophenyl phosphate substrate addition	Identification of a benzo imidazole thiazole derivative as the specific irreversible inhibitor of protein tyrosine phosphatase. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3EF	Abcam HEK293T PPM1B KO	Transformed cell line	Female
CVCL_TF35	HAP1 PPM1B (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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