PPP1R12A

Summary

PPP1R12A (protein phosphatase 1 regulatory subunit 12A, HGNC:7618) is a protein-coding gene on chromosome 12q21.2-q21.31, encoding Protein phosphatase 1 regulatory subunit 12A (O14974). Key regulator of protein phosphatase 1C (PPP1C). It is a selective cancer dependency (DepMap: 87.8% of cell lines).

Myosin phosphatase target subunit 1, which is also called the myosin-binding subunit of myosin phosphatase, is one of the subunits of myosin phosphatase. Myosin phosphatase regulates the interaction of actin and myosin downstream of the guanosine triphosphatase Rho. The small guanosine triphosphatase Rho is implicated in myosin light chain (MLC) phosphorylation, which results in contraction of smooth muscle and interaction of actin and myosin in nonmuscle cells. The guanosine triphosphate (GTP)-bound, active form of RhoA (GTP.RhoA) specifically interacted with the myosin-binding subunit (MBS) of myosin phosphatase, which regulates the extent of phosphorylation of MLC. Rho-associated kinase (Rho-kinase), which is activated by GTP. RhoA, phosphorylated MBS and consequently inactivated myosin phosphatase. Overexpression of RhoA or activated RhoA in NIH 3T3 cells increased phosphorylation of MBS and MLC. Thus, Rho appears to inhibit myosin phosphatase through the action of Rho-kinase. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4659 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genitourinary and/or brain malformation syndrome (Strong, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 287 total — 14 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 87.8% of screened cell lines
• MANE Select transcript: NM_002480

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7618
Approved symbol	PPP1R12A
Name	protein phosphatase 1 regulatory subunit 12A
Location	12q21.2-q21.31
Locus type	gene with protein product
Status	Approved
Aliases	MBS, M130
Ensembl gene	ENSG00000058272
Ensembl biotype	protein_coding
OMIM	602021
Entrez	4659

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 8 retained_intron, 2 nonsense_mediated_decay

ENST00000261207, ENST00000437004, ENST00000450142, ENST00000546369, ENST00000546762, ENST00000547131, ENST00000547253, ENST00000547330, ENST00000548318, ENST00000548908, ENST00000550001, ENST00000550007, ENST00000550107, ENST00000550299, ENST00000550351, ENST00000550510, ENST00000550903, ENST00000551191, ENST00000551781, ENST00000552892, ENST00000553081, ENST00000634739, ENST00000650220, ENST00000924854, ENST00000962776

RefSeq mRNA: 5 — MANE Select: NM_002480 NM_001143885, NM_001143886, NM_001244990, NM_001244992, NM_002480

CCDS: CCDS44947, CCDS44948, CCDS58259, CCDS58260

Canonical transcript exons

ENST00000450142 — 25 exons

Exon	Start	End
ENSE00000910604	79828320	79828464
ENSE00000910605	79832332	79832491
ENSE00000937510	79822116	79822190
ENSE00000937511	79821078	79821166
ENSE00000937512	79820774	79820931
ENSE00000937513	79817394	79817518
ENSE00000937514	79809795	79810010
ENSE00000937516	79807226	79807330
ENSE00000937517	79806166	79806333
ENSE00000937518	79805592	79805768
ENSE00000993897	79793863	79793928
ENSE00001334180	79797195	79797395
ENSE00001738944	79934695	79935097
ENSE00001767783	79790467	79790483
ENSE00002390973	79773568	79776015
ENSE00003458332	79872808	79872938
ENSE00003478265	79786374	79786478
ENSE00003542213	79798494	79798584
ENSE00003556247	79808483	79808577
ENSE00003605821	79778550	79778600
ENSE00003655833	79795638	79795759
ENSE00003673434	79788648	79788783
ENSE00003678897	79796782	79796950
ENSE00003687795	79845302	79845420
ENSE00003687854	79781815	79781862

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.7745 / max 731.2733, expressed in 1816 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132283	12.5668	1786
132281	7.8065	1665
132284	5.9268	1644
132282	5.4441	1626
132279	0.0303	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.44	gold quality
sural nerve	UBERON:0015488	99.13	gold quality
blood vessel layer	UBERON:0004797	98.95	gold quality
saphenous vein	UBERON:0007318	98.73	gold quality
cauda epididymis	UBERON:0004360	98.52	gold quality
colonic epithelium	UBERON:0000397	98.42	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.11	gold quality
lower esophagus	UBERON:0013473	98.08	gold quality
popliteal artery	UBERON:0002250	98.02	gold quality
tibial artery	UBERON:0007610	98.02	gold quality
artery	UBERON:0001637	97.87	gold quality
urethra	UBERON:0000057	97.85	gold quality
right coronary artery	UBERON:0001625	97.73	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.72	gold quality
vena cava	UBERON:0004087	97.67	gold quality
oocyte	CL:0000023	97.41	gold quality
mucosa of stomach	UBERON:0001199	97.32	gold quality
urinary bladder	UBERON:0001255	97.23	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.20	gold quality
aorta	UBERON:0000947	97.11	gold quality
body of uterus	UBERON:0009853	97.07	gold quality
superficial temporal artery	UBERON:0001614	97.05	gold quality
coronary artery	UBERON:0001621	96.81	gold quality
left coronary artery	UBERON:0001626	96.80	gold quality
trabecular bone tissue	UBERON:0002483	96.75	gold quality
myometrium	UBERON:0001296	96.74	gold quality
tendon	UBERON:0000043	96.70	gold quality
secondary oocyte	CL:0000655	96.69	gold quality
left uterine tube	UBERON:0001303	96.62	gold quality
sigmoid colon	UBERON:0001159	96.37	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	39.59
E-HCAD-11	yes	21.92
E-CURD-119	yes	12.20
E-GEOD-134144	yes	8.31
E-GEOD-110499	no	1881.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NKX2-5

miRNA regulators (miRDB)

115 targeting PPP1R12A, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
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-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
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-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 87.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Integrin-linked kinase phosphorylates the myosin phosphatase target subunit at the inhibitory site in platelet cytoskeleton. (PMID:11931630)
• Proper expression of MYPT1 or variant 2 is critical for RLC phosphorylation and actin assembly, thus maintaining normal cellular functions by simultaneously controlling cytoskeletal architecture and actomyosin activation. (PMID:15748895)
• Stable transfection of HEK 293 cells with GFP-MYPT1 was obtained. MYPT1 and its N-terminal mutants bound to retinoblastoma protein (Rb), raising the possibility that Rb is implicated in the effects caused by overexpression of MYPT1. (PMID:15999227)
• the leucine-zipper motif of PKG binds to that of MYPT1 to form a heterodimer; when the leucine-zipper motif of MYPT1 is absent, the PKG leucine-zipper motif binds to the coiled coil region and upstream segments of MYPT1 via formation of a heterotetramer (PMID:17904578)
• These data suggests different phosphorylation and regulation of MYPT1 activity by NUAK2. (PMID:18023418)
• both eEF1A and MYPT1 have roles in EGCG signaling for cancer prevention through 67LR (PMID:18079119)
• These results identify a previously unrecognized role for MYPT1 in regulating mitosis by antagonizing PLK1. (PMID:18477460)
• MYPT1 may regulate the phosphorylation level of pRb, thereby it may be involved in the control of cell cycle progression and in the mediation of chemoresistance of leukemic cells. (PMID:18755268)
• Apolipoprotein(a), through its strong lysine-binding site in KIV(10’), mediates increased endothelial cell contraction and permeability via a Rho/Rho kinase/MYPT1-dependent pathway. (PMID:18776185)
• Results show that expression of MYPT1 enhances HIF-CAD activity in a manner consistent with competition for FIH and that this property extends to other ARD proteins. (PMID:19245366)
• MYPT1 phosphorylation at Thr-696 and Thr-853 causes an autoinhibition of MLCP that accounts for Ca(2+) sensitization of smooth muscle force (PMID:19531490)
• Solution structure of the inhibitory phosphorylation domain of myosin phosphatase targeting subunit 1 (PMID:19701943)
• The ability of myosin phosphatase to modulate myosin light chain might be regulated by the degradation of its targeting subunit MYPT1 through the SIAH2-ubiquitin-proteasomal pathway. (PMID:19744480)
• cAMP/PKA regulates the endothelial barrier via inhibition of the contractile machinery, mainly by the activation of MLCP via inhibition of CPI-17 and RhoA/Rock. (PMID:20202976)
• Findings define a new conserved pathway in which sexual development and pregnancy mediate smooth and striated muscle adaptations through SMTNL1 and MYPT1. (PMID:20634291)
• hHS-M(21) is a heart-specific effector of ROCK and plays a regulatory role in the MYPT1 phosphorylation at Thr-696 by ROCK (PMID:20801872)
• Myosin phosphatase-targeting subunit 1 controls chromatid segregation. (PMID:21252232)
• MYPT1 variant 2 shows decreased binding affinity compared to MYPT1 long for radixin (novel MLCP substrate and a member of ERM family proteins). (PMID:21678426)
• the defective protein level of MYPT1 in the diabetes mellitus (DM) group can partially explain the poor patency of saphenous vein graft harvested from patients with DM. (PMID:21821002)
• Phosphorylation of MYPT1 (Thr853) changes dynamically with each contraction of the myometrium regulated by Rho-kinase. (PMID:22155728)
• Site-specific phosphorylation of protein phosphatase 1 regulatory subunit 12A stimulated or suppressed by insulin. (PMID:22516431)
• It found deoxyribonucleic acid (DNA) damage-induced LATS1 activation caused PLK1 suppression via the phosphorylation of MYPT1 S445. (PMID:22641346)
• These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cdelta, in insulin signaling. (PMID:22728334)
• Calcineurin may modulate the phosphorylation level of MLC20 by influencing the phosphorylation state of MYPT1 to regulate endothelial barrier function. (PMID:22869619)
• Mypt1 colocalizes outside the nucleus with Nkx2.5 in a manner dependent on Wnt signaling and Rho-associated protein kinase. (PMID:23168335)
• in apoptotic cells, the myosin-binding domain of myosin phosphatase targeting subunit 1 is cleaved by caspase-3, and the cleaved MYPT1 is strongly phosphorylated at Thr-696 and Thr-853, phosphorylation of which is known to inhibit myosin II binding (PMID:23345589)
• results suggested that during atherosclerosis progression oxidative stress mediates the downregulation of MYPT1, which may inhibit smooth muscle cell migration and contribute to the aberrant contractility (PMID:23419712)
• distinct roles of two inhibitory phosphorylation sites of MYPT1 (PMID:24712327)
• Expression of NUAK1 is controlled by cyclin-dependent kinase, PLK1, and the SCFbetaTrCP (Skp, Cullin and F-boxbetaTrCP) E3 ubiquitin ligase complex. (PMID:24785407)
• These results indicate that PPP1R12A indeed plays a role in skeletal muscle insulin signaling (PMID:24972320)
• the relative expression of LZ+/LZ- MYPT1 isoforms, in part, defines the vascular response to NO and NO based vasodilators, and therefore, plays a role in the regulation of vascular tone in both health and disease (PMID:25168281)
• BLT2 ligation facilitates F-actin assembly with the upregulated phosphorylation of MYPT1. (PMID:26896822)
• Study revealed the presence of two MYPT1 isoforms, full length and variant 2 in human intestinal (Caco-2) epithelial cells and isolated intestinal epithelial cells from mice. (PMID:27129938)
• he phosphorylation of the MP inhibitory MYPT1(T850) and the regulatory PRMT5(T80) residues as well as the symmetric dimethylation of H2A/4 were elevated in human hepatocellular carcinoma and in other types of cancers. (PMID:28074910)
• These results indicate shear stress induced vascular smooth muscle cell contraction was mediated by cell surface glycocalyx via a ROCK-MLC phosphatase (MLCP) pathway, providing evidence of the glycocalyx mechanotransduction in myogenic response. (PMID:28191820)
• Myosin light chain phosphatase (MLCP) is a master regulator of smooth muscle responsiveness to stimuli. (review) (PMID:28260704)
• PP2A dephosphorylates MYPT1(pThr696) and thereby stimulates MP activity inducing dephosphorylation of eNOS(pThr497) and the 20 kDa myosin II light chains. (PMID:28300193)
• The authors call the mutual sequestration mechanism through which pCPI-17 and myosin light-chain phosphatase interact inhibition by unfair competition: myosin light-chain phosphatase protects pCPI-17 from other phosphatases, while pCPI-17 blocks other substrates from the active site of myosin light-chain phosphatase. (PMID:28387646)
• Lipolysis-stimulated lipoprotein receptors (LSRs) localized to bicellular junctions in association with myosin regulatory light chain 2 (MRLC2) at low cell densities and to tricellular contacts when myosin phosphatase target subunit 1 (MYPT1) localized to the bicellular regions. (PMID:28493278)
• NO-induced cGMP signaling modulated RhoA/ROCK signaling in platelets, leading to the disinhibition of MLCP to control the phosphorylation of MLC and remodeling of platelet actin cytoskeleton. (PMID:28509344)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp1r12a	ENSDARG00000010784
mus_musculus	Ppp1r12a	ENSMUSG00000019907
rattus_norvegicus	Ppp1r12a	ENSRNOG00000004925

Paralogs (3): PPP1R12B (ENSG00000077157), PPP1R12C (ENSG00000125503), PPP1R27 (ENSG00000182676)

Protein

Protein identifiers

Protein phosphatase 1 regulatory subunit 12A — O14974 (reviewed: O14974)

Alternative names: Myosin phosphatase-targeting subunit 1, Protein phosphatase myosin-binding subunit

All UniProt accessions (11): O14974, A0A0U1RQZ1, A0A3B3ISH4, F8VW28, F8VZN8, H0YHI8, H0YHL8, H0YIL7, H0YIM2, H0YIS3, H0YIS4

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator of protein phosphatase 1C (PPP1C). Mediates binding to myosin. As part of the PPP1C complex, involved in dephosphorylation of PLK1. Capable of inhibiting HIF1AN-dependent suppression of HIF1A activity.

Subunit / interactions. PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, and one or several targeting or regulatory subunits. PPP1R12A mediates binding to myosin. Interacts with ARHA and CIT. Binds PPP1R12B, ROCK1 and IL16. Interacts directly with PRKG1. Non-covalent dimer of 2 dimers; PRKG1-PRKG1 and PPP1R12A-PPP1R12A. Interacts with SMTNL1. Interacts with PPP1CB; the interaction is direct. Interacts (when phosphorylated at Ser-445, Ser-472 and Ser-910) with 14-3-3. Interacts with ROCK1 and ROCK2. Interacts with isoform 1 and isoform 2 of ZIPK/DAPK3. Interacts with RAF1. Interacts with HIF1AN. Interacts with NCKAP1L.

Subcellular location. Cytoplasm. Cytoskeleton. Stress fiber.

Tissue specificity. Expressed in striated muscles, specifically in type 2a fibers (at protein level).

Post-translational modifications. Phosphorylated by CIT (Rho-associated kinase). Phosphorylated cooperatively by ROCK1 and CDC42BP on Thr-696. Phosphorylated on upon DNA damage, probably by ATM or ATR. In vitro, phosphorylation of Ser-695 by PKA and PKG appears to prevent phosphorylation of the inhibitory site Thr-696, probably mediated by PRKG1. Phosphorylation at Ser-445, Ser-472 and Ser-910 by NUAK1 promotes interaction with 14-3-3, leading to inhibit interaction with myosin light chain MLC2, preventing dephosphorylation of MLC2. May be phosphorylated at Thr-696 by DMPK; may inhibit the myosin phosphatase activity. Phosphorylated at Ser-473 by CDK1 during mitosis, creating docking sites for the POLO box domains of PLK1. Subsequently, PLK1 binds and phosphorylates PPP1R12A.

Disease relevance. Genitourinary and/or brain malformation syndrome (GUBS) [MIM:618820] An autosomal dominant syndrome characterized by multiple congenital anomalies including urogenital malformations and brain abnormalities ranging from agenesis of the corpus callosum to anencephaly. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Heterotetramerization is mediated by the interaction between a coiled-coil of PRKG1 and the leucine/isoleucine zipper of PPP1R12A/MBS, the myosin-binding subunit of the myosin phosphatase. The KVKF motif mediates interaction with PPP1CB.

Isoforms (5)

UniProt ID	Names	Canonical?
O14974-1	1	yes
O14974-2	2, Myosin phosphatase target subunit 1 variant
O14974-3	3, Myosin phosphatase target subunit 1 variant 2
O14974-4	4
O14974-5	5

RefSeq proteins (5): NP_001137357, NP_001137358, NP_001231919, NP_001231921, NP_002471* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR017401	MYPT1/MYPT2/Mbs85	Family
IPR031775	PRKG1_interact	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR051226	PP1_Regulatory_Subunit	Family

Pfam: PF12796, PF15898

Enzyme classification (BRENDA):

• EC 3.1.3.53 — [myosin-light-chain] phosphatase (BRENDA: 14 organisms, 76 substrates, 62 inhibitors, 13 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MYOSIN LIGHT-CHAIN PHOSPHATE	0.001–0.0112	6
MYOSIN LIGHT-CHAIN	0.0015–0.05	3
PHOSPHORYLATED MYOSIN	0.0004–0.0024	2
HEAVY MEROMYOSIN	0.0059	1
[MYOSIN LIGHT-CHAIN] PHOSPHATE	0.01	1

UniProt features (95 total): modified residue 27, compositionally biased region 23, sequence conflict 9, sequence variant 8, mutagenesis site 8, repeat 6, splice variant 4, helix 4, region of interest 3, chain 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2KJY	SOLUTION NMR
5HUZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14974-F1	59.81	0.28

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 (27): 67, 100, 226, 299, 422, 432, 443, 445, 446, 472, 473, 477, 507, 509, 601, 618, 692, 695, 696, 802 …

Mutagenesis-validated functional residues (8):

Position	Phenotype
445	abolishes phosphorylation by nuak1 and interaction with 14-3-3; when associated with a-472 and a-910.
472	abolishes phosphorylation by nuak1 and interaction with 14-3-3; when associated with a-445 and a-910.
473	abolishes binding to the polo box domains of plk1.
910	abolishes phosphorylation by nuak1 and interaction with 14-3-3; when associated with a-445 and a-472.
1007	loss of binding to prkg1; when associated with a-1014.
1014	loss of binding to prkg1; when associated with a-1007.
1021	loss of binding to prkg1; when associated with a-1028.
1028	loss of binding to prkg1; when associated with a-1021.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-2565942	Regulation of PLK1 Activity at G2/M Transition
R-HSA-5625740	RHO GTPases activate PKNs
R-HSA-5625900	RHO GTPases activate CIT
R-HSA-5627117	RHO GTPases Activate ROCKs
R-HSA-5627123	RHO GTPases activate PAKs
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-453274	Mitotic G2-G2/M phases
R-HSA-69275	G2/M Transition
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 460 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, TGCGCANK_UNKNOWN, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_NEUROGENESIS, LIEN_BREAST_CARCINOMA_METAPLASTIC, GOCC_MICROTUBULE_ORGANIZING_CENTER, ATGTTAA_MIR302C, SRF_Q5_01, PID_RHOA_PATHWAY, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_NUCLEAR_TRANSPORT, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION

GO Biological Process (10): mitotic cell cycle (GO:0000278), protein dephosphorylation (GO:0006470), centrosome cycle (GO:0007098), signal transduction (GO:0007165), regulation of cell adhesion (GO:0030155), negative regulation of catalytic activity (GO:0043086), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of nucleocytoplasmic transport (GO:0046822), neuron projection morphogenesis (GO:0048812), cellular response to xenobiotic stimulus (GO:0071466)

GO Molecular Function (6): enzyme inhibitor activity (GO:0004857), myosin phosphatase regulator activity (GO:0017020), phosphatase regulator activity (GO:0019208), protein kinase binding (GO:0019901), 14-3-3 protein binding (GO:0071889), protein binding (GO:0005515)

GO Cellular Component (15): kinetochore (GO:0000776), stress fiber (GO:0001725), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), A band (GO:0031672), contractile muscle fiber (GO:0043292), PTW/PP1 phosphatase complex (GO:0072357), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
RHO GTPase Effectors	4
G2/M Transition	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Cell Cycle, Mitotic	1
Mitotic G2-G2/M phases	1
Cell Cycle	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
intracellular membraneless organelle	4
regulation of cellular process	2
catalytic activity	2
enzyme regulator activity	2
nuclear lumen	2
cytoplasm	2
cell cycle	1
mitotic nuclear division	1
dephosphorylation	1
protein modification process	1
cell cycle process	1
microtubule organizing center organization	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
cell adhesion	1
negative regulation of molecular function	1
regulation of catalytic activity	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
nucleocytoplasmic transport	1
regulation of intracellular transport	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
molecular function inhibitor activity	1
myosin phosphatase activity	1
protein phosphatase regulator activity	1
phosphatase activity	1
phosphatase binding	1
kinase binding	1
protein binding	1
binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
actomyosin	1

Protein interactions and networks

STRING

3085 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP1R12A	PPP1CB	P37140	997
PPP1R12A	PPP1CC	P36873	991
PPP1R12A	RHOA	P06749	980
PPP1R12A	PPP1R14A	Q96A00	970
PPP1R12A	MPRIP	Q6WCQ1	913
PPP1R12A	ROCK1	Q13464	839
PPP1R12A	PRKG1	P14619	832
PPP1R12A	MYL9	P24844	817
PPP1R12A	SMTNL1	A8MU46	803
PPP1R12A	NF2	P35240	796
PPP1R12A	MYL12B	O14950	756
PPP1R12A	DAPK3	O43293	745
PPP1R12A	MYLK3	Q32MK0	727
PPP1R12A	CDK1	P06493	724
PPP1R12A	ROCK2	O75116	701

IntAct

225 interactions, top by confidence:

A	B	Type	Score
MED17	MED19	psi-mi:“MI:0914”(association)	0.840
MED23	MED19	psi-mi:“MI:2364”(proximity)	0.770
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CB	CCDC85C	psi-mi:“MI:2364”(proximity)	0.750
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PPP1R12A	ATXN10	psi-mi:“MI:0915”(physical association)	0.670
ATXN10	PPP1R12A	psi-mi:“MI:0914”(association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
NUAK2	PPP1R12A	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
PPP1R12A	CPI17	psi-mi:“MI:0407”(direct interaction)	0.540
PPP1R12A	CPI17	psi-mi:“MI:0915”(physical association)	0.540
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
FKBP6	EEF2K	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (436): PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Proximity Label-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS), PPP1R12A (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTZ2, A6QPB3, A8WR59, B3DM43, F1M8W4, O14974, O35167, O35348, O55000, O76368, O88207, O93383, P12107, P20908, P20909, P35710, P35711, P35712, P40645, P40647, P43322, P83371, Q02297, Q03637, Q05199, Q07563, Q10728, Q32NP7, Q571K4, Q5RCU4, Q60467, Q61245, Q6DR98, Q6DRG7, Q7TQG1, Q7ZXH3, Q80W00, Q86SQ0, Q8IPJ3, Q8IVL1

Diamond homologs: A2AQH4, A2AS55, A6NGH8, A6QR20, O14974, Q2T9W8, Q499M5, Q5H9F3, Q641X1, Q6P6B7, Q6W2J9, Q86WC6, Q8CGN4, Q9BQI6, Q9D119, Q9UU77, Q9XZC0, O60237, Q10728, Q3UMT1, Q6DRG7, Q8BG95, Q90623, Q923M0, Q96I34, Q9BZL4, Q9DBR7, Q8VHQ3, Q95N27, Q96T49, A4II29, B2RR83, G3I6Z6, O00522, O13987, P46531, P83757, Q01705, Q02979, Q03017

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
NUAK1	down-regulates	PPP1R12A	phosphorylation
CHEK1	“down-regulates quantity by destabilization”	PPP1R12A	phosphorylation
LATS1	“up-regulates activity”	PPP1R12A	phosphorylation
RAF1	“down-regulates activity”	PPP1R12A	phosphorylation
DAPK3	“down-regulates activity”	PPP1R12A	phosphorylation
NUAK2	“down-regulates activity”	PPP1R12A	phosphorylation
ROCK1	down-regulates	PPP1R12A	phosphorylation
ILK	down-regulates	PPP1R12A	phosphorylation
ROCK1	“down-regulates activity”	PPP1R12A	phosphorylation
ROCK2	“down-regulates activity”	PPP1R12A	phosphorylation
ILK	“down-regulates activity”	PPP1R12A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 201 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	42.6×	2e-09
Activation of BAD and translocation to mitochondria	7	42.3×	2e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	37.3×	5e-08
Activation of BH3-only proteins	7	27.6×	4e-07
RHO GTPases activate PAKs	6	25.9×	4e-06
RHO GTPases activate PKNs	10	25.2×	2e-09
Intrinsic Pathway for Apoptosis	7	16.3×	1e-05
FOXO-mediated transcription	6	16.0×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	13.0×	3e-03
substantia nigra development	6	13.0×	3e-03
intracellular protein localization	11	6.8×	9e-04
actin filament organization	9	6.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	20
Uncertain significance	143
Likely benign	52
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1174499	NM_002480.3(PPP1R12A):c.2187del (p.Glu730fs)	Pathogenic
2424024	NC_000012.11:g.(?80239062)(80328711_?)del	Pathogenic
2502874	NM_002480.3(PPP1R12A):c.2604del (p.Glu868fs)	Pathogenic
2632919	NM_002480.3(PPP1R12A):c.2533C>T (p.Arg845Ter)	Pathogenic
3042334	NM_002480.3(PPP1R12A):c.2629del (p.Ser877fs)	Pathogenic
3423767	NM_002480.3(PPP1R12A):c.1333del (p.Ser445fs)	Pathogenic
3765502	NM_002480.3(PPP1R12A):c.965_966insCC (p.Leu323fs)	Pathogenic
4082577	NM_002480.3(PPP1R12A):c.652_653del (p.Leu218fs)	Pathogenic
4281624	NM_002480.3(PPP1R12A):c.957-2A>C	Pathogenic
827962	NM_002480.3(PPP1R12A):c.1510C>T (p.Arg504Ter)	Pathogenic
827963	NM_002480.3(PPP1R12A):c.1189del (p.Thr397fs)	Pathogenic
827964	NM_002480.3(PPP1R12A):c.2033_2034del (p.Glu677_Ser678insTer)	Pathogenic
973883	NM_002480.3(PPP1R12A):c.466C>T (p.Gln156Ter)	Pathogenic
976721	NM_002480.3(PPP1R12A):c.2698C>T (p.Arg900Ter)	Pathogenic
1309399	NM_002480.3(PPP1R12A):c.3046G>A (p.Asp1016Asn)	Likely pathogenic
1334539	NM_002480.3(PPP1R12A):c.1567C>T (p.Arg523Ter)	Likely pathogenic
1679367	NM_002480.3(PPP1R12A):c.2801del (p.Lys934fs)	Likely pathogenic
1878944	NM_002480.3(PPP1R12A):c.2152C>T (p.Arg718Ter)	Likely pathogenic
2498575	GRCh37/hg19 12q21.2(chr12:80187643-80222244)x1	Likely pathogenic
2584465	NM_002480.3(PPP1R12A):c.2852del (p.His951fs)	Likely pathogenic
3062288	NM_002480.3(PPP1R12A):c.508C>T (p.Arg170Ter)	Likely pathogenic
3235968	NM_002480.3(PPP1R12A):c.647+2T>G	Likely pathogenic
3251280	NM_002480.3(PPP1R12A):c.329T>A (p.Leu110Gln)	Likely pathogenic
3345944	NM_002480.3(PPP1R12A):c.957-1G>A	Likely pathogenic
3350080	NM_002480.3(PPP1R12A):c.2307T>A (p.Tyr769Ter)	Likely pathogenic
3382842	NM_002480.3(PPP1R12A):c.1550+2T>C	Likely pathogenic
3773820	NM_002480.3(PPP1R12A):c.522_523dup (p.Arg175fs)	Likely pathogenic
3773942	NM_002480.3(PPP1R12A):c.737A>C (p.Glu246Ala)	Likely pathogenic
4292693	NM_002480.3(PPP1R12A):c.2759dup (p.Tyr920Ter)	Likely pathogenic
4687932	NM_002480.3(PPP1R12A):c.1324_1327del (p.Lys442fs)	Likely pathogenic

SpliceAI

4274 predictions. Top by Δscore:

Variant	Effect	Δscore
12:79776013:CAT:C	acceptor_gain	1.0000
12:79776014:ATC:A	acceptor_loss	1.0000
12:79776015:TCT:T	acceptor_loss	1.0000
12:79776016:C:CC	acceptor_gain	1.0000
12:79776016:CTAT:C	acceptor_loss	1.0000
12:79778545:CTT:C	donor_loss	1.0000
12:79778545:CTTA:C	donor_gain	1.0000
12:79778546:TTA:T	donor_loss	1.0000
12:79778548:A:AC	donor_gain	1.0000
12:79778549:C:CT	donor_gain	1.0000
12:79778549:CT:C	donor_gain	1.0000
12:79778549:CTT:C	donor_gain	1.0000
12:79778549:CTTT:C	donor_gain	1.0000
12:79778607:C:CT	acceptor_gain	1.0000
12:79781808:CACTT:C	donor_loss	1.0000
12:79781809:ACTTA:A	donor_loss	1.0000
12:79781810:CTTAC:C	donor_loss	1.0000
12:79781811:TTA:T	donor_loss	1.0000
12:79781812:T:TG	donor_loss	1.0000
12:79781813:A:AC	donor_gain	1.0000
12:79781813:A:AT	donor_loss	1.0000
12:79781813:AC:A	donor_gain	1.0000
12:79781813:ACC:A	donor_gain	1.0000
12:79781814:C:CA	donor_loss	1.0000
12:79781814:C:CC	donor_gain	1.0000
12:79781814:CC:C	donor_gain	1.0000
12:79781814:CCC:C	donor_gain	1.0000
12:79781814:CCCT:C	donor_gain	1.0000
12:79781814:CCCTT:C	donor_gain	1.0000
12:79786474:TAAAG:T	acceptor_gain	1.0000

AlphaMissense

6713 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:79775939:A:G	L1028P	1.000
12:79775948:A:C	I1025R	1.000
12:79775948:A:T	I1025K	1.000
12:79775953:T:A	R1023S	1.000
12:79775953:T:G	R1023S	1.000
12:79775960:A:C	L1021W	1.000
12:79775960:A:G	L1021S	1.000
12:79775970:T:C	N1018D	1.000
12:79775981:A:G	L1014P	1.000
12:79776002:A:G	L1007P	1.000
12:79778587:A:G	L990P	1.000
12:79786432:A:G	L950P	1.000
12:79786444:A:G	L946P	1.000
12:79795671:T:A	R850S	1.000
12:79795671:T:G	R850S	1.000
12:79797368:C:G	A707P	1.000
12:79797376:A:G	L704P	1.000
12:79797395:C:G	G698R	1.000
12:79797395:C:T	G698R	1.000
12:79798506:T:A	R693S	1.000
12:79798506:T:G	R693S	1.000
12:79798507:C:G	R693T	1.000
12:79798515:T:A	R690S	1.000
12:79798515:T:G	R690S	1.000
12:79798516:C:G	R690T	1.000
12:79798524:T:A	R687S	1.000
12:79798524:T:G	R687S	1.000
12:79798539:T:A	R682S	1.000
12:79798539:T:G	R682S	1.000
12:79798540:C:G	R682T	1.000

dbSNP variants (sampled 300 via entrez): RS1000017097 (12:79849995 A>G,T), RS1000031628 (12:79892495 T>A,G), RS1000039571 (12:79808265 A>C), RS1000058602 (12:79869633 G>A), RS1000077198 (12:79856018 A>G), RS1000077208 (12:79818136 C>A), RS1000112394 (12:79903798 T>G), RS1000117424 (12:79842583 G>A,T), RS1000123557 (12:79899314 A>G,T), RS1000133123 (12:79810707 A>G), RS1000140532 (12:79915862 C>T), RS1000158519 (12:79919605 C>T), RS1000166538 (12:79832092 T>A), RS1000169272 (12:79804558 A>AC), RS1000176741 (12:79849556 C>T)

Disease associations

OMIM: gene MIM:602021 | disease phenotypes: MIM:618820

GenCC curated gene-disease

Disease	Classification	Inheritance
genitourinary and/or brain malformation syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
genitourinary and/or brain malformation syndrome	Strong	AD

Mondo (1): genitourinary and/or brain malformation syndrome (MONDO:0032934)

Orphanet (0):

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000041	Chordee
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000133	Gonadal dysgenesis
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000537	Epicanthus inversus
HP:0000540	Hypermetropia
HP:0000582	Upslanted palpebral fissure
HP:0001159	Syndactyly
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001331	Absent septum pellucidum
HP:0001360	Holoprosencephaly
HP:0001387	Joint stiffness
HP:0001539	Omphalocele
HP:0002126	Polymicrogyria

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001859_21	Thiazide-induced adverse metabolic effects in hypertensive patients	4.000000e-06
GCST90002402_141	Platelet count	7.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3124 (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: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.72	IC50	1890	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178664: Inhibition of PPP1R12A (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.8900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	5
bisphenol A	decreases expression, increases expression	2
Endosulfan	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases phosphorylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
decabromobiphenyl ether	decreases expression	1
hydroxyhydroquinone	increases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	affects phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
capsazepine	decreases reaction, increases phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
18alpha-glycyrrhetinic acid	affects binding, decreases reaction, increases phosphorylation	1
5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone	decreases reaction, increases phosphorylation	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	decreases reaction, increases phosphorylation	1
hexabrominated diphenyl ether 153	decreases expression	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	decreases phosphorylation	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697394	Binding	Inhibition of PPP1R12A (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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