PREX2

Summary

PREX2 (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2, HGNC:22950) is a protein-coding gene on chromosome 8q13.2, encoding Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (Q70Z35). Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. In precision oncology, PREX2 R172I is associated with resistance to Vemurafenib in Melanoma (CIViC Level C).

The protein encoded by this gene belongs to the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger (PREX) family, which are Dbl-type guanine-nucleotide exchange factors for Rac family small G proteins. Structural domains of this protein include the catalytic diffuse B-cell lymphoma homology and pleckstrin homology (DHPH) domain, two disheveled, EGL-10, and pleckstrin homology (DEP) domains, two PDZ domains, and a C-terminal inositol polyphosphate-4 phosphatase (IP4P) domain that is found in one of the isoforms. This protein facilitates the exchange of GDP for GTP on Rac1, allowing the GTP-bound Rac1 to activate downstream effectors. Studies also show that the pleckstrin homology domain of this protein interacts with the phosphatase and tensin homolog (PTEN) gene product to inhibit PTEN phosphatase activity, thus activating the phosphoinositide-3 kinase (PI3K) signaling pathway. Conversely, the PTEN gene product has also been shown to inhibit the GEF activity of this protein. This gene plays a role in insulin-signaling pathways, and either mutations or overexpression of this gene have been observed in some cancers.

Source: NCBI Gene 80243 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 235 total — 1 likely-pathogenic
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): activating (oncogene-like) across 12 cancer types
• MANE Select transcript: NM_024870

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22950
Approved symbol	PREX2
Name	phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2
Location	8q13.2
Locus type	gene with protein product
Status	Approved
Aliases	DEP.2, FLJ12987, P-REX2, PPP1R129
Ensembl gene	ENSG00000046889
Ensembl biotype	protein_coding
OMIM	612139
Entrez	80243

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000288368, ENST00000517617, ENST00000520235, ENST00000522247, ENST00000529398, ENST00000854544

RefSeq mRNA: 2 — MANE Select: NM_024870 NM_024870, NM_025170

CCDS: CCDS6201

Canonical transcript exons

ENST00000288368 — 40 exons

Exon	Start	End
ENSE00001090107	68138415	68138517
ENSE00001090115	68134059	68134276
ENSE00001090119	68157322	68157436
ENSE00001090122	68224559	68224626
ENSE00001090129	68146209	68146352
ENSE00001090139	68120196	68120286
ENSE00001090151	68120921	68121049
ENSE00001192103	68231333	68237032
ENSE00001376826	68118550	68118644
ENSE00001382524	68115753	68115932
ENSE00001415983	67952046	67952535
ENSE00001430194	68127378	68127419
ENSE00002693281	68119432	68119514
ENSE00003485129	68053097	68053246
ENSE00003507630	68217616	68217718
ENSE00003509435	68030497	68030658
ENSE00003511035	68109416	68109623
ENSE00003517235	68060679	68060779
ENSE00003518449	68017846	68017917
ENSE00003518609	68055830	68055974
ENSE00003522653	68069033	68069136
ENSE00003523732	68069835	68069884
ENSE00003529549	68072495	68072570
ENSE00003530247	68097017	68097201
ENSE00003531468	68108109	68108331
ENSE00003548094	68083240	68083388
ENSE00003550394	68044487	68044590
ENSE00003557183	68093605	68093722
ENSE00003564184	68038159	68038292
ENSE00003578140	68080746	68080838
ENSE00003585462	68019549	68019671
ENSE00003589549	68022036	68022140
ENSE00003593763	68077397	68077469
ENSE00003606607	68080443	68080585
ENSE00003611874	68087724	68087809
ENSE00003614659	68090579	68090715
ENSE00003623957	68192335	68192525
ENSE00003630493	68191722	68191788
ENSE00003650969	68027222	68027323
ENSE00003680555	68099682	68099843

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 91.26.

FANTOM5 (CAGE): breadth broad, TPM avg 6.5158 / max 217.0966, expressed in 524 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89243	2.3763	435
89237	1.3923	393
89238	0.7344	234
89240	0.3869	227
89235	0.3264	192
89242	0.2665	159
89236	0.2592	136
89233	0.1690	96
89234	0.1685	89
89239	0.1654	95

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	91.26	gold quality
endothelial cell	CL:0000115	88.65	silver quality
visceral pleura	UBERON:0002401	88.63	gold quality
corpus callosum	UBERON:0002336	87.63	gold quality
ventricular zone	UBERON:0003053	85.70	gold quality
tendon	UBERON:0000043	85.40	gold quality
pleura	UBERON:0000977	85.06	gold quality
parietal pleura	UBERON:0002400	84.97	gold quality
colonic epithelium	UBERON:0000397	84.65	gold quality
adipose tissue	UBERON:0001013	82.53	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.22	gold quality
caudate nucleus	UBERON:0001873	82.21	gold quality
lower lobe of lung	UBERON:0008949	82.18	gold quality
right uterine tube	UBERON:0001302	82.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.73	gold quality
sural nerve	UBERON:0015488	81.62	gold quality
connective tissue	UBERON:0002384	81.54	gold quality
right lobe of thyroid gland	UBERON:0001119	81.28	gold quality
left lobe of thyroid gland	UBERON:0001120	81.03	gold quality
thyroid gland	UBERON:0002046	80.93	gold quality
tendon of biceps brachii	UBERON:0008188	80.84	gold quality
putamen	UBERON:0001874	80.47	gold quality
medial globus pallidus	UBERON:0002477	80.44	gold quality
ganglionic eminence	UBERON:0004023	80.34	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.99	gold quality
amygdala	UBERON:0001876	79.70	gold quality
omental fat pad	UBERON:0010414	79.69	gold quality
peritoneum	UBERON:0002358	79.65	gold quality
globus pallidus	UBERON:0001875	79.03	gold quality
mucosa of paranasal sinus	UBERON:0005030	78.89	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	84.31
E-CURD-119	yes	30.36
E-ANND-3	yes	20.09
E-GEOD-84465	yes	11.23
E-CURD-10	no	1060.99
E-MTAB-6386	no	17.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting PREX2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-4804-3P	99.65	67.78	866

Literature-anchored findings (GeneRIF, showing 27)

• P-REX2 may serve as a novel link between Rac activation and the PI-3 kinase pathway. (PMID:15304342)
• P-Rex2 is a 183 kDa protein that activates the small GTPase Rac and is regulated by phosphatidylinositol (3,4,5)-trisphosphate. (PMID:15304343)
• the pleckstrin homology domain of the Dbl family guanine nucleotide exchange factor P-Rex2 has a role in substrate specificity and recognition (PMID:15897194)
• identified P-REX2a as a PTEN-interacting protein; P-REX2a inhibited PTEN lipid phosphatase activity & stimulated the PI3K pathway only in the presence of PTEN; P-REX2a is a component of the PI3K pathway that can antagonize PTEN in cancer cells (PMID:19729658)
• suggests that aberrant control of PTEN by P-REX2a may represent a key tumorigenic mechanism, in agreement with recent studies supporting the pathological relevance of several other proposed PTEN regulators (PMID:19861688)
• Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)–a PTEN-interacting protein and negative regulator of PTEN in breast cancer–as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas (PMID:22622578)
• Studies indicate relevance of P-Rex1 and P-Rex2a, in breast tumorigenesis, and suggest that the exchange factors Vav2 and Vav3 play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and metastasis. (PMID:23033535)
• MiR-338-3p affects the PTEN/Akt pathway by down-regulating PREX2a. (PMID:24140344)
• P-REX2 PH-domain-mediated inhibition of PTEN has a role in regulating insulin sensitivity and glucose homeostasis (PMID:24367090)
• Results demonstrate that miR-338-3p affects gastric cancer progression through PTEN-AKT signaling by targeting P-Rex2a in gastric cancer cells (PMID:24375644)
• CXCL9 is involved in the invasion ability of hepatocellular carcinoma cells possibly through up-regulation of its potential effector PREX2. (PMID:25151370)
• PREX2 mutants are likely selected in cancer to escape PTEN-mediated inhibition of invasion. (PMID:25829446)
• second messengers activate the Rac1 signal, which sets in motion a cascade whereby PAKs phosphorylate and negatively regulate PREX2 to decrease Rac1 activation. (PMID:26438819)
• findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator (PMID:26884185)
• complex signaling mechanisms that involve PREX2, PI3K/AKT/PTEN and downstream epigenetic machinery to deregulate expression of key cell cycle regulators (PMID:27111337)
• PREX2 was identified as a frequently mutated gene in human melanoma. .. mutation of PREX2 can accelerate human melanoma growth. (PMID:28100393)
• The rapid tumor onset observed in this replication attempt, compared to the original study, makes the detection of accelerated tumor growth in PREX2 expressing NRAS(G12D) melanocytes extremely difficult. (PMID:28100394)
• Elevated PREX2 protein expression is associated with pathogenesis of hepatocellular carcinoma. (PMID:28205209)
• MiR-338-3p suppresses the TNF-alpha-induced lipogenesis in sebocytes by targeting PREX2a and down-regulating PI3K/AKT signaling. (PMID:28597147)
• Data suggest that PREX1 and PREX2 share similarities in amino acid sequence, domain structure, activation by PIP(3) [phosphatidylinositol 3,4,5-triphosphate] and G-protein-coupled receptors beta/gamma subunits; expression of PREX1 and PREX2 is altered in many cancers. [REVIEW] (PMID:28710285)
• Study demonstrates that miR-637 inhibites melanoma cell proliferation by activation of AKT signaling pathway and induces apoptosis through regulation of Bcl-2/Bax expression via targeting P-REX2a. (PMID:30213289)
• Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma. (PMID:30796242)
• CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction. (PMID:31241130)
• MicroRNA-561 Affects Proliferation and Cell Cycle Transition Through PTEN/AKT Signaling Pathway by Targeting P-REX2a in NSCLC. (PMID:31711559)
• Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1. (PMID:33947796)
• Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Rac Exchanger 2 Protein Facilitates Glioma Progression via Akt and Stat3 Signaling. (PMID:34322848)
• PREX2 gene’s expression in gastric antral epithelial cells of patients with H. pylori infection. (PMID:34705970)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	prex2	ENSDARG00000071692
mus_musculus	Prex2	ENSMUSG00000048960
rattus_norvegicus	Prex2	ENSRNOG00000005391

Paralogs (3): PREX1 (ENSG00000124126), DEPTOR (ENSG00000155792), GPR155 (ENSG00000163328)

Protein

Protein identifiers

Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein — Q70Z35 (reviewed: Q70Z35)

Alternative names: DEP domain-containing protein 2

All UniProt accessions (1): Q70Z35

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. Mediates the activation of RAC1 in a PI3K-dependent manner. May be an important mediator of Rac signaling, acting directly downstream of both G protein-coupled receptors and phosphoinositide 3-kinase.

Subunit / interactions. Interacts with RAC1.

Tissue specificity. Isoform 1 is highly expressed in skeletal muscle, heart and placenta, absent from peripheral blood leukocytes. Isoform 2 is expressed in skeletal muscle, kidney, small intestine, and placenta. Isoform 3 is expressed in the heart.

Domain organisation. PH domain confers substrate specificity and recognition. Able to discriminate between RAC1, RHOA, and CDC42. DH domain alone was unable to confer substrate specificity and recognition.

Isoforms (3)

UniProt ID	Names	Canonical?
Q70Z35-1	1, P-Rex2	yes
Q70Z35-3	3
Q70Z35-4	4

RefSeq proteins (1): NP_079146* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000591	DEP_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001478	PDZ	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR037367	Rex2_DEP_1	Domain
IPR051832	mTOR-Rac_regulators	Family
IPR055251	SOS1_NGEF_PH	Domain

Pfam: PF00595, PF00610, PF00621, PF22697

UniProt features (32 total): strand 8, domain 6, splice variant 5, helix 4, sequence variant 3, sequence conflict 3, chain 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6BNM	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q70Z35-F1	79.49	0.34

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8948751	Regulation of PTEN stability and activity
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle

MSigDB gene sets: 216 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_BEHAVIOR, GCANCTGNY_MYOD_Q6, GOBP_ADULT_BEHAVIOR, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEUROGENESIS, FOXO1_01, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_DENDRITE_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_TOR_SIGNALING, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, FOXJ2_01, HP1SITEFACTOR_Q6

GO Biological Process (8): G protein-coupled receptor signaling pathway (GO:0007186), adult locomotory behavior (GO:0008344), negative regulation of TOR signaling (GO:0032007), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), dendrite morphogenesis (GO:0048813), regulation of small GTPase mediated signal transduction (GO:0051056), signal transduction (GO:0007165), intracellular signal transduction (GO:0035556)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), protein serine/threonine kinase inhibitor activity (GO:0030291), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	3
PTEN Regulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
GTPase regulator activity	2
G protein-coupled receptor activity	1
locomotory behavior	1
adult behavior	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
intracellular signaling cassette	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular anatomical structure	1
GTP binding	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
protein serine/threonine kinase activity	1
protein kinase inhibitor activity	1
binding	1
cytoplasm	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1154 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PREX2	PTEN	P60484	969
PREX2	RABIF	P47224	665
PREX2	PIK3CA	P42336	566
PREX2	GNB1	P04697	542
PREX2	CDC42	P21181	526
PREX2	GNG2	P59768	497
PREX2	RHOA	P06749	486
PREX2	PLEK	P08567	473
PREX2	NRAS	P01111	458
PREX2	RIC8B	Q9NVN3	448
PREX2	PIK3CG	P48736	433
PREX2	PPP6C	O00743	424
PREX2	WHR1	P49842	419
PREX2	RUNX1T1	Q06455	410
PREX2	PRR5	P85299	406

IntAct

72 interactions, top by confidence:

A	B	Type	Score
PREX2	BRAF	psi-mi:“MI:2364”(proximity)	0.470
BRAF	PREX2	psi-mi:“MI:0915”(physical association)	0.470
PPP1CA	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
FZD7	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
PREX2	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF16	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
ABCC4	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
ASIC3	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B4	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
CYSLTR2	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKK	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
PREX2	DGKK	psi-mi:“MI:0407”(direct interaction)	0.440
PREX2	DGKZ	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
E6	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440
PREX2	E6	psi-mi:“MI:0407”(direct interaction)	0.440
ORF putative E6	PREX2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (20): GNMT (Affinity Capture-Western), PREX2 (Affinity Capture-Western), GNMT (Reconstituted Complex), HUWE1 (Affinity Capture-Western), PREX2 (Affinity Capture-Western), HUWE1 (Affinity Capture-Western), GNMT (Affinity Capture-Western), HIST1H2BH (Proximity Label-MS), PREX2 (FRET), PREX2 (FRET), PREX2 (FRET), ARHGAP18 (Affinity Capture-MS), NT5C2 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), PREX2 (Negative Genetic)

ESM2 similar proteins: A1A5G2, A2AFR3, A7MBL8, B9EJ86, E1C1R4, E1C3P4, F1LXF1, O94806, O94967, P0C6S7, P0CAX5, P11274, P22682, Q0V9G5, Q14161, Q14CM0, Q15139, Q16513, Q1RMU2, Q3KR37, Q3LAC4, Q3UGM2, Q5RED8, Q5T6S3, Q5U252, Q62101, Q66H62, Q6DFZ1, Q6P5G6, Q6PAJ1, Q70Z35, Q7Z6G8, Q80TI0, Q80TQ2, Q80YA9, Q8BIZ1, Q8BWW9, Q8BY87, Q8K1Y2, Q8NEL9

Diamond homologs: A1IGU3, A1IGU4, A1IGU5, A1ZAY1, E7F1U2, O15068, O15085, O77775, P10569, P15498, P19878, P35991, Q08DN7, Q3LAC4, Q5DU57, Q60992, Q63406, Q69ZK0, Q70Z35, Q80VK6, Q8TCU6, Q96N96, Q9NHV9, Q9NXL2, O60229, P40995, Q1LUA6, Q5BKC9, Q5RDX5, Q64096, Q6RFZ7, Q8CHT1, Q8N5V2, Q9ES67, P52735, Q55E26, Q6TXD4, A2AWR3, Q0CHV5, Q4PE51

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
PREX2	“down-regulates activity”	PTEN	binding
PTEN	“down-regulates activity”	PREX2	binding
PREX2	“up-regulates activity”	RAC1	“catalytic activity”
PREX2	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
PREX2	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”
PREX2	“up-regulates activity”	CDC42	“guanine nucleotide exchange factor”
PAK1	“down-regulates activity”	PREX2	phosphorylation
PAK2	“down-regulates activity”	PREX2	phosphorylation
PPP1CA	“up-regulates activity”	PREX2	dephosphorylation
PPP2CA	“up-regulates activity”	PREX2	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Diseases of signal transduction by growth factor receptors and second messengers	6	11.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein stabilization	5	9.6×	7e-03
positive regulation of gene expression	6	6.6×	8e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 12 cancer types — BLCA, BRCA, COAD, DLBCLNOS, ESCA, ESCC, HCC, MEL, OVT, PANCREAS, PRAD, STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	155
Likely benign	18
Benign	27

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
545110	NM_024870.4(PREX2):c.3355G>A (p.Ala1119Thr)	Likely pathogenic

SpliceAI

7241 predictions. Top by Δscore:

Variant	Effect	Δscore
8:67952532:GTCG:G	donor_gain	1.0000
8:67952534:CGG:C	donor_loss	1.0000
8:67952536:G:GG	donor_gain	1.0000
8:67952537:TGAGT:T	donor_loss	1.0000
8:68019543:TTACA:T	acceptor_loss	1.0000
8:68019544:TACA:T	acceptor_loss	1.0000
8:68019545:ACAG:A	acceptor_loss	1.0000
8:68019546:CA:C	acceptor_loss	1.0000
8:68019547:A:G	acceptor_loss	1.0000
8:68019645:G:GT	donor_gain	1.0000
8:68019645:GAA:G	donor_gain	1.0000
8:68019648:G:GG	donor_gain	1.0000
8:68019672:G:GG	donor_gain	1.0000
8:68022024:AT:A	acceptor_gain	1.0000
8:68022025:T:G	acceptor_gain	1.0000
8:68030496:GGA:G	acceptor_gain	1.0000
8:68030630:A:T	donor_gain	1.0000
8:68030656:G:GT	donor_gain	1.0000
8:68030656:G:T	donor_gain	1.0000
8:68044473:A:AG	acceptor_gain	1.0000
8:68044474:A:G	acceptor_gain	1.0000
8:68044479:A:AG	acceptor_gain	1.0000
8:68044480:T:G	acceptor_gain	1.0000
8:68044482:TTAAG:T	acceptor_loss	1.0000
8:68044483:TAAGA:T	acceptor_loss	1.0000
8:68044484:AAGAC:A	acceptor_gain	1.0000
8:68044485:A:G	acceptor_gain	1.0000
8:68044485:AGAC:A	acceptor_gain	1.0000
8:68044486:GACG:G	acceptor_gain	1.0000
8:68044586:CACCG:C	donor_gain	1.0000

AlphaMissense

10699 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:67952464:C:A	R24S	1.000
8:68019661:T:C	F109S	1.000
8:68027286:C:G	P169R	1.000
8:68027296:A:C	R172S	1.000
8:68027296:A:T	R172S	1.000
8:68027300:T:C	C174R	1.000
8:68027301:G:A	C174Y	1.000
8:68027302:C:G	C174W	1.000
8:68030598:G:C	K215N	1.000
8:68030598:G:T	K215N	1.000
8:68030653:T:A	W234R	1.000
8:68030653:T:C	W234R	1.000
8:68038265:T:C	L271P	1.000
8:68044543:G:C	R299P	1.000
8:68053133:G:A	G327E	1.000
8:68053135:T:A	W328R	1.000
8:68053135:T:C	W328R	1.000
8:68053157:A:T	K335I	1.000
8:68053165:T:A	W338R	1.000
8:68053165:T:C	W338R	1.000
8:68053172:T:A	V340D	1.000
8:68053207:T:A	W352R	1.000
8:68053207:T:C	W352R	1.000
8:68060696:T:C	L419P	1.000
8:68080482:T:C	F561S	1.000
8:68087762:T:C	F689S	1.000
8:68087792:T:A	V699E	1.000
8:68087797:G:C	A701P	1.000
8:68090603:T:C	L713P	1.000
8:68090669:T:A	V735D	1.000

dbSNP variants (sampled 300 via entrez): RS1000009479 (8:68040553 C>G), RS1000015626 (8:68071067 A>G), RS1000034428 (8:68090132 C>T), RS1000042767 (8:67982441 G>A,C), RS1000042815 (8:68113041 G>A), RS1000048843 (8:67957700 A>G), RS1000061668 (8:68214304 G>T), RS1000081532 (8:68026976 C>A,T), RS1000104264 (8:68114175 T>C), RS1000107004 (8:68049369 G>A), RS1000118666 (8:68149251 G>T), RS1000122023 (8:68064999 G>A), RS1000161768 (8:68075715 A>G), RS1000178873 (8:68036591 T>C), RS1000181223 (8:68157071 G>A)

Disease associations

OMIM: gene MIM:612139 | disease phenotypes: MIM:108010

GenCC curated gene-disease

Mondo (3): prostate cancer (MONDO:0008315), lip and oral cavity carcinoma (MONDO:0023644), arteriovenous malformations of the brain (MONDO:0007154)

Orphanet (2): Familial prostate cancer (Orphanet:1331), Brain arteriovenous malformation (Orphanet:46724)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004485_46	Survival in pancreatic cancer	5.000000e-06
GCST006628_28	Systolic blood pressure	1.000000e-10
GCST009391_394	Metabolite levels	9.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0000638	overall survival
EFO:0006335	systolic blood pressure
EFO:0010437	triacylglycerol 58:10 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
PREX2 R172I	Vemurafenib	Melanoma	Resistance	CIViC C	EID6268

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression	2
methylmercuric chloride	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
muconaldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Venlafaxine Hydrochloride	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Clorgyline	increases expression	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression	1
Methotrexate	decreases expression	1
Thimerosal	increases expression	1
Aflatoxin B1	affects methylation	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8Q4	JHUEM-14 Prex2a shRNA type 1	Cancer cell line	Female
CVCL_A8Q5	JHUEM-14 Prex2a shRNA type 2	Cancer cell line	Female
CVCL_A8Q6	OMC-2 Prex2a shRNA type 1	Cancer cell line	Female
CVCL_A8Q7	OMC-2 Prex2a shRNA type 2	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer