PIK3R3

Summary

PIK3R3 (phosphoinositide-3-kinase regulatory subunit 3, HGNC:8981) is a protein-coding gene on chromosome 1p34.1, encoding Phosphatidylinositol 3-kinase regulatory subunit gamma (Q92569). Binds to activated (phosphorylated) protein-tyrosine kinases through its SH2 domain and regulates their kinase activity.

Phosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol and similar compounds, which then serve as second messengers in growth signaling pathways. PI3K is composed of a catalytic and a regulatory subunit. The protein encoded by this gene represents a regulatory subunit of PI3K. The encoded protein contains two SH2 domains through which it binds activated protein tyrosine kinases to regulate their activity.

Source: NCBI Gene 8503 — RefSeq curated summary.

At a glance

• GWAS associations: 30
• Clinical variants (ClinVar): 8 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8981
Approved symbol	PIK3R3
Name	phosphoinositide-3-kinase regulatory subunit 3
Location	1p34.1
Locus type	gene with protein product
Status	Approved
Aliases	p55
Ensembl gene	ENSG00000117461
Ensembl biotype	protein_coding
OMIM	606076
Entrez	8503

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000262741, ENST00000372006, ENST00000420542, ENST00000423209, ENST00000425892, ENST00000488808, ENST00000493202, ENST00000862328, ENST00000955777, ENST00000955778, ENST00000955779, ENST00000955780, ENST00000955781

RefSeq mRNA: 11 — MANE Select: NM_003629 NM_001114172, NM_001303428, NM_001303429, NM_001328648, NM_001328649, NM_001328650, NM_001328651, NM_001328652, NM_001328653, NM_001328654, NM_003629

CCDS: CCDS529, CCDS76154

Canonical transcript exons

ENST00000262741 — 10 exons

Exon	Start	End
ENSE00001375056	46040140	46043871
ENSE00001689520	46131847	46132629
ENSE00003606242	46077515	46077613
ENSE00003712182	46046551	46046625
ENSE00003715367	46066911	46067091
ENSE00003725261	46055795	46055971
ENSE00003726322	46045918	46046088
ENSE00003744033	46061929	46062071
ENSE00003746938	46066054	46066179
ENSE00003754454	46080642	46080750

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 97.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2621 / max 264.2584, expressed in 1549 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12160	11.2621	1549
12159	0.4648	270
12162	0.2459	122
12164	0.0093	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	97.58	gold quality
paraflocculus	UBERON:0005351	96.54	gold quality
nasal cavity epithelium	UBERON:0005384	95.91	gold quality
cerebellum	UBERON:0002037	93.50	gold quality
adult organism	UBERON:0007023	93.30	gold quality
cerebellar cortex	UBERON:0002129	93.10	gold quality
cerebellar hemisphere	UBERON:0002245	93.00	gold quality
lower lobe of lung	UBERON:0008949	92.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.32	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.26	gold quality
endometrium epithelium	UBERON:0004811	91.61	gold quality
heart right ventricle	UBERON:0002080	91.28	gold quality
right lung	UBERON:0002167	91.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.00	gold quality
ganglionic eminence	UBERON:0004023	91.00	gold quality
cortical plate	UBERON:0005343	90.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.90	gold quality
nasal cavity mucosa	UBERON:0001826	90.81	gold quality
pericardium	UBERON:0002407	90.64	gold quality
mammary duct	UBERON:0001765	90.39	gold quality
epithelium of bronchus	UBERON:0002031	90.37	gold quality
bronchial epithelial cell	CL:0002328	90.22	gold quality
bronchus	UBERON:0002185	90.13	gold quality
epithelium of mammary gland	UBERON:0003244	89.92	gold quality
left ventricle myocardium	UBERON:0006566	89.82	silver quality
pons	UBERON:0000988	89.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.49	gold quality
secondary oocyte	CL:0000655	89.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.28	gold quality
myocardium	UBERON:0002349	89.26	silver quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	1858.38
E-GEOD-135922	yes	779.01
E-HCAD-35	yes	18.85
E-MTAB-9689	no	170.67
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MIA3	Activation

Upstream regulators (CollecTRI, top): FOS, MZF1, SREBF1

miRNA regulators (miRDB)

202 targeting PIK3R3, 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-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548AW	99.99	72.57	3559
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-367-3P	99.98	74.83	1819
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-363-3P	99.98	74.72	1821
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-4725-3P	99.96	69.53	2520

Literature-anchored findings (GeneRIF, showing 40)

• IGF2-PIK3R3 signaling axis is involved in promoting the growth of a subclass of highly aggressive human glioblastomas that lack EGF receptor amplification. (PMID:17360667)
• We have identified novel nonclassical mediators of the SREBP-1 response, including p55gamma, supporting the hypothesis that SREBP-1 regulates stress response and signaling genes. (PMID:17452746)
• A fusion peptide containing the p55PIK amino terminus, TAT-N24, which not only inhibited cell proliferation, but also stimulated differentiation. (PMID:22722333)
• PIK3R3 was up-regulated in gastric cancer and promoted cell cycle progression and proliferation. (PMID:22876838)
• Data show that miR-7 inhibits the effects of TLR9 signaling on lung cancer cells through regulation of the PIK3R3/Akt pathway. (PMID:23135998)
• p55PIK is transcriptionally activated by MZF1, resulting in increased proliferation of colorectal cancer cells (PMID:23509792)
• Containing the N24 of PI3K-p55PIK. (PMID:23904382)
• our results show that the-PCNA interaction is important in regulating DNA synthesis and contributes to tumorigenesis. (PMID:23939377)
• p55PIK could be a substrate of activated caspase 6 during paraquat-induced apoptosis, leading to loss of original biological functions and redistribution to disturb cell cycle progression. (PMID:24130211)
• discovered that ERBB4 and S6K2 were the direct targets of miR-193a-3p and that PIK3R3 and mTOR were the direct targets of miR-193a-5p in non-small-cell lung cancer (PMID:24469061)
• study shows that the p53/miR-148b/p55PIK axis has an important role in cell proliferation and tumor growth, and may represent a novel therapeutic target for treating cancers containing p53 mutations or losses. (PMID:24632606)
• Overexpression of PIK3R3 depends on SNAI2, inducing significant epithelial-to-mesenchymal transition (EMT). (PMID:24837077)
• PIK3R3, ITGB1, ITGAL, and ITGA6, were involved in the regulation of actin cytoskeleton that link to triple-negative breast cancer migration. (PMID:24982892)
• TGF-beta/NKX2.1/PIK3R3 axis is crucial in the TGF-beta-induced inhibition of cell proliferation, and the NKX2.1/PIK3R3 axis might become a target in TGF-beta receptor-repressed lung adenocarcinoma (PMID:25371235)
• p55gamma sequentially up-regulated p53 and p21, resulting in cell-cycle arrest in S phase; small-interfering RNA knockdown of either p53 or p21 blocked p55gamma-induced vascular smooth muscle cell growth arrest. (PMID:25388664)
• our findings provide new insights into tumor suppression by miR-511 by negatively regulating the PIK3R3/AKT/mTOR signaling pathway (PMID:25608840)
• p55PIK-PI3K signaling can contribute to imatinib resistance in gastrointestinal stromal tumors by increasing KIT expression. (PMID:26587973)
• The proliferation, migration and invasion was decreased in ovarian SKOV3 when HOTAIR or PIK3R3 was silenced. (PMID:26826873)
• miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro They also effectively impeded tumor formation and growth in vivo miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55gamma) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway (PMID:27503199)
• Study showed that PIK3R3 was a target of miR-365 and its expression was upregulated and inversely correlated with miR-365 expression in glioma tissues. (PMID:28260020)
• p55PIK significantly stimulated the expression of AFP by activating NF-kappaB signaling pathway in hepatocellular carcinoma cells. (PMID:28970114)
• PIK3R3 regulates the expression of PPAR-alpha in hepatocytes.The novel PIK3R3-HNF4alpha-PPAR-alpha signaling axis plays a significant role in hepatic lipid metabolism. (PMID:29350678)
• Database analysis indicates that better disease-free survival in colorectal cancer patients with higher expression of PIK3R3, but there is no significant difference in overall survival. Study in tumor cell lines showed that PIK3R3 could enhance 5-FU induced apoptosis by regulating the expression of thymidine phosphorylase. (PMID:29370570)
• PIK3R3 could promote the metastasis of Pancreatic Cancer by facilitating ZEB1 induced Epithelial-Mesenchymal Transition. (PMID:29719293)
• Using case-control study and functional analyses, study have identified SNP rs7536272 A > G, located in the promoter region of PIK3R3, acts as a risk factor of GC through enhancing the transcriptional activity of PIK3R3, contributing to increased expression of PIK3R3. (PMID:29802999)
• HOXD-AS1/miR-186-5p/PIK3R3 is a novel pathway to promote cell migration, invasion, and epithelial-mesenchymal transition in epithelial ovarian cancer (PMID:30823895)
• miR-224-5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanoma. (PMID:30825222)
• MicroRNA-29c-3p inhibits osteosarcoma cell proliferation through targeting PIK3R3. (PMID:32196574)
• PIK3R3 regulates ZO-1 expression through the NF-kB pathway in inflammatory bowel disease. (PMID:32473571)
• miR-29a-3p suppresses hepatic fibrosis pathogenesis by modulating hepatic stellate cell proliferation via targeting PIK3R3 gene expression. (PMID:32819600)
• Inhibition of exosomal miR-24-3p in diabetes restores angiogenesis and facilitates wound repair via targeting PIK3R3. (PMID:33142041)
• p55PIK deficiency and its NH2-terminal derivative inhibit inflammation and emphysema in COPD mouse model. (PMID:33949204)
• MiR-513b-5p represses autophagy during the malignant progression of hepatocellular carcinoma by targeting PIK3R3. (PMID:34120890)
• LncRNA JHDM1D-AS1 Suppresses MPP + -Induced Neuronal Injury in Parkinson’s Disease via miR-134-5p/PIK3R3 Axis. (PMID:34773593)
• PIK3R3, a regulatory subunit of PI3K, modulates ovarian cancer stem cells and ovarian cancer development and progression by integrative analysis. (PMID:35761259)
• KMT2C Induced by FABP5P3 Aggravates Keratinocyte Hyperproliferation and Psoriasiform Skin Inflammation by Upregulating the Transcription of PIK3R3. (PMID:35870559)
• PIK3R3 Missense and NOTCH2 Synonymous Single Nucleotide Polymorphisms Are Associated with Liver Cancer. (PMID:36535266)
• PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDKN1C and SMC1A. (PMID:37212524)
• p55gamma degrades RIP3 via MG53 to suppress ischaemia-induced myocardial necroptosis and mediates cardioprotection of preconditioning. (PMID:37527538)
• VHL governs m6A modification and PIK3R3 mRNA stability in clear cell renal cell carcinomas. (PMID:38618953)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pik3r3b	ENSDARG00000034409
danio_rerio	pik3r3a	ENSDARG00000103038
mus_musculus	Pik3r3	ENSMUSG00000028698
rattus_norvegicus	Pik3r3	ENSRNOG00000000145
drosophila_melanogaster	Pi3K21B	FBGN0020622
caenorhabditis_elegans	aap-1	WBGENE00000001

Paralogs (2): PIK3R2 (ENSG00000105647), PIK3R1 (ENSG00000145675)

Protein

Protein identifiers

Phosphatidylinositol 3-kinase regulatory subunit gamma — Q92569 (reviewed: Q92569)

Alternative names: Phosphatidylinositol 3-kinase 55 kDa regulatory subunit gamma, p55PIK

All UniProt accessions (2): Q92569, Q5T4P3

UniProt curated annotations — full annotation on UniProt →

Function. Binds to activated (phosphorylated) protein-tyrosine kinases through its SH2 domain and regulates their kinase activity. During insulin stimulation, it also binds to IRS-1.

Subunit / interactions. Heterodimer of a regulatory subunit PIK3R3 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts with AXL.

Tissue specificity. Highest levels in brain and testis. Lower levels in adipose tissue, kidney, heart, lung and skeletal muscle.

Similarity. Belongs to the PI3K p85 subunit family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92569-1	1	yes
Q92569-2	2
Q92569-3	3

RefSeq proteins (11): NP_001107644, NP_001290357, NP_001290358, NP_001315577, NP_001315578, NP_001315579, NP_001315580, NP_001315581, NP_001315582, NP_001315583, NP_003620* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR032498	PI3K_P85_iSH2	Domain
IPR035020	PI3kinase_P85_cSH2	Domain
IPR035022	PI3kinase_P85_nSH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017, PF16454

UniProt features (8 total): domain 2, splice variant 2, chain 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92569-F1	80.93	0.46

Functional residue map

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

Post-translational modifications (1): 341

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1266695	Interleukin-7 signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-389357	CD28 dependent PI3K/Akt signaling
R-HSA-416476	G alpha (q) signalling events
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8853659	RET signaling
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-912526	Interleukin receptor SHC signaling
R-HSA-912631	Regulation of signaling by CBL
R-HSA-9670439	Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants
R-HSA-9927354	Co-stimulation by ICOS

MSigDB gene sets: 550 (showing top): WENDT_COHESIN_TARGETS_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, CREL_01, ELVIDGE_HYPOXIA_DN, E2F_Q4_01, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GU_PDEF_TARGETS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION

GO Biological Process (10): cell migration involved in sprouting angiogenesis (GO:0002042), immune response (GO:0006955), insulin receptor signaling pathway (GO:0008286), positive regulation of gene expression (GO:0010628), B cell differentiation (GO:0030183), T cell differentiation (GO:0030217), positive regulation of cell migration (GO:0030335), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), negative regulation of anoikis (GO:2000811), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092)

GO Molecular Function (4): phosphotyrosine residue binding (GO:0001784), 1-phosphatidylinositol-3-kinase activity (GO:0016303), 1-phosphatidylinositol-3-kinase regulator activity (GO:0046935), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), phosphatidylinositol 3-kinase complex, class IA (GO:0005943), phosphatidylinositol 3-kinase complex (GO:0005942)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signaling by Interleukins	2
RHO GTPase cycle	2
Interleukin-3, Interleukin-5 and GM-CSF signaling	2
Platelet activation, signaling and aggregation	1
Intracellular signaling by second messengers	1
Signaling by Receptor Tyrosine Kinases	1
PI Metabolism	1
PI3K/AKT Signaling in Cancer	1
Co-stimulation by CD28	1
GPCR downstream signalling	1
Negative regulation of the PI3K/AKT network	1
Axon guidance	1
ESR-mediated signaling	1
Interleukin-2 family signaling	1
Signaling by KIT in disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymphocyte differentiation	2
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
immune system process	1
response to stimulus	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
B cell activation	1
T cell activation	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
intracellular signaling cassette	1
negative regulation of apoptotic process	1
anoikis	1
regulation of anoikis	1
phosphatidylinositol phosphate biosynthetic process	1
protein phosphorylated amino acid binding	1
phosphatidylinositol-3-phosphate biosynthetic process	1
phosphatidylinositol kinase activity	1
1-phosphatidylinositol-3-kinase activity	1
kinase regulator activity	1
binding	1
cytoplasm	1
cellular anatomical structure	1
phosphatidylinositol 3-kinase complex, class I	1
extrinsic component of membrane	1
transferase complex, transferring phosphorus-containing groups	1
membrane protein complex	1

Protein interactions and networks

STRING

1438 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIK3R3	PIK3CD	O00329	997
PIK3R3	PIK3CB	P42338	997
PIK3R3	PIK3CA	P42336	995
PIK3R3	PIK3CG	P48736	991
PIK3R3	PIK3R2	O00459	957
PIK3R3	IRS1	P35568	916
PIK3R3	PIK3R5	Q8WYR1	824
PIK3R3	PIK3R1	P27986	768
PIK3R3	AKT3	Q9Y243	733
PIK3R3	IGF1R	P08069	697
PIK3R3	PIK3R6	Q5UE93	693
PIK3R3	INSR	P06213	631
PIK3R3	AKT1	P31749	611
PIK3R3	ERBB2	P04626	593
PIK3R3	PTEN	P60484	559

IntAct

602 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R3	psi-mi:“MI:0915”(physical association)	0.900
PIK3CB	PIK3R3	psi-mi:“MI:0915”(physical association)	0.800
PIK3R3	PIK3CD	psi-mi:“MI:0914”(association)	0.800
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.750
PIK3R3	IRS1	psi-mi:“MI:0915”(physical association)	0.670
PIK3R3	CEP19	psi-mi:“MI:0915”(physical association)	0.670
IRS1	PIK3R3	psi-mi:“MI:0915”(physical association)	0.670
DRAP1	PIK3R3	psi-mi:“MI:0915”(physical association)	0.670
PIK3R3	PTK2	psi-mi:“MI:0915”(physical association)	0.630
PIK3R3	CRK	psi-mi:“MI:0915”(physical association)	0.620
PIK3R3	SRC	psi-mi:“MI:0915”(physical association)	0.620
CRK	PIK3R3	psi-mi:“MI:0915”(physical association)	0.620
SRC	PIK3R3	psi-mi:“MI:0915”(physical association)	0.620
TSPAN2	PIK3R3	psi-mi:“MI:0915”(physical association)	0.590
PIK3R3	TSPAN2	psi-mi:“MI:0407”(direct interaction)	0.590
PLEKHS1	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
ARL6IP4	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
PARD6A	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
SPSB2	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
RBP7	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
CBL	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
SH2D2A	PIK3R3	psi-mi:“MI:0915”(physical association)	0.570
PIK3R3	FRS3	psi-mi:“MI:0915”(physical association)	0.570
PIK3R3	HCK	psi-mi:“MI:0915”(physical association)	0.570

BioGRID (282): TRIM54 (Two-hybrid), L3MBTL3 (Two-hybrid), FSD2 (Two-hybrid), PIK3R3 (Two-hybrid), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), PIK3R3 (Affinity Capture-MS), DRAP1 (Two-hybrid), PIK3CA (Two-hybrid)

ESM2 similar proteins: A0A0G2JTR4, A0A2R8QFQ6, A0JM95, A4IFE4, A6QNS3, C1C3R6, D3Z649, D4ABL6, E9PV86, F1QH17, G3MWR8, O46404, Q0VAM2, Q12800, Q12979, Q13507, Q28EC1, Q3ULA2, Q3UNW5, Q4V860, Q5R6F2, Q5RB16, Q5RC04, Q5SSL4, Q5VWJ9, Q5ZLX4, Q63789, Q64143, Q6DHR3, Q6NZH6, Q6UVM3, Q6UVM4, Q6ZPR4, Q7RTP6, Q7T2U9, Q7Z6J6, Q8CE50, Q8CJ19, Q8JZL7, Q8N431

Diamond homologs: G5ECJ6, O00459, O08908, O14508, O14544, O35717, O46404, O88582, P00519, P00520, P00521, P10447, P14234, P15498, P23726, P23727, P26450, P27986, P41242, P41243, P42679, P42684, P54100, P62993, P62994, Q08012, Q08DN7, Q45FX5, Q4JIM5, Q54RB7, Q5R4J7, Q5R685, Q5RCM6, Q60631, Q62662, Q63787, Q63788, Q63789, Q64143, Q6P6U0

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
PIK3R3	up-regulates	PI3K	binding
ALK	“up-regulates activity”	PIK3R3	phosphorylation
PIK3R3	“up-regulates activity”	TP53	binding
PLEKHG2	“up-regulates activity”	PIK3R3	binding
INSR	unknown	PIK3R3	phosphorylation
IGF1R	up-regulates	PIK3R3	binding
PIK3R3	up-regulates	PIK3CA	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 112 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
Regulation of signaling by CBL	8	61.1×	2e-10
Signaling by ALK	6	52.7×	9e-08
Regulation of KIT signaling	5	46.2×	4e-06
Signaling by CSF1 (M-CSF) in myeloid cells	8	42.6×	2e-09
Downstream signal transduction	7	41.0×	3e-08
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	39.9×	7e-06
Nephrin family interactions	5	36.6×	1e-05
Signaling by SCF-KIT	9	34.4×	9e-10

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	7	30.4×	3e-06
ephrin receptor signaling pathway	6	21.3×	1e-04
phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	15.2×	1e-04
insulin receptor signaling pathway	5	11.4×	5e-03
cell surface receptor protein tyrosine kinase signaling pathway	6	10.8×	2e-03
positive regulation of neuron projection development	6	8.5×	5e-03
cytokine-mediated signaling pathway	6	8.1×	5e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	9	7.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2146 predictions. Top by Δscore:

Variant	Effect	Δscore
1:46043667:T:TA	donor_gain	1.0000
1:46043676:T:C	donor_gain	1.0000
1:46043867:CGGCC:C	acceptor_gain	1.0000
1:46043868:GGCCC:G	acceptor_loss	1.0000
1:46043870:CC:C	acceptor_gain	1.0000
1:46043870:CCCTG:C	acceptor_loss	1.0000
1:46043871:CC:C	acceptor_gain	1.0000
1:46043872:CT:C	acceptor_loss	1.0000
1:46043873:T:A	acceptor_loss	1.0000
1:46045094:C:CC	acceptor_gain	1.0000
1:46045916:A:AC	donor_gain	1.0000
1:46045916:ACAC:A	donor_gain	1.0000
1:46045917:C:CC	donor_gain	1.0000
1:46045917:CA:C	donor_gain	1.0000
1:46045917:CACC:C	donor_gain	1.0000
1:46045917:CACCA:C	donor_gain	1.0000
1:46045934:AGCAT:A	donor_gain	1.0000
1:46045938:T:TA	donor_gain	1.0000
1:46045954:T:A	donor_gain	1.0000
1:46046086:TTC:T	acceptor_gain	1.0000
1:46046087:TC:T	acceptor_gain	1.0000
1:46046088:CC:C	acceptor_gain	1.0000
1:46046089:C:CC	acceptor_gain	1.0000
1:46046090:T:C	acceptor_loss	1.0000
1:46046544:AACTT:A	donor_loss	1.0000
1:46046545:ACTT:A	donor_loss	1.0000
1:46046546:CTTA:C	donor_loss	1.0000
1:46046547:TTAC:T	donor_loss	1.0000
1:46046548:TAC:T	donor_loss	1.0000
1:46046549:A:AC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001784 (1:46064396 C>G,T), RS1000011558 (1:46127768 C>A,T), RS1000014672 (1:46131119 T>G), RS1000050297 (1:46062929 G>A,C), RS1000053163 (1:46176126 T>C), RS1000091804 (1:46057898 A>G,T), RS1000131101 (1:46137720 G>C), RS1000144799 (1:46165719 T>C), RS1000154662 (1:46105414 G>A,C), RS1000159854 (1:46058271 C>T), RS1000160088 (1:46104969 C>T), RS1000183957 (1:46137415 G>A), RS1000209754 (1:46145388 T>G), RS1000241691 (1:46076556 A>T), RS1000255275 (1:46054184 T>C,G)

Disease associations

OMIM: gene MIM:606076 | disease phenotypes: MIM:114480

GenCC curated gene-disease

Mondo (1): hereditary breast carcinoma (MONDO:0016419)

Orphanet (1): Hereditary breast cancer (Orphanet:227535)

HPO phenotypes

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

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST004557_1	Body mass index	2.000000e-08
GCST004557_172	Body mass index	3.000000e-07
GCST004558_120	Body mass index (joint analysis main effects and physical activity interaction)	7.000000e-07
GCST004558_185	Body mass index (joint analysis main effects and physical activity interaction)	3.000000e-08
GCST004559_140	Body mass index in physically active individuals	2.000000e-07
GCST004610_26	White blood cell count	1.000000e-10
GCST004613_9	Sum neutrophil eosinophil counts	3.000000e-10
GCST004988_634	Breast cancer	3.000000e-08
GCST005951_37	Body mass index	8.000000e-10
GCST006032_2	Sodium levels	5.000000e-12
GCST006630_84	Diastolic blood pressure	1.000000e-14
GCST008058_229	Estimated glomerular filtration rate	7.000000e-12
GCST008059_28	Estimated glomerular filtration rate	6.000000e-15
GCST009391_1593	Metabolite levels	6.000000e-06
GCST010696_7	Cortical thickness (min-P)	3.000000e-08
GCST010697_28	Cortical surface area (min-P)	2.000000e-08
GCST010698_30	Subcortical volume (min-P)	3.000000e-08
GCST010699_45	Brain morphology (min-P)	3.000000e-08
GCST010700_23	Cortical thickness (MOSTest)	1.000000e-10
GCST010701_9	Cortical surface area (MOSTest)	2.000000e-08
GCST010702_139	Subcortical volume (MOSTest)	4.000000e-14
GCST010703_258	Brain morphology (MOSTest)	2.000000e-13
GCST010796_3548	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-10
GCST010796_3549	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST012020_66	Serum metabolite levels	5.000000e-27
GCST90002389_86	Lymphocyte percentage of white cells	9.000000e-12
GCST90002398_480	Neutrophil count	1.000000e-24
GCST90002399_34	Neutrophil percentage of white cells	4.000000e-09
GCST90002404_464	Red cell distribution width	3.000000e-14
GCST90002407_651	White blood cell count	8.000000e-25

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0009282	sodium measurement
EFO:0006336	diastolic blood pressure
EFO:0010376	phosphatidylcholine 34:2 measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004327	electrocardiography
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3559702 (SINGLE PROTEIN), CHEMBL3559703 (PROTEIN COMPLEX GROUP)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 67 (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
CHEMBL3683575	ROGINOLISIB	2	67

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Phosphatidylinositol kinases

ChEMBL bioactivities

421 potent at pChembl≥5 of 431 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.22	IC50	6	nM	CHEMBL3683580
8.15	IC50	7	nM	CHEMBL3683671
7.96	IC50	11	nM	CHEMBL3683555
7.89	IC50	13	nM	CHEMBL3683606
7.89	IC50	13	nM	CHEMBL3683649
7.89	IC50	13	nM	CHEMBL3683695
7.85	IC50	14	nM	CHEMBL3683596
7.85	IC50	14	nM	CHEMBL3683693
7.82	IC50	15	nM	CHEMBL3683611
7.82	IC50	15	nM	CHEMBL3683686
7.80	IC50	16	nM	CHEMBL3683556
7.80	IC50	16	nM	CHEMBL3683584
7.80	IC50	16	nM	CHEMBL3683641
7.80	IC50	16	nM	CHEMBL3683644
7.77	IC50	17	nM	CHEMBL3683594
7.75	IC50	18	nM	CHEMBL3683680
7.75	IC50	18	nM	CHEMBL3683684
7.72	IC50	19	nM	CHEMBL3683613
7.70	IC50	20	nM	CHEMBL3683667
7.70	IC50	20	nM	CHEMBL3683675
7.68	IC50	21	nM	CHEMBL3683552
7.68	IC50	21	nM	CHEMBL3683632
7.68	IC50	21	nM	CHEMBL3683681
7.66	IC50	22	nM	CHEMBL3683530
7.66	IC50	22	nM	CHEMBL3683685
7.62	IC50	24	nM	CHEMBL3683612
7.62	IC50	24	nM	CHEMBL3683617
7.62	IC50	24	nM	CHEMBL5537039
7.60	IC50	25	nM	CHEMBL3683593
7.60	IC50	25	nM	CHEMBL3683595
7.60	IC50	25	nM	CHEMBL3683647
7.60	IC50	25	nM	CHEMBL3683661
7.60	IC50	25	nM	CHEMBL3683690
7.57	IC50	27	nM	CHEMBL3683600
7.55	IC50	28	nM	CHEMBL3683672
7.55	IC50	28	nM	CHEMBL3683674
7.54	IC50	29	nM	CHEMBL3683548
7.54	IC50	29	nM	CHEMBL3683614
7.52	IC50	30	nM	CHEMBL3683615
7.51	IC50	31	nM	CHEMBL3683656
7.50	IC50	32	nM	CHEMBL3683599
7.47	IC50	34	nM	CHEMBL3683531
7.47	IC50	34	nM	CHEMBL3683533
7.47	IC50	34	nM	CHEMBL3683556
7.47	IC50	34	nM	CHEMBL3683666
7.44	IC50	36	nM	CHEMBL3683523
7.44	IC50	36	nM	CHEMBL3683610
7.42	IC50	38	nM	CHEMBL3683551
7.42	IC50	38	nM	CHEMBL3683642
7.41	IC50	39	nM	CHEMBL3683651

PubChem BioAssay actives

5 with measured affinity, of 6 total; 5 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
4-[5-amino-6-(cyclopropanecarbonyl)pyrazin-2-yl]-N-(4-hydroxycyclohexyl)-3-methylbenzenesulfonamide	2066709: Inhibition of human recombinant PI3Kgamma using phosphatidylinositol as substrate in presence of [gamma33P]ATP by scintillation proximity assay	ic50	0.0240	uM
4-[6-amino-5-(2-methyl-1,3-oxazol-5-yl)-3-pyridinyl]-N-(2-hydroxy-2-methylpropyl)-3-methylbenzenesulfonamide	2066709: Inhibition of human recombinant PI3Kgamma using phosphatidylinositol as substrate in presence of [gamma33P]ATP by scintillation proximity assay	ic50	0.0400	uM
4-[1-[(4-chlorophenyl)methyl]pyrazol-4-yl]-2-(5-phenyl-1H-imidazol-2-yl)pyridine	2066705: Inhibition of P13Kgamma (unknown origin) in the presence of ATP by scintillation proximity assay	ic50	0.0500	uM
2-[(1S)-1-cyclopropylethyl]-7-methylsulfonyl-5-[2-(5-methyl-1H-1,2,4-triazol-3-yl)-4-pyridinyl]-3H-isoindol-1-one	2066705: Inhibition of P13Kgamma (unknown origin) in the presence of ATP by scintillation proximity assay	ic50	0.1000	uM
4-(8-amino-7-chloroimidazo[1,2-a]pyridin-3-yl)-N-(4-hydroxycyclohexyl)-3-methylbenzenesulfonamide	2066705: Inhibition of P13Kgamma (unknown origin) in the presence of ATP by scintillation proximity assay	ic50	0.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	decreases expression, affects methylation, decreases methylation, increases abundance, increases response to substance (+1 more)	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Tobacco Smoke Pollution	increases expression, increases methylation	3
Valproic Acid	affects expression, decreases methylation, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Fulvestrant	increases expression, affects cotreatment, increases methylation	2
Acetaminophen	increases expression, affects cotreatment	2
Glyphosate	decreases expression, increases expression	2
Carbamazepine	affects expression	2
Cisplatin	increases expression	2
Formaldehyde	decreases expression, increases expression	2
Genistein	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
sotorasib	increases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
nuciferine	affects cotreatment, decreases phosphorylation, decreases reaction	1
2-methyl-4-isothiazolin-3-one	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
sulforaphane	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	decreases expression	1
ferrous chloride	decreases expression	1
cupric chloride	decreases expression	1
di-n-butylphosphoric acid	affects 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
CHEMBL5505526	Binding	Inhibition of P13Kgamma (unknown origin) in the presence of ATP by scintillation proximity assay	Designing Small Molecule PI3Kγ Inhibitors: A Review of Structure-Based Methods and Computational Approaches. — J Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7XD	Ubigene A-549 PIK3R3 KO	Cancer cell line	Male
CVCL_D8SU	Ubigene HCT 116 PIK3R3 KO	Cancer cell line	Male
CVCL_D9NB	Ubigene HEK293 PIK3R3 KO	Transformed cell line	Female
CVCL_E0KP	Ubigene HeLa PIK3R3 KO	Cancer cell line	Female
CVCL_TD70	HAP1 PIK3R3 (-) 1	Cancer cell line	Male
CVCL_TD71	HAP1 PIK3R3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT07292246	Not specified	RECRUITING	A Prospective CohorT Study of HandX - Assisted ENdoscopic MAstectomy: Feasibility and Safety (ATHENA I Study)
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer