SH3BGRL

Summary

SH3BGRL (SH3 domain binding glutamate rich protein like, HGNC:10823) is a protein-coding gene on chromosome Xq21.1, encoding Adapter SH3BGRL (O75368). Appears to function as an adapter protein that bridges proteins together or proteins with mRNAs.

Enables protein-RNA adaptor activity and ubiquitin-like ligase-substrate adaptor activity. Involved in positive regulation of cytoplasmic translational initiation and proteasome-mediated ubiquitin-dependent protein catabolic process. Located in cytosol.

Source: NCBI Gene 6451 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 40 total
• MANE Select transcript: NM_003022

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10823
Approved symbol	SH3BGRL
Name	SH3 domain binding glutamate rich protein like
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC117402
Ensembl gene	ENSG00000131171
Ensembl biotype	protein_coding
OMIM	300190
Entrez	6451

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000373212, ENST00000463546, ENST00000474113, ENST00000481106, ENST00000877843, ENST00000877844, ENST00000963204, ENST00000963205

RefSeq mRNA: 1 — MANE Select: NM_003022 NM_003022

CCDS: CCDS14449

Canonical transcript exons

ENST00000373212 — 4 exons

Exon	Start	End
ENSE00001143043	81297195	81298547
ENSE00001459835	81202102	81202245
ENSE00003521278	81276984	81277169
ENSE00003615618	81278331	81278411

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 188.5587 / max 3186.7990, expressed in 1809 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196806	173.5475	1806
196805	5.7094	1511
196804	4.4051	1438
196808	2.6201	348
196807	1.1001	493
196809	0.7838	207
196812	0.2048	103
196810	0.1879	106

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	99.55	gold quality
cauda epididymis	UBERON:0004360	99.49	gold quality
blood vessel layer	UBERON:0004797	99.43	gold quality
monocyte	CL:0000576	99.40	gold quality
mononuclear cell	CL:0000842	99.39	gold quality
superficial temporal artery	UBERON:0001614	99.37	gold quality
leukocyte	CL:0000738	99.34	gold quality
trabecular bone tissue	UBERON:0002483	99.33	gold quality
saphenous vein	UBERON:0007318	99.33	gold quality
urethra	UBERON:0000057	99.31	gold quality
mammary duct	UBERON:0001765	99.29	gold quality
germinal epithelium of ovary	UBERON:0001304	99.24	gold quality
popliteal artery	UBERON:0002250	99.23	gold quality
tibial artery	UBERON:0007610	99.23	gold quality
choroid plexus epithelium	UBERON:0003911	99.22	gold quality
right coronary artery	UBERON:0001625	99.20	gold quality
epithelium of mammary gland	UBERON:0003244	99.17	gold quality
visceral pleura	UBERON:0002401	99.11	gold quality
synovial joint	UBERON:0002217	99.08	gold quality
aorta	UBERON:0000947	99.03	gold quality
descending thoracic aorta	UBERON:0002345	99.01	gold quality
trigeminal ganglion	UBERON:0001675	98.99	gold quality
caput epididymis	UBERON:0004358	98.98	gold quality
pleura	UBERON:0000977	98.95	gold quality
subthalamic nucleus	UBERON:0001906	98.95	gold quality
gall bladder	UBERON:0002110	98.93	gold quality
vena cava	UBERON:0004087	98.92	gold quality
parietal pleura	UBERON:0002400	98.90	gold quality
pons	UBERON:0000988	98.86	gold quality
skin of hip	UBERON:0001554	98.86	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	49.14
E-HCAD-10	yes	44.93
E-MTAB-6701	yes	40.12
E-MTAB-8410	yes	24.97
E-HCAD-5	yes	23.30
E-HCAD-11	yes	22.29
E-CURD-46	yes	9.13
E-GEOD-75367	no	1861.54
E-MTAB-7606	no	580.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): REL

miRNA regulators (miRDB)

126 targeting SH3BGRL, 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-4682	100.00	68.89	1258
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 8)

• h-SH3BGRL should present a novel class of the thioredoxin fold proteins (PMID:16080146)
• mutations in predicted EVH1-binding domain of SH3BGRL had a modest effect on suppression of v-Rel transformation. This study provides the first example of a gene that is downregulated in v-Rel-expressing cells also playng a role in v-Rel transformation (PMID:16186799)
• Results indicate Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (SH3BGRL) in driving tumor metastasis through c-Src activation, and suggests that hSH3BGRL mutation status could be relevant to cancer diagnosis and therapy. (PMID:26455318)
• Study results demonstrated that SH3BGRL is a novel crucial player in acute myeloid leukemia progression and could be both a potential diagnostic and prognostic marker. (PMID:28679293)
• Distinct functions of CAR-T cells possessing a dectin-1 intracellular signaling domain. (PMID:33953316)
• Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation. (PMID:34331014)
• Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers. (PMID:34870550)
• Decitabine Enhances Acute Myeloid Leukemia Cell Apoptosis through SH3BGRL Upregulation. (PMID:34963436)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3bgrl	ENSDARG00000058302
mus_musculus	Sh3bgrl	ENSMUSG00000031246
rattus_norvegicus	Sh3bgrl1	ENSRNOG00000069303

Paralogs (3): SH3BGRL3 (ENSG00000142669), SH3BGR (ENSG00000185437), SH3BGRL2 (ENSG00000198478)

Protein

Protein identifiers

Adapter SH3BGRL — O75368 (reviewed: O75368)

Alternative names: SH3 domain-binding glutamic acid-rich-like protein 1

All UniProt accessions (2): O75368, V9HW48

UniProt curated annotations — full annotation on UniProt →

Function. Appears to function as an adapter protein that bridges proteins together or proteins with mRNAs. May function as a ubiquitin ligase-substrate adapter. Additionally, associates with translating cytoplasmic ribosomes and may promote the expression of specific mRNAs.

Subunit / interactions. Monomer. Interacts with PFN1/Profilin-1. Interacts with ERBB2. Interacts with ATG12. Interacts with BECN1. Interacts with translating ribosomes.

Subcellular location. Cytoplasm. Cytosol. Cell membrane.

Tissue specificity. Ubiquitous.

Disease relevance. Promotes breast cancer progression by enhancing the interaction between E3 ligase STUB1 and PFN1, thereby promoting proteasomal degradation of PFN1 and subsequent activation of downstream signaling pathways including PI3K/AKT, NF-kB and WNT. Promotes autophagy presumably by stabilizing the ubuiquitin-like protein ATG12. Enhances mRNA translation of E3 ligase STUB1 and the autophagy-related protein PIK3C3. Promotes activation and phosphorylation of ERBB2 at ‘Tyr-877’ and ‘Tyr-1196’, and prolongs localization of ERBB2 to the cell membrane. Breast cancer patients with SH3BGRL overexpression usually experience frequent relapse and poor prognosis.

Domain organisation. The SH3-binding motif is buried in the tertiary structure, and it is therefore unclear whether it directly mediates protein-binding.

Similarity. Belongs to the SH3BGR family.

RefSeq proteins (1): NP_003013* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006993	Glut_rich_SH3-bd	Family
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR051033	SH3BGR	Family

Pfam: PF04908

UniProt features (17 total): helix 6, strand 5, region of interest 2, sequence conflict 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1U6T	X-RAY DIFFRACTION	1.9
1WRY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75368-F1	95.37	0.91

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 270 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, MODULE_97, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MORF_HDAC1, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_182, GOBP_TRANSLATIONAL_INITIATION, GGGTGGRR_PAX4_03, GOLDRATH_ANTIGEN_RESPONSE, GOBP_TRANSLATION, RODRIGUES_NTN1_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_TRANSLATIONAL_INITIATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, MILI_PSEUDOPODIA_HAPTOTAXIS_UP

GO Biological Process (2): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of cytoplasmic translational initiation (GO:1904690)

GO Molecular Function (3): SH3 domain binding (GO:0017124), protein-RNA adaptor activity (GO:0140517), ubiquitin-like ligase-substrate adaptor activity (GO:1990756)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
cytoplasmic translational initiation	1
positive regulation of translational initiation	1
regulation of cytoplasmic translational initiation	1
protein domain specific binding	1
protein-macromolecule adaptor activity	1
enzyme-substrate adaptor activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
extracellular vesicle	1

Protein interactions and networks

STRING

1082 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3BGRL	CNGB1	Q14028	834
SH3BGRL	HMGN1	P05114	834
SH3BGRL	LCA5L	O95447	568
SH3BGRL	PSMG1	O95456	531
SH3BGRL	APOOL	Q6UXV4	526
SH3BGRL	TMEM150A	Q86TG1	464
SH3BGRL	PHKB	Q93100	461
SH3BGRL	RPS6KA6	Q9UK32	459
SH3BGRL	KLHL4	Q9C0H6	431
SH3BGRL	EGFR	P00533	420
SH3BGRL	BLMH	Q13867	400
SH3BGRL	FRMD4A	Q9P2Q2	399
SH3BGRL	CYLC1	P35663	394
SH3BGRL	NDN	Q99608	394
SH3BGRL	BRWD1	Q9NSI6	388

IntAct

10 interactions, top by confidence:

A	B	Type	Score
SH3BGRL	EGFR	psi-mi:“MI:0915”(physical association)	0.680
EGFR	SH3BGRL	psi-mi:“MI:0915”(physical association)	0.680
SH3BGRL		psi-mi:“MI:0915”(physical association)	0.370
SH3BGRL	MYO1C	psi-mi:“MI:0914”(association)	0.350
RP9	C1orf226	psi-mi:“MI:0914”(association)	0.350
SH3BGRL	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
	SH3BGRL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (161): SH3BGRL (Co-fractionation), SH3BGRL (Co-fractionation), SH3BGRL (Affinity Capture-MS), SH3BGRL (Affinity Capture-MS), SH3BGRL (Affinity Capture-MS), SH3BGRL (Affinity Capture-MS), LYPLAL1 (Co-fractionation), AK1 (Co-fractionation), AK2 (Co-fractionation), AK4 (Co-fractionation), HINT1 (Co-fractionation), DCXR (Co-fractionation), COA4 (Co-fractionation), DGUOK (Co-fractionation), FABP3 (Co-fractionation)

ESM2 similar proteins: A1Z8J0, A4IFC4, A8XT16, O14078, O75368, P00276, P0DOQ9, P0DOR0, P17695, P20690, P32642, P34277, P34345, P68690, P68691, P68692, P79764, P81706, Q03835, Q05926, Q09652, Q28FJ0, Q39591, Q3KPU0, Q4R7R5, Q54QV7, Q556G3, Q58DU7, Q5REQ9, Q5RFN7, Q65XA0, Q6AXY0, Q6GMK7, Q6RZN3, Q71A38, Q76ZV3, Q775X4, Q77TL9, Q78Y63, Q7T0M3

Diamond homologs: A4IFC4, B2RZ27, O75368, P55822, Q28FJ0, Q3KPU0, Q3ZCL8, Q4R7R5, Q58DU7, Q5RC61, Q5REQ9, Q5RFN7, Q6GMK7, Q7T0M3, Q8BG73, Q91VW3, Q9H299, Q9JJU8, Q9NFP5, Q9UJC5, Q9WUZ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1140 predictions. Top by Δscore:

Variant	Effect	Δscore
X:81277165:GCGGG:G	donor_gain	1.0000
X:81277166:CGGG:C	donor_gain	1.0000
X:81277167:GGG:G	donor_gain	1.0000
X:81277167:GGGG:G	donor_gain	1.0000
X:81277168:GG:G	donor_gain	1.0000
X:81277168:GGG:G	donor_gain	1.0000
X:81277169:GG:G	donor_gain	1.0000
X:81277170:G:GG	donor_gain	1.0000
X:81278326:T:G	acceptor_gain	1.0000
X:81278329:A:G	acceptor_gain	1.0000
X:81202200:G:GT	donor_gain	0.9900
X:81202243:GCG:G	donor_gain	0.9900
X:81202252:A:T	donor_gain	0.9900
X:81276975:T:TA	acceptor_gain	0.9900
X:81276979:CCTA:C	acceptor_loss	0.9900
X:81276980:CTAG:C	acceptor_loss	0.9900
X:81276981:TAGAT:T	acceptor_loss	0.9900
X:81276982:A:AG	acceptor_gain	0.9900
X:81276983:G:GG	acceptor_gain	0.9900
X:81278325:A:AG	acceptor_gain	0.9900
X:81278326:TCAA:T	acceptor_loss	0.9900
X:81278328:A:AG	acceptor_gain	0.9900
X:81278328:AAG:A	acceptor_gain	0.9900
X:81278329:A:AG	acceptor_loss	0.9900
X:81278330:G:GG	acceptor_gain	0.9900
X:81278408:AAAGG:A	donor_loss	0.9900
X:81278409:AAG:A	donor_loss	0.9900
X:81278410:AG:A	donor_loss	0.9900
X:81278411:GGT:G	donor_loss	0.9900
X:81278413:T:G	donor_loss	0.9900

AlphaMissense

746 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:81277084:T:C	M49T	0.999
X:81277014:T:C	F26L	0.997
X:81277016:C:A	F26L	0.997
X:81277016:C:G	F26L	0.997
X:81277138:C:A	P67H	0.997
X:81277146:T:C	F70L	0.997
X:81277148:C:A	F70L	0.997
X:81277148:C:G	F70L	0.997
X:81276998:A:C	Q20H	0.996
X:81276998:A:T	Q20H	0.996
X:81277015:T:C	F26S	0.996
X:81277050:G:C	D38H	0.996
X:81277075:G:C	R46P	0.996
X:81278379:T:C	F94L	0.996
X:81278381:C:A	F94L	0.996
X:81278381:C:G	F94L	0.996
X:81278383:T:C	L95S	0.996
X:81202237:T:C	S13P	0.995
X:81276989:G:C	K17N	0.995
X:81276989:G:T	K17N	0.995
X:81277051:A:C	D38A	0.995
X:81277137:C:T	P67S	0.995
X:81278352:G:C	A85P	0.995
X:81202235:G:A	G12D	0.994
X:81276997:A:C	Q20P	0.994
X:81277135:C:A	P66Q	0.994
X:81277167:G:T	G77W	0.994
X:81278380:T:C	F94S	0.994
X:81277000:A:C	Q21P	0.993
X:81277051:A:G	D38G	0.993

dbSNP variants (sampled 300 via entrez): RS1000047803 (X:81207116 G>T), RS1000055491 (X:81232604 ACT>A,ACTCT,ACTCTCT), RS1000070790 (X:81206640 T>G), RS1000102812 (X:81293727 G>A), RS1000167202 (X:81296873 A>G), RS1000173876 (X:81294971 C>T), RS1000278185 (X:81254252 T>C), RS1000302754 (X:81237450 A>G), RS1000433832 (X:81251375 C>T), RS1000462423 (X:81247287 G>A,T), RS1000493438 (X:81245368 T>A), RS1000500288 (X:81298532 A>G,T), RS1000534784 (X:81268339 T>A,G), RS1000543115 (X:81247220 T>C), RS1000613358 (X:81244883 A>G)

Disease associations

OMIM: gene MIM:300190 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	4
Air Pollutants	increases oxidation, decreases expression, affects cotreatment, increases abundance	3
Valproic Acid	affects expression, decreases expression, decreases methylation	3
Arsenic Trioxide	decreases expression, increases response to substance	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
bufotalin	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
1-UFT protocol	decreases response to substance	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
quinocetone	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1

Clinical trials (associated diseases)

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