SH3RF1

Summary

SH3RF1 (SH3 domain containing ring finger 1, HGNC:17650) is a protein-coding gene on chromosome 4q32.3-q33, encoding E3 ubiquitin-protein ligase SH3RF1 (Q7Z6J0). Has E3 ubiquitin-protein ligase activity.

This gene encodes a protein containing an N-terminus RING-finger, four SH3 domains, and a region implicated in binding of the Rho GTPase Rac. Via the RING-finger, the encoded protein has been shown to function as an ubiquitin-protein ligase involved in protein sorting at the trans-Golgi network. The encoded protein may also act as a scaffold for the c-Jun N-terminal kinase signaling pathway, facilitating the formation of a functional signaling module.

Source: NCBI Gene 57630 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 121 total
• MANE Select transcript: NM_020870

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17650
Approved symbol	SH3RF1
Name	SH3 domain containing ring finger 1
Location	4q32.3-q33
Locus type	gene with protein product
Status	Approved
Aliases	POSH, RNF142, KIAA1494
Ensembl gene	ENSG00000154447
Ensembl biotype	protein_coding
OMIM	618642
Entrez	57630

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000284637, ENST00000502315, ENST00000508685, ENST00000510806, ENST00000511421, ENST00000871180, ENST00000924372, ENST00000924373

RefSeq mRNA: 1 — MANE Select: NM_020870 NM_020870

CCDS: CCDS34099

Canonical transcript exons

ENST00000284637 — 12 exons

Exon	Start	End
ENSE00001016003	169094259	169096687
ENSE00001151908	169106847	169107205
ENSE00001306975	169268820	169269307
ENSE00001358980	169270859	169270956
ENSE00003500983	169156404	169156679
ENSE00003508448	169122100	169122266
ENSE00003515259	169116269	169116630
ENSE00003540149	169117523	169117782
ENSE00003577645	169136318	169136620
ENSE00003581806	169130046	169130156
ENSE00003613736	169155480	169155575
ENSE00003656728	169120819	169120989

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 95.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.8337 / max 146.0693, expressed in 1627 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54801	8.3984	1532
54802	1.8543	1056
54804	0.8176	474
54803	0.7149	415
54800	0.0484	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	95.94	gold quality
ileal mucosa	UBERON:0000331	95.24	gold quality
palpebral conjunctiva	UBERON:0001812	95.02	gold quality
kidney epithelium	UBERON:0004819	94.28	gold quality
pancreatic ductal cell	CL:0002079	93.21	gold quality
endothelial cell	CL:0000115	92.47	silver quality
germinal epithelium of ovary	UBERON:0001304	91.47	gold quality
eye	UBERON:0000970	91.30	gold quality
ventricular zone	UBERON:0003053	91.28	gold quality
colonic mucosa	UBERON:0000317	90.81	gold quality
jejunal mucosa	UBERON:0000399	90.37	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.27	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.26	gold quality
pylorus	UBERON:0001166	89.66	gold quality
nasal cavity epithelium	UBERON:0005384	89.14	gold quality
amniotic fluid	UBERON:0000173	87.23	gold quality
epithelium of mammary gland	UBERON:0003244	86.21	gold quality
mammary duct	UBERON:0001765	86.18	gold quality
stromal cell of endometrium	CL:0002255	86.05	gold quality
renal medulla	UBERON:0000362	85.84	gold quality
tibialis anterior	UBERON:0001385	85.77	gold quality
synovial joint	UBERON:0002217	85.75	gold quality
layer of synovial tissue	UBERON:0007616	85.41	gold quality
visceral pleura	UBERON:0002401	85.24	gold quality
jejunum	UBERON:0002115	85.19	gold quality
duodenum	UBERON:0002114	85.13	gold quality
Brodmann (1909) area 46	UBERON:0006483	85.09	gold quality
islet of Langerhans	UBERON:0000006	84.96	gold quality
saphenous vein	UBERON:0007318	84.87	gold quality
bronchial epithelial cell	CL:0002328	84.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	2128.83
E-GEOD-81608	yes	17.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, EWSR1

miRNA regulators (miRDB)

211 targeting SH3RF1, 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-3163	100.00	77.23	8605
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-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
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-590-3P	99.96	74.34	6478

Literature-anchored findings (GeneRIF, showing 11)

• POSH disassociates from the JNK complex after phosphorylation of MLK3 by Akt2, which leads to down-regulation of the JNK signaling pathway (PMID:14504284)
• A previously undescribed step in HIV biogenesis that suggests a direct function for hPOSH-mediated ubiquitination in protein sorting at the trans-Golgi network. (PMID:15659549)
• Results identified ALIX as an ubiquitination substrate of POSH and indicate that POSH and ALIX cooperate to facilitate efficient virus release. (PMID:19393081)
• POSH inhibits ROMK channels by enhancing dynamin-dependent and clathrin-independent endocytosis and by stimulating ubiquitination of ROMK channels. (PMID:19710010)
• POSH promotes cell survival in Drosophila and in human rheumatoid arthritis synovial fibroblasts (PMID:20974134)
• The data presented here define POSH and Siah2 as important mediators of death receptor mediated apoptosis and suggest targeting the interaction of these two E3 ligases is a promising novel cancer therapeutic strategy. (PMID:21586138)
• We found a genome-wide significant association for rs2282987 in CDK6 and a consistent association for rs2706748 in SH3RF1 . (PMID:23644744)
• Data show that the two N-terminal SH3 domains of SH3 domain containing ring finger 1 (SH3RF1) protein interact with FAT1 protein. (PMID:28129444)
• These results show that POSH plays a critical role in the progression of epileptic seizures via N-methyl-D-aspartate receptor trafficking (PMID:29057721)
• Assessing the role of SH3RF1 and SH3RF2 polymorphisms in susceptibility to tuberculosis: A case-control study in the Han Chinese population. (PMID:33129950)
• This publication pertains to studies in mice. (PMID:9482736)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3rf1	ENSDARG00000070470
mus_musculus	Sh3rf1	ENSMUSG00000031642
rattus_norvegicus	Sh3rf1	ENSRNOG00000010358
drosophila_melanogaster	Dlish	FBGN0034264
caenorhabditis_elegans		WBGENE00012891
caenorhabditis_elegans		WBGENE00015128

Paralogs (12): SORBS1 (ENSG00000095637), SH3GLB1 (ENSG00000097033), NCF4 (ENSG00000100365), SH3GL2 (ENSG00000107295), SH3D19 (ENSG00000109686), SORBS3 (ENSG00000120896), SH3GL3 (ENSG00000140600), SH3GL1 (ENSG00000141985), SH3GLB2 (ENSG00000148341), SORBS2 (ENSG00000154556), SH3RF2 (ENSG00000156463), SH3RF3 (ENSG00000172985)

Protein

Protein identifiers

E3 ubiquitin-protein ligase SH3RF1 — Q7Z6J0 (reviewed: Q7Z6J0)

Alternative names: Plenty of SH3s, RING finger protein 142, RING-type E3 ubiquitin transferase SH3RF1, SH3 domain-containing RING finger protein 1, SH3 multiple domains protein 2

All UniProt accessions (4): Q7Z6J0, D6RAL3, D6RHX5, H0YA90

UniProt curated annotations — full annotation on UniProt →

Function. Has E3 ubiquitin-protein ligase activity. In the absence of an external substrate, it can catalyze self-ubiquitination. Stimulates ubiquitination of potassium channel KCNJ1, enhancing its dynamin-dependent and clathrin-independent endocytosis. Acts as a scaffold protein that coordinates with MAPK8IP1/JIP1 in organizing different components of the JNK pathway, including RAC1 or RAC2, MAP3K11/MLK3 or MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and/or MAPK9/JNK2 into a functional multiprotein complex to ensure the effective activation of the JNK signaling pathway. Regulates the differentiation of CD4(+) and CD8(+) T-cells and promotes T-helper 1 (Th1) cell differentiation. Regulates the activation of MAPK8/JNK1 and MAPK9/JNK2 in CD4(+) T-cells and the activation of MAPK8/JNK1 in CD8(+) T-cells. Plays a crucial role in the migration of neocortical neurons in the developing brain. Controls proper cortical neuronal migration and the formation of proximal cytoplasmic dilation in the leading process (PCDLP) in migratory neocortical neurons by regulating the proper localization of activated RAC1 and F-actin assembly. (Microbial infection) Plays an essential role in the targeting of HIV-1 Gag to the plasma membrane, this function is dependent on its RING domain, and hence its E3 ligase activity.

Subunit / interactions. Interacts with RAC1; in a GTP-dependent manner. Interacts with MAP3K10/MLK2 and MAP3K11/MLK3. Interacts with MAPK8IP; this interaction leads to the PJAC complex (POSH-JIP or SH3RF1/MAPK8IP apoptotic complex) with a 1:1 ratio. Interacts with SIAH1. Interacts with HERP1. Probably part of a signaling complex that may contain SH3RF1, MAPK8IP, DLK1, MAP2K4/MKK4, MAP2K7/MKK7, MAPK8/JNK1, MAPK9/JNK2, AKT1 and AKT2. Found in a complex with RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2. Found in a complex with RAC1, MAP3K11/MLK3, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1. Interacts with SH3RF2.

Subcellular location. Cytoplasm. Perinuclear region. Cell projection. Lamellipodium. Golgi apparatus. trans-Golgi network.

Post-translational modifications. Phosphorylated at Ser-304 by AKT1 and AKT2. When phosphorylated, it has reduced ability to bind Rac. Autoubiquitinated. Ubiquitinated by SH3RF2, leading to proteasome-mediated degradation.

Domain organisation. The RING finger domain is required for ubiquitin ligase activity and autoubiquitination.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the SH3RF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z6J0-1	1	yes
Q7Z6J0-3	2

RefSeq proteins (1): NP_065921* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR035795	SH3RF1_SH3_2	Domain
IPR035816	SH3RF1/SH3RF3_SH3_4	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR050384	Endophilin_SH3RF	Family

Pfam: PF00018, PF13923, PF14604

UniProt features (30 total): region of interest 7, mutagenesis site 6, compositionally biased region 5, domain 4, modified residue 3, splice variant 2, chain 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7NZC	X-RAY DIFFRACTION	1.11
9RFF	X-RAY DIFFRACTION	1.25
7NZD	X-RAY DIFFRACTION	1.45
9RFB	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z6J0-F1	59.24	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 (3): 304, 532, 735

Mutagenesis-validated functional residues (6):

Position	Phenotype
14	loss of ubl activity.
28	significant reduction in autoubiquitination; when associated with a-30.
30	significant reduction in autoubiquitination; when associated with a-28.
304	decreased level of phosphorylation and no change in the ability to induce apoptosis.
304	decreased level of phosphorylation and rac-binding ability and important loss of the ability to induce apoptosis.
304	decreased rac-binding ability.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-9013424	RHOV GTPase cycle
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 270 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_FGF3, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, CCAWYNNGAAR_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_RESPONSE_TO_CORTICOSTEROID, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE

GO Biological Process (11): neuron migration (GO:0001764), protein ubiquitination (GO:0016567), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of apoptotic process (GO:0043066), regulation of CD4-positive, alpha-beta T cell differentiation (GO:0043370), positive regulation of JNK cascade (GO:0046330), protein autoubiquitination (GO:0051865), response to aldosterone (GO:1904044), regulation of CD8-positive, alpha-beta T cell proliferation (GO:2000564), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), MAPK cascade (GO:0000165)

GO Molecular Function (6): MAP kinase scaffold activity (GO:0005078), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): Golgi apparatus (GO:0005794), cytosol (GO:0005829), lamellipodium (GO:0030027), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
RHO GTPase cycle	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
cell migration	1
generation of neurons	1
protein modification by small protein conjugation	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
CD4-positive, alpha-beta T cell differentiation	1
regulation of alpha-beta T cell differentiation	1
regulation of CD4-positive, alpha-beta T cell activation	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
protein ubiquitination	1
response to mineralocorticoid	1
response to alcohol	1
response to ketone	1
CD8-positive, alpha-beta T cell proliferation	1
regulation of alpha-beta T cell proliferation	1
regulation of CD8-positive, alpha-beta T cell activation	1
extrinsic apoptotic signaling pathway	1
negative regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
intracellular signaling cassette	1
MAPK cascade	1
signaling adaptor activity	1
mitogen-activated protein kinase binding	1
protein complex scaffold activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
endomembrane system	1

Protein interactions and networks

STRING

740 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3RF1	MAPK9	P45984	936
SH3RF1	AKT1	P31749	711
SH3RF1	MAP3K11	Q16584	632
SH3RF1	AKT2	P31751	507
SH3RF1	G3V2F7	G3V2F7	505
SH3RF1	MAP3K13	O43283	486
SH3RF1	UBE2K	P27924	479
SH3RF1	H0Y8G9	H0Y8G9	474
SH3RF1	HERC3	Q15034	474
SH3RF1	TRIM36	Q9NQ86	471
SH3RF1	JUN	P05412	464
SH3RF1	CUL2	Q13617	462
SH3RF1	NEDD4L	Q96PU5	457
SH3RF1	CSKMT	A8MUP2	452
SH3RF1	MYLIP	Q8WY64	452

IntAct

36 interactions, top by confidence:

A	B	Type	Score
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
SIAH2	SH3RF1	psi-mi:“MI:0915”(physical association)	0.630
SH3RF1	SIAH2	psi-mi:“MI:0915”(physical association)	0.630
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
RAC1	SH3RF1	psi-mi:“MI:0407”(direct interaction)	0.590
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
SH3RF1	YWHAE	psi-mi:“MI:0915”(physical association)	0.500
SFN	SH3RF1	psi-mi:“MI:0915”(physical association)	0.500
AKT1	SH3RF1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
AKT2	SH3RF1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SH3RF1	PAK2	psi-mi:“MI:0915”(physical association)	0.400
ADAM15	SH3RF1	psi-mi:“MI:0915”(physical association)	0.400
SH3RF1	UBC	psi-mi:“MI:0915”(physical association)	0.400
SH3RF1	bipA	psi-mi:“MI:0915”(physical association)	0.370
SEMA6A	SH3RF1	psi-mi:“MI:0915”(physical association)	0.370
SIAH2	OGDH	psi-mi:“MI:0914”(association)	0.350
TANK	CNOT1	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
SFN	ANKRD17	psi-mi:“MI:0914”(association)	0.350
YWHAQ	MCRIP1	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
NINL	CCDC66	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (149): SH3RF1 (Proximity Label-MS), HERPUD1 (Two-hybrid), HERPUD1 (Affinity Capture-Western), SH3RF1 (Affinity Capture-Western), SH3RF1 (Reconstituted Complex), SH3RF1 (Biochemical Activity), HERPUD1 (Biochemical Activity), UBE2N (Reconstituted Complex), UBE2D3 (Reconstituted Complex), SH3RF1 (Two-hybrid), SH3RF1 (Affinity Capture-Western), FAT1 (Affinity Capture-Western), SH3RF1 (Proximity Label-MS), SH3RF1 (Affinity Capture-RNA), GRIN1 (Affinity Capture-Western)

ESM2 similar proteins: A1L1I3, A5PKW4, O08919, O70405, O75385, O75420, O75553, P16554, P42128, P49757, P53814, P85037, P97318, P98081, Q04637, Q2LC84, Q3UCQ1, Q4KMP7, Q5DTT2, Q5I1X5, Q5RBR0, Q5VZ18, Q69ZH9, Q69ZI1, Q7TN02, Q7Z6J0, Q80VC9, Q80XI3, Q80Z38, Q86V15, Q8BGT6, Q8BHL3, Q8BSD5, Q8C120, Q8CI12, Q8IY33, Q8K4J6, Q8N3F8, Q8TEH3, Q8TEJ3

Diamond homologs: A4IF63, A5D7F8, A5D8S5, D2GXS7, D3ZHA0, D3ZQG6, F7H9X2, O70277, O75369, O75382, P13466, P21333, Q14315, Q1XHU0, Q28E95, Q3UIW8, Q5RBR0, Q60953, Q69ZI1, Q6NRD3, Q71F54, Q7Z6J0, Q80X90, Q80XJ2, Q8BTM8, Q8C120, Q8TEJ3, Q8VHX6, Q9C040, Q9ESN6, Q9HCM9, Q9R1R2, Q9VEN1, A0JNB0, A1CEK6, A1DFN5, A1Y2K1, A2QW93, A4RF61, A6QLK6

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
SH3RF1	up-regulates	MAP3K12	binding
SH3RF1	up-regulates	MAPK8IP1	binding
AKT	down-regulates	SH3RF1	phosphorylation
AKT2	down-regulates	SH3RF1	phosphorylation
AKT1	down-regulates	SH3RF1	phosphorylation
Ub:E2	“up-regulates activity”	SH3RF1	ubiquitination
SH3RF1	“down-regulates quantity”	HGS	ubiquitination
SH3RF1	“up-regulates activity”	HERPUD1	ubiquitination
SH3RF1	up-regulates	MAPK8	binding
SH3RF1	up-regulates	RAC2	binding
SH3RF1	up-regulates	MAP2K4	binding
SH3RF1	up-regulates	MAP2K7	binding
SH3RF1	up-regulates	MAP3K10	binding
SH3RF1	up-regulates	MAP3K11	binding

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
Activation of BAD and translocation to mitochondria	9	228.4×	2e-18
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	156.8×	5e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	156.8×	5e-13
Activation of BH3-only proteins	9	149.0×	2e-16
Intrinsic Pathway for Apoptosis	9	87.8×	4e-14
RHO GTPases activate PKNs	8	84.6×	1e-12
FOXO-mediated transcription	7	78.4×	9e-11
Apoptosis	10	56.0×	7e-14

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	53.9×	9e-06
insulin receptor signaling pathway	5	32.6×	6e-05
phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	31.0×	6e-05
intracellular protein localization	7	21.6×	9e-06
cell migration	5	9.0×	7e-03
negative regulation of apoptotic process	8	8.2×	4e-04
intracellular signal transduction	6	6.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	101
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2428 predictions. Top by Δscore:

Variant	Effect	Δscore
4:169117587:AG:A	donor_gain	1.0000
4:169120813:CCATA:C	donor_loss	1.0000
4:169120814:CATAC:C	donor_loss	1.0000
4:169120815:ATAC:A	donor_loss	1.0000
4:169120816:TA:T	donor_loss	1.0000
4:169120817:A:AT	donor_loss	1.0000
4:169120985:CATAC:C	acceptor_gain	1.0000
4:169120987:TAC:T	acceptor_gain	1.0000
4:169130044:A:AC	donor_gain	1.0000
4:169130044:ACT:A	donor_gain	1.0000
4:169130045:C:CC	donor_gain	1.0000
4:169130045:CT:C	donor_gain	1.0000
4:169130045:CTC:C	donor_gain	1.0000
4:169136313:TTTA:T	donor_loss	1.0000
4:169136314:TTAC:T	donor_loss	1.0000
4:169136315:TACC:T	donor_loss	1.0000
4:169136316:A:T	donor_loss	1.0000
4:169136317:C:T	donor_loss	1.0000
4:169136616:TTAAA:T	acceptor_gain	1.0000
4:169136617:TAAA:T	acceptor_gain	1.0000
4:169136619:AA:A	acceptor_gain	1.0000
4:169136620:ACTG:A	acceptor_loss	1.0000
4:169136621:C:CC	acceptor_gain	1.0000
4:169136621:CTGC:C	acceptor_loss	1.0000
4:169136631:A:T	acceptor_gain	1.0000
4:169136635:A:T	acceptor_gain	1.0000
4:169156398:CTTTA:C	donor_loss	1.0000
4:169156400:TTA:T	donor_loss	1.0000
4:169156435:T:TA	donor_gain	1.0000
4:169156549:T:TA	donor_gain	1.0000

AlphaMissense

5731 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:169096534:A:C	F884L	1.000
4:169096534:A:T	F884L	1.000
4:169096535:A:C	F884C	1.000
4:169096535:A:G	F884S	1.000
4:169096536:A:G	F884L	1.000
4:169096544:G:T	P881Q	1.000
4:169096546:G:C	F880L	1.000
4:169096546:G:T	F880L	1.000
4:169096547:A:C	F880C	1.000
4:169096547:A:G	F880S	1.000
4:169096548:A:G	F880L	1.000
4:169096553:C:T	G878D	1.000
4:169096554:C:G	G878R	1.000
4:169096580:C:T	G869D	1.000
4:169096581:C:G	G869R	1.000
4:169096588:C:A	W866C	1.000
4:169096588:C:G	W866C	1.000
4:169096590:A:G	W866R	1.000
4:169096590:A:T	W866R	1.000
4:169096613:A:T	V858D	1.000
4:169096619:A:T	V856E	1.000
4:169096637:A:G	L850P	1.000
4:169096637:A:T	L850H	1.000
4:169096643:A:G	L848P	1.000
4:169096643:A:T	L848H	1.000
4:169096668:A:C	Y840D	1.000
4:169120843:C:T	G498D	1.000
4:169120846:G:T	P497H	1.000
4:169120847:G:A	P497S	1.000
4:169120847:G:T	P497T	1.000

dbSNP variants (sampled 300 via entrez): RS1000004472 (4:169213702 C>A,T), RS1000033456 (4:169227880 A>G), RS10000418 (4:169152535 C>T), RS1000051019 (4:169183059 A>C,T), RS1000075170 (4:169114421 T>A), RS1000103094 (4:169260142 G>A), RS10001105 (4:169235862 G>A), RS1000134118 (4:169156042 G>T), RS1000135521 (4:169204739 C>T), RS1000149917 (4:169272120 C>T), RS1000151944 (4:169122779 G>A), RS1000161739 (4:169255825 T>C), RS1000177137 (4:169201384 C>G,T), RS1000182844 (4:169251775 C>T), RS1000203110 (4:169110495 T>C)

Disease associations

OMIM: gene MIM:618642 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003427_175	Alzheimer disease and age of onset	6.000000e-07
GCST003542_34	Night sleep phenotypes	8.000000e-06
GCST003992_44	Photic sneeze reflex	9.000000e-15
GCST007201_332	Schizophrenia	6.000000e-08
GCST008152_30	Weight	2.000000e-07
GCST008157_53	Body fat mass	2.000000e-06
GCST008158_149	Body mass index	7.000000e-06
GCST008595_153	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	4.000000e-09
GCST011494_99	Daytime nap	4.000000e-07

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0004338	body weight
EFO:0004340	body mass index
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, decreases expression, increases expression	6
Tetrachlorodibenzodioxin	increases expression	3
Valproic Acid	affects expression, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
afimoxifene	decreases expression, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
tobacco tar	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	increases phosphorylation	1
1-nitropyrene	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Azathioprine	increases expression	1
Cadmium	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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