SMURF2

Summary

SMURF2 (SMAD specific E3 ubiquitin protein ligase 2, HGNC:16809) is a protein-coding gene on chromosome 17q23.3-q24.1, encoding E3 ubiquitin-protein ligase SMURF2 (Q9HAU4). E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

Enables SMAD binding activity; identical protein binding activity; and ubiquitin protein ligase activity. Involved in negative regulation of transforming growth factor beta receptor signaling pathway; positive regulation of trophoblast cell migration; and ubiquitin-dependent protein catabolic process. Located in nuclear speck. Part of ubiquitin ligase complex.

Source: NCBI Gene 64750 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 88 total
• Druggable target: yes
• MANE Select transcript: NM_022739

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16809
Approved symbol	SMURF2
Name	SMAD specific E3 ubiquitin protein ligase 2
Location	17q23.3-q24.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000108854
Ensembl biotype	protein_coding
OMIM	605532
Entrez	64750

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000262435, ENST00000578200, ENST00000578386, ENST00000580072, ENST00000580246, ENST00000582081, ENST00000585301, ENST00000935092, ENST00000935093

RefSeq mRNA: 1 — MANE Select: NM_022739 NM_022739

CCDS: CCDS32707

Canonical transcript exons

ENST00000262435 — 19 exons

Exon	Start	End
ENSE00001110065	64598382	64598490
ENSE00001213862	64606602	64606640
ENSE00001331843	64661829	64662307
ENSE00002732551	64542282	64545947
ENSE00003458226	64591084	64591149
ENSE00003470544	64547600	64547801
ENSE00003473650	64578492	64578576
ENSE00003475001	64583461	64583544
ENSE00003475895	64580789	64580991
ENSE00003486101	64561500	64561603
ENSE00003497833	64593440	64593573
ENSE00003512387	64562771	64562966
ENSE00003538897	64586086	64586170
ENSE00003560284	64555820	64555998
ENSE00003571656	64557608	64557722
ENSE00003592531	64551584	64551704
ENSE00003601944	64571798	64571956
ENSE00003605078	64554856	64554993
ENSE00003665397	64546263	64546338

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5393 / max 307.1147, expressed in 1777 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167597	11.2317	1769
167596	1.3654	553
167591	0.8599	410
167595	0.0822	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.83	gold quality
secondary oocyte	CL:0000655	95.74	gold quality
amniotic fluid	UBERON:0000173	94.55	gold quality
oocyte	CL:0000023	94.28	gold quality
pylorus	UBERON:0001166	94.25	gold quality
saphenous vein	UBERON:0007318	94.04	gold quality
mammary duct	UBERON:0001765	93.88	gold quality
visceral pleura	UBERON:0002401	93.18	gold quality
pericardium	UBERON:0002407	92.96	gold quality
caput epididymis	UBERON:0004358	92.71	gold quality
adrenal tissue	UBERON:0018303	92.53	gold quality
epithelium of mammary gland	UBERON:0003244	92.50	gold quality
calcaneal tendon	UBERON:0003701	92.45	gold quality
corpus epididymis	UBERON:0004359	92.21	gold quality
jejunal mucosa	UBERON:0000399	92.08	gold quality
medial globus pallidus	UBERON:0002477	91.92	gold quality
stromal cell of endometrium	CL:0002255	91.59	gold quality
colonic epithelium	UBERON:0000397	91.37	gold quality
cardia of stomach	UBERON:0001162	91.18	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.78	gold quality
ganglionic eminence	UBERON:0004023	90.76	gold quality
tendon	UBERON:0000043	90.67	gold quality
renal medulla	UBERON:0000362	90.67	gold quality
synovial joint	UBERON:0002217	90.66	gold quality
adult organism	UBERON:0007023	90.56	gold quality
cauda epididymis	UBERON:0004360	90.37	gold quality
urethra	UBERON:0000057	90.16	gold quality
parotid gland	UBERON:0001831	90.15	gold quality
skin of hip	UBERON:0001554	89.91	gold quality
vena cava	UBERON:0004087	89.85	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.56
E-CURD-89	no	153.58

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
KLF5	Repression

Upstream regulators (CollecTRI, top): ESR1, KLF5, SMAD7, ZNF165

miRNA regulators (miRDB)

188 targeting SMURF2, 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-9-5P	100.00	72.28	2361
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• Smurf2 recruits the Rb and p53 pathways for induction of cellular replicative senescence. (PMID:15574587)
• SMURF2 ubiquitin ligase is transcriptionally induced by TGFbeta. (PMID:15862290)
• A 2.1 A resolution X-ray crystal structure of the Smurf2 HECT domain reveals that it has a suboptimal E2 binding pocket that could be optimized by mutagenesis. (PMID:16061177)
• analysis of the WW domain recognition motif for the interaction of Smad7 and the E3 ubiquitin ligase Smurf2 (PMID:16641086)
• Autoinhibition of the HECT-type ubiquitin ligase SMURF2 through its C2 domain. (PMID:17719543)
• Ectopic expression of Smurf2 driven by the Col2a1 promoter accelerated the process of endochondral ossification including chondrocyte maturation and osteoblast differentiation through upregulation of beta-catenin (PMID:18052755)
• Smurf2 action may be a useful strategy for inhibition of cancer cell growth. (PMID:18181147)
• dysregulation of Smurf2 could contribute to an aberrant TGF-beta/Smad signaling in the pathogenesis of kidney fibrosis (PMID:18353873)
• A significant elevation in expression of SMURF2 in oral squamous cell carcinoma cells was seen in carbon and neon-irradiated cells. (PMID:18514338)
• These results suggest an important role for Smurf2 binding to TRAF2 in determining specific signalling outputs of TNF-R2. (PMID:18671942)
• Smurf2 is up-regulated during Osteoarthritis in humans (PMID:18821706)
• Inhibition of PI3K or mTOR reduced the level of Rap1B, which acts downstream of Rheb and mTOR. The ubiquitin E3 ligase Smurf2 mediates the restriction of Rap1B by initiating its degradation. (PMID:18842593)
• Smurf2 regulates the localization and stability of Mad2. (PMID:18852296)
• two related E3 ubiquitin ligases, Smurf1 and Smurf2, act in the same direction in TGF-beta family signaling but play opposite roles in cell migration. (PMID:18927080)
• Pin1 negatively regulates TGF-beta signaling by down-regulating Smad2/3 protein levels via induction of Smurf2-mediated ubiquitin-proteasomal degradation. (PMID:19122240)
• Results establish an important role for Smurf2 in breast cancer progression and indicate that Smurf2 is a novel regulator of breast cancer cell migration and invasion. (PMID:19155312)
• Smurf2 promotes trophoblast cell migration and invasion, and this function may involve downregulation of TGF-beta type I receptor. (PMID:19255252)
• Smurf2-mediated upregulation of beta-catenin through induction of proteasomal degradation of GSK-beta in chondrocytes may activate articular chondrocyte maturation and associated alteration of gene expression, the early events of osteoarthritis. (PMID:19481076)
• Data show that REDD1 is subject to ubiquitin-mediated degradation mediated by the CUL4A-DDB1-ROC1-beta-TRCP E3 ligase complex and through the activity of glycogen synthase kinase 3beta. (PMID:19557001)
• E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 is needed for COP1 for degradation via the ubiquitin-proteasome pathway. (PMID:19805145)
• Inhibition of Smad signaling may be achieved at the transcriptional level through c-Ski/receptor-Smad/co-mediator Smad4 interactions–REVIEW (PMID:19898560)
• These findings suggest that Smurf2 plays a significant role in the pathomechanism of progressive supranuclear palsy (PMID:20819168)
• SMURF2-mediated protective ubiquitination of EGFR may be responsible for EGFR overexpression in certain tumors. (PMID:21750651)
• RLIM directly binds to Smurf2, enhancing TGF-beta responsiveness in osteosarcoma U2OS cells. (PMID:21945933)
• SMURF2 is a novel E3 ubiquitin ligase for KLF5 and negatively regulates KLF5 by targeting it for proteasomal degradation. (PMID:21953463)
• mediates degradation of ubiquitinated HSP27 through the ubiquitin-proteasome pathway (PMID:21967197)
• In summary we established a new mechanism of IL17RB regulation-Smurf2 dependent degradation of its adaptor protein DAZAP2. (PMID:22070932)
• tumor suppression function that maintains genomic stability by control of the epigenetic landscape of histone modifications through RNF20 (PMID:22231558)
• TGFbeta induces expression of Smad7, Smurf2, and SIK1, the products of which physically and functionally interlink to control the activity of this pathway. (PMID:22378783)
• Smurf2 interacts with Smad7 to suppress TGF-beta-mediated liver fibrosis through the ubiquitin-dependent degradation of TbetaRI during the early period of liver fibrosis. (PMID:22624557)
• Depleting SMURF2 reduced MITF expression and substantially lowered the threshold for MEK inhibitor-induced apoptosis, and sensitized melanoma cells to the cytotoxic effects of selumetinib. (PMID:23250956)
• Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke. (PMID:23526793)
• This study showed that, by targeting SMURF2, NS3-4A appears to block the negative regulation of TGF-beta signaling, increasing the responsiveness of cells to TGF-beta. (PMID:23781096)
• Smurf2 mediates ubiquitination and degradation of YY1, a key germinal centre transcription factor. (PMID:24121673)
• Provide evidence of posttranscriptional downregulation of Smurf2 in triple-negative breast cancers, and demonstrate that the loss of RB function is involved in microRNA-mediated interference with Smurf2 translation. (PMID:24485087)
• The SMURF2:UBCH5 complex is critical in maintaining KRAS protein stability. (PMID:24709419)
• that Smurf2 is an important nonredundant negative regulator of virus-triggered type I IFN signaling by targeting VISA for K48-linked ubiquitination and degradation. (PMID:24729608)
• These results suggest a novel regulatory mechanism for YY1 function by Smurf2. (PMID:24803334)
• Results suggest that elevated transcription and expression levels of ubiquitin ligase E3s WWP1, Smurf1 and Smurf2 genes may be the mechanisms of occurrence, development and metastasis of prostate cancer. (PMID:25051198)
• Studies on Smurf2 and Nedd4 show that the C2 domain has the potential to regulate E3 activity by maintaining the HECT domain in a low-activity state where its ability for transthiolation and noncovalent Ubiquitin binding are impaired. (PMID:25438670)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	smurf2	ENSDARG00000038067
mus_musculus	Smurf2	ENSMUSG00000018363
rattus_norvegicus	Smurf2	ENSRNOG00000014623
drosophila_melanogaster	Smurf	FBGN0029006

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

E3 ubiquitin-protein ligase SMURF2 — Q9HAU4 (reviewed: Q9HAU4)

Alternative names: HECT-type E3 ubiquitin transferase SMURF2, SMAD ubiquitination regulatory factor 2, SMAD-specific E3 ubiquitin-protein ligase 2

All UniProt accessions (4): Q9HAU4, J3QLG1, J3QQM4, J3QRY2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Interacts with SMAD7 to trigger SMAD7-mediated transforming growth factor beta/TGF-beta receptor ubiquitin-dependent degradation, thereby down-regulating TGF-beta signaling. In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with AIMP1. Also forms a stable complex with TGF-beta receptor-mediated phosphorylated SMAD1, SMAD2 and SMAD3, and targets SMAD1 and SMAD2 for ubiquitination and proteasome-mediated degradation. SMAD2 may recruit substrates, such as SNON, for ubiquitin-dependent degradation. Negatively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation. Acts as an activator of ferroptosis by mediating ubiquitination and degradation of GSTP1, thereby preventing detoxification of 4-hydroxynonenal (4-HNE) reactive aldehyde. (Microbial infection) In case of filoviruses Ebola/EBOV and Marburg/MARV infection, the complex formed by viral matrix protein VP40 and SMURF2 facilitates virus budding.

Subunit / interactions. Interacts (via WW domains) with SMAD1. Interacts (via WW domains) with SMAD2 (via PY-motif). Interacts (via WW domains) with SMAD3 (via PY-motif). Interacts with SMAD6. Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its degradation. Does not interact with SMAD4; SMAD4 lacks a PY-motif. Interacts with AIMP1. Interacts with SNON. Interacts with STAMBP and RNF11. May interact with NDFIP1 and NDFIP2; this interaction induces the E3 ubiquitin-protein ligase activity. Interacts with TTC3. (Microbial infection) Interacts (via WW domains) with EBOV and MARV VP40 (via PPXY motif); the interaction facilitates VP40 virus-like particle budding.

Subcellular location. Nucleus. Cytoplasm. Cell membrane. Membrane raft.

Tissue specificity. Widely expressed.

Post-translational modifications. Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1. Ubiquitinated by the SCF(FBXL15) complex and TTC3, leading to its degradation by the proteasome. ‘Lys-48’-linked polyubiquitination mediated by TRAF4 at Lys-119 leads to SMURF2 proteasomal degradation.

Activity regulation. Activated by NDFIP1- and NDFIP2-binding.

Domain organisation. The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3). The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain. (Microbial infection) The WW domains mediate binding with matrix protein VP40.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_073576* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000569	HECT_dom	Domain
IPR001202	WW_dom	Domain
IPR024928	E3_ub_ligase_SMURF1	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR050409	E3_ubiq-protein_ligase	Family

Pfam: PF00168, PF00397, PF00632

Enzyme classification (BRENDA):

• EC 2.3.2.26 — HECT-type E3 ubiquitin transferase (BRENDA: 14 organisms, 64 substrates, 19 inhibitors, 5 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBC5B]-L-LYSINE	0.0046–0.037	5

UniProt features (83 total): strand 30, helix 24, mutagenesis site 12, turn 8, domain 5, chain 1, sequence conflict 1, active site 1, cross-link 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9FSH	X-RAY DIFFRACTION	2.08
1ZVD	X-RAY DIFFRACTION	2.1
6FX4	X-RAY DIFFRACTION	2.5
7M3Q	X-RAY DIFFRACTION	2.5
2DJY	SOLUTION NMR
2JQZ	SOLUTION NMR
2KXQ	SOLUTION NMR
2LTZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAU4-F1	77.54	0.37

Functional residue map

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

Catalytic / active sites (1): 716 (glycyl thioester intermediate)

Post-translational modifications (1): 119

Mutagenesis-validated functional residues (12):

Position	Phenotype
57	increases auto-ubiquitination; when associated with a-56.
251–284	abolishes interaction with smad2 and smad7.
297–330	abolishes interaction with smad7.
535	loss of catalytic activity.
547	partial loss of catalytic activity.
547	activates autocatalytic activity.
581	loss of catalytic activity.
716	loss of catalytic activity. increases smad7-bound tgf-beta receptors in membrane rafts. decreases interaction with ttc3.
716	loss of activity. loss of ability to ubiquitinate smad1 and smad2 and no down-regulation of smad1 and smad2 protein leve
29–30	increases auto-ubiquitination.
56	increases auto-ubiquitination; when associated with a-57.

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-4641257	Degradation of AXIN
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8941858	Regulation of RUNX3 expression and activity
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-170834	Signaling by TGF-beta Receptor Complex
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-3858494	Beta-catenin independent WNT signaling
R-HSA-392499	Metabolism of proteins
R-HSA-4086400	PCP/CE pathway
R-HSA-5358351	Signaling by Hedgehog
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9006936	Signaling by TGFB family members
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 336 (showing top): GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, XU_HGF_TARGETS_REPRESSED_BY_AKT1_UP, CCAWYNNGAAR_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, WANG_RECURRENT_LIVER_CANCER_UP, GOZGIT_ESR1_TARGETS_DN, AAGCCAT_MIR135A_MIR135B, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_493

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of DNA-templated transcription (GO:0045892), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of ferroptosis (GO:0160020), positive regulation of trophoblast cell migration (GO:1901165)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), identical protein binding (GO:0042802), SMAD binding (GO:0046332), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (9): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear speck (GO:0016607), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by TGFB family members	2
Signaling by WNT	2
Signaling by TGF-beta Receptor Complex	2
TGF-beta receptor signaling activates SMADs	1
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
PCP/CE pathway	1
TCF dependent signaling in response to WNT	1
Signaling by Hedgehog	1
Deubiquitination	1
Transcriptional regulation by RUNX3	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Signal Transduction	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transforming growth factor beta receptor signaling pathway	2
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to transforming growth factor beta stimulus	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
non-canonical Wnt signaling pathway	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
positive regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
positive regulation of cell migration	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
trophoblast cell migration	1
regulation of trophoblast cell migration	1
positive regulation of reproductive process	1
ubiquitin-like protein transferase activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

2236 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMURF2	SMAD7	O15105	998
SMURF2	SMAD2	Q15796	993
SMURF2	SMAD3	P84022	958
SMURF2	TGFBR1	P36897	945
SMURF2	USP15	Q9Y4E8	945
SMURF2	SMAD6	O43541	934
SMURF2	RNF11	Q9Y3C5	921
SMURF2	CTNNB1	P35222	828
SMURF2	STAMBP	O95630	821
SMURF2	SMAD4	Q13485	813
SMURF2	RNF111	Q6ZNA4	743
SMURF2	UBE2D1	P51668	726
SMURF2	SMAD5	Q99717	724
SMURF2	SKIL	P12756	690
SMURF2	RUNX2	Q13950	678

IntAct

162 interactions, top by confidence:

A	B	Type	Score
SMURF2	SMAD1	psi-mi:“MI:0407”(direct interaction)	0.850
SMAD1	SMURF2	psi-mi:“MI:0915”(physical association)	0.850
SMURF2	SMAD2	psi-mi:“MI:0407”(direct interaction)	0.810
SMURF2	SMAD2	psi-mi:“MI:0915”(physical association)	0.810
SMURF2	SMAD7	psi-mi:“MI:0407”(direct interaction)	0.800
SMAD7	SMURF2	psi-mi:“MI:0407”(direct interaction)	0.800
SMAD3	SMURF2	psi-mi:“MI:0915”(physical association)	0.800
SMAD7	SMURF2	psi-mi:“MI:0915”(physical association)	0.800
SMURF2	SMAD3	psi-mi:“MI:0915”(physical association)	0.800
SMURF2	SMAD3	psi-mi:“MI:0407”(direct interaction)	0.800
RNF11	SMURF2	psi-mi:“MI:0407”(direct interaction)	0.740
RNF11	SMURF2	psi-mi:“MI:0915”(physical association)	0.740
SMURF2	RNF11	psi-mi:“MI:0915”(physical association)	0.740
SMURF2	SMURF2	psi-mi:“MI:0407”(direct interaction)	0.710
SMURF2	SMURF2	psi-mi:“MI:0915”(physical association)	0.710
UBB	STAMBP	psi-mi:“MI:0220”(ubiquitination reaction)	0.680

BioGRID (480): SMURF2 (Biochemical Activity), UBE2L3 (Reconstituted Complex), SMURF2 (Protein-peptide), SMURF2 (Biochemical Activity), RHOA (Biochemical Activity), Rasd2 (Affinity Capture-Luminescence), Arhgef1 (Affinity Capture-Luminescence), Nek6 (Affinity Capture-Luminescence), Anapc5 (Affinity Capture-Luminescence), Rnf14 (Affinity Capture-Luminescence), Rnf2 (Affinity Capture-Luminescence), Ing2 (Affinity Capture-Luminescence), Gar1 (Affinity Capture-Luminescence), Smad3 (Affinity Capture-Luminescence), Smad6 (Affinity Capture-Luminescence)

ESM2 similar proteins: A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4GEU5, B8N7E5, G0S9J5, G5ECY0, H2L056, O00308, O14326, O42643, P10823, P39055, P39940, P46935, Q0CCL1, Q2TAS2, Q2UBP1, Q45FX5, Q4WTF3, Q5BDP1, Q5RBF2, Q5RD78, Q5U5R9, Q62940, Q757T0, Q8BZZ3, Q8C863, Q8CFI0, Q92462, Q96J02, Q96PU5, Q9CUN6, Q9DBH0, Q9H0M0, Q9HAU4, Q9HCE7

Diamond homologs: A0A8C0NGY6, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

38 interactions.

A	Effect	B	Mechanism
SMAD7	“up-regulates activity”	SMURF2	relocalization
SMURF2	“down-regulates activity”	TGFBR1	ubiquitination
SMAD2	“up-regulates activity”	SMURF2	binding
SMURF2	“form complex”	SMAD2/SMURF2	binding
SMURF2	“down-regulates quantity by destabilization”	SMAD1	ubiquitination
SMURF2	down-regulates	SMAD1	ubiquitination
SMURF2	“down-regulates quantity by destabilization”	SMAD5	ubiquitination
AIMP1	up-regulates	SMURF2	binding
SMURF2	“down-regulates activity”	SMAD7	ubiquitination
SMURF2	down-regulates	BMPR1A	ubiquitination
SMURF2	down-regulates	BMPR2	ubiquitination
SMURF2	down-regulates	SMAD5	ubiquitination
SMURF2	down-regulates	SMAD9	ubiquitination
SMURF2	“down-regulates activity”	TGFBR2	ubiquitination
AIMP1	“up-regulates activity”	SMURF2	binding
SMURF2	“down-regulates activity”	SKIL	ubiquitination
SMURF2	“down-regulates activity”	SMAD2	ubiquitination
ZNF165	“down-regulates quantity by repression”	SMURF2	“transcriptional regulation”
SMURF2	down-regulates	SMAD1/5/8	ubiquitination
Ub:E2	“up-regulates activity”	SMURF2	ubiquitination
SMURF2	“down-regulates quantity by destabilization”	SMAD2	polyubiquitination
SMURF2	“down-regulates quantity by destabilization”	STAMBP	polyubiquitination
RNF11	“up-regulates activity”	SMURF2	binding
SMURF2	“down-regulates quantity by destabilization”	YY1	ubiquitination
TRAF4	“down-regulates quantity by destabilization”	SMURF2	ubiquitination
SMURF2	“up-regulates activity”	TNFRSF1B	ubiquitination
SMURF2	“up-regulates activity”	UBE2D1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)	5	49.4×	5e-06
Striated Muscle Contraction	9	40.9×	4e-10
Downregulation of SMAD2/3:SMAD4 transcriptional activity	7	37.9×	1e-07
Downregulation of TGF-beta receptor signaling	6	36.0×	2e-06
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	7	31.8×	4e-07
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	5	27.1×	4e-05
Metalloprotease DUBs	5	22.1×	9e-05
Signaling by TGF-beta Receptor Complex	5	14.7×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
SMAD protein signal transduction	6	49.4×	8e-07
cardiac muscle contraction	7	31.6×	8e-07
ureteric bud development	6	30.7×	9e-06
skeletal muscle contraction	5	28.7×	1e-04
sarcomere organization	6	25.8×	2e-05
transforming growth factor beta receptor signaling pathway	6	10.7×	2e-03
anatomical structure morphogenesis	6	9.4×	3e-03
protein ubiquitination	9	4.2×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	9
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

4243 predictions. Top by Δscore:

Variant	Effect	Δscore
17:64545754:T:TA	donor_gain	1.0000
17:64545820:AGAGT:A	donor_gain	1.0000
17:64545835:T:TA	donor_gain	1.0000
17:64545948:C:CC	acceptor_gain	1.0000
17:64546258:CTTAC:C	donor_loss	1.0000
17:64546261:A:AC	donor_gain	1.0000
17:64546261:AC:A	donor_loss	1.0000
17:64546262:C:CC	donor_gain	1.0000
17:64546262:CC:C	donor_loss	1.0000
17:64546336:CAC:C	acceptor_gain	1.0000
17:64546338:CCTG:C	acceptor_loss	1.0000
17:64546339:C:CC	acceptor_gain	1.0000
17:64546339:C:CG	acceptor_loss	1.0000
17:64546340:T:C	acceptor_loss	1.0000
17:64546345:A:AC	acceptor_gain	1.0000
17:64546345:A:C	acceptor_gain	1.0000
17:64547798:TGAG:T	acceptor_gain	1.0000
17:64547799:GAGC:G	acceptor_loss	1.0000
17:64547801:GC:G	acceptor_loss	1.0000
17:64547802:C:A	acceptor_loss	1.0000
17:64547802:C:CC	acceptor_gain	1.0000
17:64547803:T:G	acceptor_loss	1.0000
17:64554991:TCA:T	acceptor_gain	1.0000
17:64554992:CA:C	acceptor_gain	1.0000
17:64554992:CAC:C	acceptor_gain	1.0000
17:64554994:C:CC	acceptor_gain	1.0000
17:64555818:A:AC	donor_gain	1.0000
17:64555819:C:CC	donor_gain	1.0000
17:64555819:CA:C	donor_gain	1.0000
17:64555819:CAGT:C	donor_gain	1.0000

AlphaMissense

4920 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:64545860:A:C	F745L	1.000
17:64545860:A:T	F745L	1.000
17:64545861:A:C	F745C	1.000
17:64545861:A:G	F745S	1.000
17:64545862:A:G	F745L	1.000
17:64545864:C:T	G744E	1.000
17:64545882:G:T	A738D	1.000
17:64545883:C:G	A738P	1.000
17:64545891:A:G	L735P	1.000
17:64545934:C:G	D721H	1.000
17:64545936:A:T	I720K	1.000
17:64545939:C:G	R719P	1.000
17:64545941:A:C	N718K	1.000
17:64545941:A:T	N718K	1.000
17:64545944:G:C	F717L	1.000
17:64545944:G:T	F717L	1.000
17:64545945:A:C	F717C	1.000
17:64545945:A:G	F717S	1.000
17:64545946:A:C	F717V	1.000
17:64545946:A:G	F717L	1.000
17:64545946:A:T	F717I	1.000
17:64545947:G:C	C716W	1.000
17:64546263:C:T	C716Y	1.000
17:64546264:A:G	C716R	1.000
17:64546268:G:C	H714Q	1.000
17:64546268:G:T	H714Q	1.000
17:64546269:T:C	H714R	1.000
17:64546270:G:C	H714D	1.000
17:64546272:G:T	A713D	1.000
17:64546278:G:C	P711R	1.000

dbSNP variants (sampled 300 via entrez): RS1000080779 (17:64623199 T>C), RS1000081556 (17:64572533 A>C), RS1000115261 (17:64653637 G>A), RS1000124956 (17:64622957 T>C), RS1000163009 (17:64659562 T>G), RS1000177544 (17:64554633 T>C), RS1000213724 (17:64640394 C>A), RS1000278056 (17:64547923 C>A,T), RS1000279725 (17:64647388 A>G), RS1000290028 (17:64664298 G>A), RS1000311004 (17:64646884 A>G), RS1000322197 (17:64617523 T>C), RS1000385075 (17:64646667 C>T), RS1000389859 (17:64548563 T>G), RS1000438457 (17:64610753 A>G)

Disease associations

OMIM: gene MIM:605532 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002127_3	Periodontitis (Mean PAL)	9.000000e-06
GCST003998_12	Joint mobility (Beighton score)	9.000000e-09
GCST007429_134	Lung function (FVC)	3.000000e-10
GCST007431_58	Lung function (FEV1/FVC)	9.000000e-13
GCST008309_3	Cardiac troponin-I levels	3.000000e-11
GCST010396_144	Gut microbiota (bacterial taxa, hurdle binary method)	2.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007905	joint hypermobility measurement
EFO:0004312	vital capacity
EFO:0004713	FEV/FVC ratio
EFO:0010071	cardiac troponin I measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523460 (SINGLE PROTEIN)

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

ChEMBL bioactivities

30 potent at pChembl≥5 of 33 total, top 30 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.76	IC50	175	nM	CHEMBL4584197
6.41	IC50	390	nM	CHEMBL4475920
6.14	IC50	725	nM	CHEMBL4559578
6.13	IC50	740	nM	CHEMBL4468431
6.08	IC50	830	nM	CHEMBL4473531
5.98	IC50	1051	nM	CHEMBL4441459
5.54	IC50	2900	nM	CHEMBL5405373
5.43	IC50	3700	nM	CHEMBL5413507
5.26	IC50	5550	nM	CHEMBL4533744
5.25	IC50	5600	nM	CHEMBL4532439
5.24	IC50	5800	nM	CHEMBL4462198
5.16	IC50	6850	nM	CHEMBL4532915
5.11	IC50	7850	nM	CHEMBL4446476
5.08	IC50	8350	nM	CHEMBL4585952
5.07	IC50	8550	nM	CHEMBL4540707
5.02	IC50	9500	nM	CHEMBL4583928
5.00	IC50	1e+04	nM	CHEMBL4465535
5.00	IC50	1e+04	nM	CHEMBL4464627
5.00	IC50	1e+04	nM	CHEMBL4439888
5.00	IC50	1e+04	nM	CHEMBL4566754
5.00	IC50	1e+04	nM	CHEMBL4543477
5.00	IC50	1e+04	nM	CHEMBL4462646
5.00	IC50	1e+04	nM	CHEMBL4559108
5.00	IC50	1e+04	nM	CHEMBL4567819
5.00	IC50	1e+04	nM	CHEMBL4460342
5.00	IC50	1e+04	nM	CHEMBL4568724
5.00	IC50	1e+04	nM	CHEMBL4522525
5.00	IC50	1e+04	nM	CHEMBL4592708
5.00	IC50	1e+04	nM	CHEMBL4547904
5.00	IC50	1e+04	nM	CHEMBL4469047

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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
5-(2-chloro-4-cyclopropylphenyl)-4-methyl-1,2-oxazole-3-carboxylic acid	1991372: Inhibition of SMURF2 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	2.9000	uM
5-(2-chloro-4-cyclopropylphenyl)-N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-4-methyl-1,2-oxazole-3-carboxamide	1991372: Inhibition of SMURF2 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	3.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression, affects expression	6
Cyclosporine	decreases expression, increases expression	3
cobaltous chloride	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Estradiol	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Particulate Matter	decreases expression, increases abundance	2
moringin	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	decreases expression	1
1-nitropyrene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	increases expression	1
PCI 5002	increases expression, affects cotreatment	1
Bortezomib	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Aspirin	increases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	decreases phosphorylation	1
Cannabidiol	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418374	Binding	Inhibition of SMURF2 (unknown origin) in presence of E1/E2/Ub mix measured after 45 mins by europium-labeled streptavidin based TR-FRET assay	Carboxamide inhibitors

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_B2GQ	Abcam HeLa SMURF2 KO	Cancer cell line	Female
CVCL_D8B1	Ubigene A-549 SMURF2 KO	Cancer cell line	Male
CVCL_D8VR	Ubigene HCT 116 SMURF2 KO	Cancer cell line	Male
CVCL_D9SF	Ubigene HEK293 SMURF2 KO	Transformed cell line	Female
CVCL_E0PH	Ubigene HeLa SMURF2 KO	Cancer cell line	Female
CVCL_XT58	HAP1 SMURF2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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