SMURF1

Summary

SMURF1 (SMAD specific E3 ubiquitin protein ligase 1, HGNC:16807) is a protein-coding gene on chromosome 7q22.1, encoding E3 ubiquitin-protein ligase SMURF1 (Q9HCE7). E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway.

This gene encodes a ubiquitin ligase that is specific for receptor-regulated SMAD proteins in the bone morphogenetic protein (BMP) pathway. This protein plays a key roll in the regulation of cell motility, cell signalling, and cell polarity. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 57154 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 79 total
• Druggable target: yes
• MANE Select transcript: NM_181349

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16807
Approved symbol	SMURF1
Name	SMAD specific E3 ubiquitin protein ligase 1
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1625
Ensembl gene	ENSG00000198742
Ensembl biotype	protein_coding
OMIM	605568
Entrez	57154

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000361125, ENST00000361368, ENST00000472627, ENST00000480055, ENST00000885288, ENST00000885289, ENST00000885290, ENST00000932465, ENST00000932466, ENST00000932467

RefSeq mRNA: 3 — MANE Select: NM_181349 NM_001199847, NM_020429, NM_181349

CCDS: CCDS34689, CCDS34690

Canonical transcript exons

ENST00000361368 — 18 exons

Exon	Start	End
ENSE00000434332	99051357	99051441
ENSE00000707924	99033037	99033121
ENSE00000707928	99040378	99040556
ENSE00000707932	99047684	99047882
ENSE00000877603	99035515	99035716
ENSE00000877605	99038388	99038525
ENSE00000877607	99042118	99042232
ENSE00000877608	99045698	99045801
ENSE00000877610	99049563	99049709
ENSE00000877613	99052205	99052446
ENSE00001871515	99027440	99030683
ENSE00002487041	99037067	99037187
ENSE00003534108	99054790	99054865
ENSE00003547012	99061799	99061837
ENSE00003580271	99143726	99144108
ENSE00003583540	99057418	99057551
ENSE00003599176	99057205	99057270
ENSE00003663412	99060599	99060707

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 91.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0812 / max 743.7405, expressed in 1782 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85085	9.8735	1758
85084	2.8906	1374
85086	0.2019	61
204537	0.1152	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	91.47	gold quality
tibial artery	UBERON:0007610	91.46	gold quality
sural nerve	UBERON:0015488	88.49	gold quality
lower esophagus mucosa	UBERON:0035834	87.99	gold quality
adrenal tissue	UBERON:0018303	87.96	gold quality
islet of Langerhans	UBERON:0000006	86.88	gold quality
left ovary	UBERON:0002119	86.83	gold quality
esophagus mucosa	UBERON:0002469	86.79	gold quality
ovary	UBERON:0000992	86.23	gold quality
skin of leg	UBERON:0001511	86.23	gold quality
zone of skin	UBERON:0000014	86.03	gold quality
mucosa of stomach	UBERON:0001199	85.86	gold quality
skin of abdomen	UBERON:0001416	85.74	gold quality
right lung	UBERON:0002167	85.67	gold quality
left coronary artery	UBERON:0001626	85.54	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.54	gold quality
left testis	UBERON:0004533	85.50	gold quality
testis	UBERON:0000473	85.38	gold quality
right coronary artery	UBERON:0001625	85.35	gold quality
thoracic aorta	UBERON:0001515	85.13	gold quality
ascending aorta	UBERON:0001496	85.12	gold quality
corpus callosum	UBERON:0002336	85.08	gold quality
right testis	UBERON:0004534	84.88	gold quality
upper lobe of left lung	UBERON:0008952	84.81	gold quality
right ovary	UBERON:0002118	84.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.69	gold quality
body of stomach	UBERON:0001161	84.62	gold quality
tibial nerve	UBERON:0001323	84.54	gold quality
pancreas	UBERON:0001264	84.52	gold quality
stomach	UBERON:0000945	84.51	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	31.95
E-ANND-3	yes	4.95
E-ENAD-17	no	40.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, JUN, JUNB, RUNX2, SMAD7

miRNA regulators (miRDB)

156 targeting SMURF1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
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-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-8082	99.95	67.27	1170
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-15A-5P	99.90	72.80	2787

Literature-anchored findings (GeneRIF, showing 40)

• plasma membrane localization of Smad7 by Smurf1 requires the C2 domain of Smurf1 and is essential for the inhibitory effect of Smad7 in the transforming growth factor-beta signaling pathway (PMID:12151385)
• CRM1-dependent nuclear export of Smurf1 is essential for the negative regulation of TGF-beta signaling by Smad7. (PMID:12519765)
• Smurf1 links the Cdc42/Rac1-PAR6 polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signaling during dynamic membrane movements (PMID:14657501)
• Smad7 and Smurf1 have roles in regulation of TGF-beta signaling in scleroderma fibroblasts (PMID:14722617)
• rhoA GTP-Binding Protein is targeted for ubiquitination and degradation via Smurf1 (PMID:15710384)
• Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation (PMID:16299379)
• Escherichia coli producing cytotoxic necrotizing factor and transforming growth factor-beta trigger activated RhoA ubiquitylation through Smurf1 ubiquitin-ligase. (PMID:16540523)
• LIM-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads (PMID:16611643)
• These findings indicate a new inhibitory function of FKBP12 as an adaptor molecule for the Smad7-Smurf1 complex to regulate the duration of the activin signal through activin type I receptors. (PMID:16720724)
• These results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling. (PMID:17190792)
• present a homology-based modeling of the Smurf1 WW2 domain and its interacting motif of LMP-1 (PMID:17510966)
• results present a homology-based model of the Smurf1 WW2 domain and the target octa-peptides containing PPXY motif of Smurf1-interacting Smads (PMID:17676934)
• Results suggest that Smurf1 plays a crucial role in the spatiotemporal regulation of Rho GTPase family members. (PMID:18208356)
• SMURF1 was identified by amplication in a pancreatic cancer cell line. (PMID:18380791)
• 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)
• a molecular mechanism for the pathogenesis of cerebral cavernous malformations (CCM) resulting from loss of CCM2-mediated localization of Smurf1, which controls RhoA degradation required for maintenance of normal endothelial cell physiology. (PMID:19318350)
• These results suggest a new role of Smurf1 in inflammation and immunity through controlling the degradation of TRAFs. (PMID:19937093)
• This study provided the first evidence that Smurf1 functions as an E3 ligase to promote the ubiquitination and proteasomal degradation of KLF2. (PMID:21382345)
• the Smurf1 C2 domain has a role in substrate selection and cellular localization (PMID:21402695)
• ER stress induces Smurf1 degradation and WFS1 up-regulation (PMID:21454619)
• Data report that the C2 domain of Smurf1 is necessary and sufficient for binding RhoA, and therefore is crucial for targeting RhoA for ubiquitination. (PMID:21708152)
• SMURF1 is an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer (PMID:21887346)
• Inflammatory cytokines led to direct activation of Smurf1 and downregulation of miR-17, thereby increasing degradation of Smurf1-mediated osteoblast-specific factors. (PMID:21898695)
• studies uncover a cell-cycle-independent function of Cdh1, establishing Cdh1 as an upstream component that governs Smurf1 activity (PMID:22152476)
• Smurf1 is a negative feedback regulator for IFN-gamma signaling by targeting STAT1 for ubiquitination and proteasomal degradation. (PMID:22474288)
• Resistance exercise resulted in a significant downregulation of MSTN and FBXO32 mRNA expression and a significant upregulation in FSTL3 and SMURF1 mRNA expression, and carbohydrate and protein feeding have little influence on the these markers expression. (PMID:22476926)
• A Cdh1-APC/Smurf1/RhoA pathway that mediates axonal growth suppression in the developing mammalian brain. (PMID:22949615)
• Smurf1 turnover is mediated by Ckip-1 and Rpt6. (PMID:23032291)
• The expression of SMURF1 is enhanced in hepatocellular carcinoma, which may have played a role in the disease through affecting apoptosis and proliferation of hepatic cancer cells. (PMID:23042388)
• Ndfip1 negatively regulates RIG-I-dependent immune signaling by enhancing E3 ligase Smurf1-mediated MAVS degradation. (PMID:23087404)
• USP9X is an important regulatory protein of SMURF1. (PMID:23184937)
• Data indicate that Smad ubiquitin regulatory factor Smurf1 regulates cell migration through ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4). (PMID:23760265)
• CKIP-1 controlled Smurf1 expression in colon cancer (PMID:23995790)
• impaired phosphorylation and ubiquitination by p70S6K and Smurf1 increase the protein stability of TRIB2 in liver cancer (PMID:24089522)
• Smurf1 is localized within the Hirano bodies of Alzheimer’s disease brains. (PMID:24238996)
• Results suggest that EGF-induced SMURF1 plays a role in breast cancer cell migration and invasion through the downregulation of RhoA. (PMID:24241683)
• association of cortactin with Pfn-1 is regulated by c-Abl-mediated cortactin phosphorylation (PMID:24700460)
• Inhibiting Smurf1 mediated ubiquitination of Smad1/5. (PMID:24828823)
• 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)
• Smurf1 determines cell apoptosis rates downstream of DNA damage-induced ATR/Chk1 signalling by promoting degradation of RhoB. (PMID:25249323)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	smurf1	ENSDARG00000016086
danio_rerio		ENSDARG00000109826
mus_musculus	Smurf1	ENSMUSG00000038780
rattus_norvegicus	Smurf1	ENSRNOG00000000999

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), 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)

Protein

Protein identifiers

E3 ubiquitin-protein ligase SMURF1 — Q9HCE7 (reviewed: Q9HCE7)

Alternative names: HECT-type E3 ubiquitin transferase SMURF1, SMAD ubiquitination regulatory factor 1, SMAD-specific E3 ubiquitin-protein ligase 1

All UniProt accessions (1): Q9HCE7

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA. Promotes ubiquitination and subsequent proteasomal degradation of MAVS. Acts as an antagonist of TGF-beta signaling by ubiquitinating TGFBR1 and targeting it for degradation. Plays a role in dendrite formation by melanocytes.

Subunit / interactions. Interacts with TRAF4. Interacts (via HECT domain) with FBXL15 (via LRR repeats). Interacts with SMAD7 and TGFBR1; SMAD7 recruits SMURF1 to TGFBR1 and regulates TGF-beta receptor degradation. Interacts with MAVS; the interaction is mediated by NDFIP1.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in melanocytes.

Post-translational modifications. Auto-ubiquitinated in presence of NDFIP1. Ubiquitinated by the SCF(FBXL15) complex at Lys-381 and Lys-383, leading to its degradation by the proteasome. Lys-383 is the primary ubiquitination site.

Domain organisation. The C2 domain mediates membrane localization and substrate selection.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HCE7-1	Long	yes
Q9HCE7-2	Short

RefSeq proteins (3): NP_001186776, NP_065162, NP_851994* (*=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 (42 total): strand 14, mutagenesis site 6, turn 6, domain 4, sequence conflict 2, helix 2, cross-link 2, chain 1, splice variant 1, sequence variant 1, region of interest 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
3PYC	X-RAY DIFFRACTION	1.96
9FSJ	X-RAY DIFFRACTION	2.05
9FSK	X-RAY DIFFRACTION	2.75
2LAZ	SOLUTION NMR
2LB0	SOLUTION NMR
2LB1	SOLUTION NMR
2LTX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCE7-F1	74.35	0.38

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): 725 (glycyl thioester intermediate)

Post-translational modifications (3): 200, 381, 383

Mutagenesis-validated functional residues (6):

Position	Phenotype
28	fails to ubiquitinate rhoa; when associated with a-85.
85	fails to ubiquitinate rhoa; when associated with a-28.
350	abolishes fbxl15-mediated ubiquitination and degradation; when associated with r-381 and r-381.
381	abolishes fbxl15-mediated ubiquitination and degradation; when associated with r-350 and r-383. abolishes fbxl15-mediate
383	abolishes fbxl15-mediated ubiquitination and degradation; when associated with r-350 and r-381. abolishes fbxl15-mediate
725	loss of enzyme activity, without abolishing fbxl15-mediated ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-2173791	TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-8939902	Regulation of RUNX2 expression and activity
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-212436	Generic Transcription Pathway
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-3858494	Beta-catenin independent WNT signaling
R-HSA-4086400	PCP/CE pathway
R-HSA-5358351	Signaling by Hedgehog
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-9006936	Signaling by TGFB family members
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 356 (showing top): PID_HDAC_CLASSI_PATHWAY, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GU_PDEF_TARGETS_DN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_VACUOLE_ORGANIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY

GO Biological Process (20): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), protein export from nucleus (GO:0006611), ectoderm development (GO:0007398), cell differentiation (GO:0030154), BMP signaling pathway (GO:0030509), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), receptor catabolic process (GO:0032801), negative regulation of activin receptor signaling pathway (GO:0032926), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of axon extension (GO:0045773), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), engulfment of target by autophagosome (GO:0061736), substrate localization to autophagosome (GO:0061753), protein targeting to vacuole involved in autophagy (GO:0071211), protein localization to plasma membrane (GO:0072659), positive regulation of dendrite extension (GO:1903861), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), protein ubiquitination (GO:0016567)

GO Molecular Function (10): ubiquitin-protein transferase activity (GO:0004842), transforming growth factor beta receptor binding (GO:0005160), phospholipid binding (GO:0005543), SMAD binding (GO:0046332), ubiquitin protein ligase activity (GO:0061630), I-SMAD binding (GO:0070411), R-SMAD binding (GO:0070412), activin receptor binding (GO:0070697), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (9): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), axon (GO:0030424), neuronal cell body (GO:0043025), extracellular exosome (GO:0070062), mitochondrion (GO:0005739), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by TGFB family members	2
Signaling by TGF-beta Receptor Complex	2
Signal Transduction	2
TGF-beta receptor signaling activates SMADs	1
PCP/CE pathway	1
Signaling by Hedgehog	1
Transcriptional regulation by RUNX2	1
Transcriptional regulation by RUNX3	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
RNA Polymerase II Transcription	1
Signaling by WNT	1
Beta-catenin independent WNT signaling	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	3
protein ubiquitination	2
ubiquitin-dependent protein catabolic process	2
positive regulation of cell growth	2
positive regulation of developmental growth	2
autophagosome assembly	2
SMAD binding	2
cytoplasm	2
modification-dependent protein catabolic process	1
intracellular protein transport	1
nuclear export	1
tissue development	1
cellular developmental process	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
transforming growth factor beta receptor signaling pathway	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
macromolecule catabolic process	1
receptor metabolic process	1
activin receptor signaling pathway	1
regulation of activin receptor signaling pathway	1
proteasomal protein catabolic process	1
regulation of axon extension	1
axon extension	1
positive regulation of axonogenesis	1
non-canonical Wnt signaling pathway	1
membrane invagination	1
establishment of localization in cell	1
protein targeting to vacuole	1
autophagy	1
protein localization to membrane	1
protein localization to cell periphery	1
dendrite extension	1
regulation of dendrite extension	1
positive regulation of protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1

Protein interactions and networks

STRING

2414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMURF1	SMAD7	O15105	996
SMURF1	SMAD6	O43541	996
SMURF1	SMAD2	Q15796	935
SMURF1	RUNX2	Q13950	935
SMURF1	SMAD5	Q99717	923
SMURF1	RHOA	P06749	865
SMURF1	SMAD3	P84022	839
SMURF1	CCM2	Q9BSQ5	822
SMURF1	SMAD4	Q13485	811
SMURF1	TGFBR1	P36897	733
SMURF1	SMAD1	Q15797	724
SMURF1	PRKN	O60260	720
SMURF1	BTRC	Q9Y297	702
SMURF1	CDC42	P21181	692
SMURF1	PLEKHO1	Q53GL0	690

IntAct

50 interactions, top by confidence:

A	B	Type	Score
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
SPART	ITCH	psi-mi:“MI:0914”(association)	0.640
SMURF1	FBXL15	psi-mi:“MI:0915”(physical association)	0.640
FBXL15	SMURF1	psi-mi:“MI:0407”(direct interaction)	0.640
FBXL15	SMURF1	psi-mi:“MI:0915”(physical association)	0.640
FBXL15	SMURF1	psi-mi:“MI:0403”(colocalization)	0.640
SMURF1	PLEKHO1	psi-mi:“MI:0407”(direct interaction)	0.620
PSME3	SMURF1	psi-mi:“MI:0915”(physical association)	0.590
SMURF1	PSME3	psi-mi:“MI:0407”(direct interaction)	0.590
SMURF1	PSME3	psi-mi:“MI:0915”(physical association)	0.590
SMURF1	SMAD1	psi-mi:“MI:0915”(physical association)	0.570
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.530
SMURF1	KLF2	psi-mi:“MI:0915”(physical association)	0.510
SMURF1	AKT1	psi-mi:“MI:2364”(proximity)	0.470
AKT1	SMURF1	psi-mi:“MI:0915”(physical association)	0.470
SMURF1	DVL2	psi-mi:“MI:0915”(physical association)	0.400
VHL	SMURF1	psi-mi:“MI:0915”(physical association)	0.400
SMURF1	RHOA	psi-mi:“MI:0915”(physical association)	0.400
ING2	SMURF1	psi-mi:“MI:0915”(physical association)	0.400
RUNX2	SMURF1	psi-mi:“MI:0915”(physical association)	0.400
PSMC5	SMURF1	psi-mi:“MI:0915”(physical association)	0.400
SMURF1	CHEK1	psi-mi:“MI:0915”(physical association)	0.400
SMURF1	RNF11	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (873): SMURF1 (Biochemical Activity), UBE2L3 (Reconstituted Complex), POLR2A (Biochemical Activity), SMURF1 (Affinity Capture-Western), SMAD1 (Biochemical Activity), SMURF1 (Protein-peptide), SMURF1 (Reconstituted Complex), SMURF1 (Biochemical Activity), SMAD5 (Biochemical Activity), UBE2D3 (Reconstituted Complex), SMURF1 (Biochemical Activity), SMAD1 (Biochemical Activity), SMURF1 (Affinity Capture-Western), SMURF1 (Reconstituted Complex), PLEKHO1 (Affinity Capture-Western)

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, A0A8I3PQN6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A4IIJ3, B0XQ72, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, B8N7E5, D6C652, G0S9J5, H2LBU8, O14326, O88382, P39940, P46934, P46935, P46936, P46937, P46938, Q0CCL1, Q19404, Q1L8J7, Q2EJA0, Q2UBP1, Q32NJ6, Q45VV3, Q4L1J4, Q4WTF3, Q54T86, Q5BDP1, Q5F488, Q5RBF2

SIGNOR signaling

70 interactions.

A	Effect	B	Mechanism
SMURF1	“down-regulates activity”	SMAD6	relocalization
SMURF1	down-regulates	BMPR1A	ubiquitination
SMURF1	down-regulates	BMPR2	ubiquitination
SMURF1	“down-regulates activity”	TGFBR1	ubiquitination
SMAD7	“up-regulates activity”	SMURF1	relocalization
SMURF1	down-regulates	SMAD1	ubiquitination
SMURF1	down-regulates	SMAD5	ubiquitination
SMURF1	down-regulates	SMAD9	ubiquitination
SMURF1	“down-regulates activity”	TGFBR2	ubiquitination
SMURF1	“form complex”	PARD6/SMURF1	binding
SMURF1	“down-regulates activity”	RUNX2	ubiquitination
SMURF1	“down-regulates activity”	SMAD4	ubiquitination
SMURF1	“down-regulates quantity by destabilization”	DAB2IP	ubiquitination
SMURF1	down-regulates	SMAD1/5/8	ubiquitination
Ub:E2	“up-regulates activity”	SMURF1	ubiquitination
FBXO3	“down-regulates quantity by destabilization”	SMURF1	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	SMURF1	polyubiquitination
SMURF1	“down-regulates quantity by destabilization”	TBX6	polyubiquitination
SMAD6	“up-regulates activity”	SMURF1	binding
SMURF1	“down-regulates activity”	UVRAG	ubiquitination
SMURF1	“down-regulates quantity by destabilization”	TRIB2	ubiquitination
SMURF1	“down-regulates quantity by destabilization”	FERMT2	ubiquitination
SMURF1	“down-regulates quantity by destabilization”	SRSF5	ubiquitination
SMURF1	“down-regulates quantity”	NFIC	ubiquitination
AKT1	“up-regulates activity”	SMURF1	phosphorylation
hsa-miR-424-5p	“down-regulates quantity by destabilization”	SMURF1	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 40 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
Signaling by TGFB family members	6	23.9×	6e-05
Deubiquitination	5	21.4×	4e-04
Ub-specific processing proteases	6	11.0×	7e-04
Diseases of signal transduction by growth factor receptors and second messengers	5	9.8×	2e-03
Antigen processing: Ubiquitination & Proteasome degradation	7	9.0×	7e-04
Signaling by Receptor Tyrosine Kinases	5	8.9×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
SMAD protein signal transduction	5	93.9×	1e-06
ubiquitin-dependent protein catabolic process	6	11.4×	7e-04
protein ubiquitination	9	9.6×	6e-05
proteasome-mediated ubiquitin-dependent protein catabolic process	7	9.4×	5e-04
negative regulation of apoptotic process	9	8.0×	2e-04
positive regulation of gene expression	8	8.0×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3817 predictions. Top by Δscore:

Variant	Effect	Δscore
7:99030679:TAAAG:T	acceptor_gain	1.0000
7:99030680:AAAG:A	acceptor_gain	1.0000
7:99030681:AAG:A	acceptor_gain	1.0000
7:99030682:AG:A	acceptor_gain	1.0000
7:99030682:AGCTG:A	acceptor_loss	1.0000
7:99030683:GC:G	acceptor_loss	1.0000
7:99030684:C:CA	acceptor_loss	1.0000
7:99030684:C:CC	acceptor_gain	1.0000
7:99030685:T:G	acceptor_loss	1.0000
7:99032770:A:AC	donor_gain	1.0000
7:99032771:C:CC	donor_gain	1.0000
7:99033031:GCTT:G	donor_loss	1.0000
7:99033032:CTTAC:C	donor_loss	1.0000
7:99033033:TTACC:T	donor_loss	1.0000
7:99033034:TACCA:T	donor_loss	1.0000
7:99033035:ACC:A	donor_loss	1.0000
7:99033121:CCT:C	acceptor_gain	1.0000
7:99033123:T:C	acceptor_gain	1.0000
7:99035584:T:TA	donor_gain	1.0000
7:99035712:ATCAG:A	acceptor_gain	1.0000
7:99035713:TCAG:T	acceptor_gain	1.0000
7:99035714:CAG:C	acceptor_gain	1.0000
7:99035714:CAGC:C	acceptor_gain	1.0000
7:99035717:C:CC	acceptor_gain	1.0000
7:99038387:CCGGA:C	donor_gain	1.0000
7:99038401:T:A	donor_gain	1.0000
7:99038405:ATTCT:A	donor_gain	1.0000
7:99038521:TCTCT:T	acceptor_gain	1.0000
7:99038522:CTCT:C	acceptor_gain	1.0000
7:99038522:CTCTC:C	acceptor_gain	1.0000

AlphaMissense

4804 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:99030596:A:C	F754L	1.000
7:99030596:A:T	F754L	1.000
7:99030597:A:G	F754S	1.000
7:99030598:A:G	F754L	1.000
7:99030618:G:T	A747D	1.000
7:99030627:A:G	L744P	1.000
7:99030675:C:G	R728P	1.000
7:99030677:G:C	N727K	1.000
7:99030677:G:T	N727K	1.000
7:99030680:A:C	F726L	1.000
7:99030680:A:T	F726L	1.000
7:99030681:A:C	F726C	1.000
7:99030681:A:G	F726S	1.000
7:99030682:A:C	F726V	1.000
7:99030682:A:G	F726L	1.000
7:99030682:A:T	F726I	1.000
7:99033038:A:G	C725R	1.000
7:99033042:A:C	H723Q	1.000
7:99033042:A:T	H723Q	1.000
7:99033044:G:C	H723D	1.000
7:99033046:G:T	A722D	1.000
7:99033052:G:C	P720R	1.000
7:99033052:G:T	P720Q	1.000
7:99033091:A:G	F707S	1.000
7:99035528:G:C	F692L	1.000
7:99035528:G:T	F692L	1.000
7:99035529:A:G	F692S	1.000
7:99035530:A:G	F692L	1.000
7:99035556:C:T	G683E	1.000
7:99035557:C:A	G683W	1.000

dbSNP variants (sampled 300 via entrez): RS1000003305 (7:99138872 T>G), RS1000061479 (7:99146045 C>T), RS1000101350 (7:99051564 G>C), RS1000108178 (7:99062960 A>G), RS1000123996 (7:99044627 G>A), RS1000138033 (7:99093365 C>T), RS1000169431 (7:99069557 A>C), RS1000216604 (7:99108081 G>A), RS1000272056 (7:99115778 C>T), RS1000273884 (7:99055605 G>T), RS1000280057 (7:99145793 T>C), RS1000302667 (7:99030553 T>A,C,G), RS1000308980 (7:99038811 T>C), RS1000340879 (7:99075796 C>T), RS1000355718 (7:99129591 T>A,C)

Disease associations

OMIM: gene MIM:605568 | 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
GCST000623_2	Ulcerative colitis	9.000000e-11
GCST001725_94	Inflammatory bowel disease	8.000000e-12
GCST004131_62	Inflammatory bowel disease	8.000000e-09
GCST004133_29	Ulcerative colitis	7.000000e-07
GCST004730_2	Facial emotion recognition (sad faces)	3.000000e-06
GCST007623_3	Lack of premeditation	2.000000e-06
GCST90002392_330	Mean corpuscular volume	1.000000e-09
GCST90002397_304	Mean spheric corpuscular volume	3.000000e-13
GCST90002403_581	Red blood cell count	3.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008329	facial emotion recognition measurement
EFO:0006946	behavioural disinhibition measurement
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3879859 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

73 measured of 73 human assays (73 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(4,4-dimethylcyclohexen-1-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	0.9 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-[(2S,5R)-5-methyloxan-2-yl]-1,2-oxazole-3-carboxamide	IC50	1.4 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(4-ethylcyclohexen-1-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	1.8 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(6-ethyl-4-methylcyclohexen-1-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	2.1 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-spiro[4.5]dec-8-en-8-yl-1,2-oxazole-3-carboxamide	IC50	2.5 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(4-propan-2-ylcyclohexen-1-yl)-1,2-oxazole-3-carboxamide	IC50	2.8 nM	US-9403810: Carboxamide derivatives
5-(4-tert-butylcyclohexen-1-yl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	3.2 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(4,4-dimethylcyclohexyl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	5.7 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(4-methylcyclohexen-1-yl)-1,2-oxazole-3-carboxamide	IC50	6 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(4,4-dimethylcyclopenten-1-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	6 nM	US-9403810: Carboxamide derivatives
5-(cyclohepten-1-yl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	8 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(6,6-dimethylcyclohexen-1-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	14 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(3,3-dimethylbutyl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	19 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(3,3-dimethylcyclopentyl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	23 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-[4-(trifluoromethyl)cyclohexen-1-yl]-1,2-oxazole-3-carboxamide	IC50	33 nM	US-9403810: Carboxamide derivatives
5-(6-tert-butyloxan-2-yl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	37 nM	US-9403810: Carboxamide derivatives
5-((2S,6R)-6-(tert-butyl)tetrahydro-2H-pyran-2-yl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methylisoxazole-3-carboxamide or 5-((2R,6S)-6-(tert-butyl)tetrahydro-2H-pyran-2-yl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methylisoxazole-3-carboxamide	IC50	37 nM	US-10195181: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-[(Z)-3,3-dimethylbut-1-enyl]-4-methyl-1,2-oxazole-3-carboxamide	IC50	46 nM	US-9403810: Carboxamide derivatives
5-cyclohexyl-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	50 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-8-(trifluoromethoxy)-5,6-dihydro-4H-triazolo[1,5-a][1]benzazepine-3-carboxamide	IC50	55 nM	US-9403833: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-[(E)-3,3-dimethylbut-1-enyl]-4-methyl-1,2-oxazole-3-carboxamide	IC50	58 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(1-oxaspiro[4.5]dec-7-en-8-yl)-1,2-oxazole-3-carboxamide	IC50	64 nM	US-9403810: Carboxamide derivatives
5-[(2S,4S)-4-tert-butyl-1,3-dioxolan-2-yl]-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	74 nM	US-9403810: Carboxamide derivatives
5-[(2R,4S)-4-tert-butyl-1,3-dioxolan-2-yl]-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	75 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(6-propan-2-yl-3,6-dihydro-2H-pyran-2-yl)-1,2-oxazole-3-carboxamide	IC50	91 nM	US-9403810: Carboxamide derivatives
N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-((2R,6R)-6-isopropyl-3,6-dihydro-2H-pyran-2-yl)-4-methylisoxazole-3-carboxamide and N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-((2R,6S)-6-isopropyl-5,6-dihydro-2H-pyran-2-yl)-4-methylisoxazole-3-carboxamide and N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-((2S,6R)-6-isopropyl-5,6-dihydro-2H-pyran-2-yl)-4-methylisoxazole-3-carboxamide	IC50	91 nM	US-10195181: Carboxamide derivatives
1-(2-chloro-4-cyclopropylphenyl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-methyltriazole-4-carboxamide	IC50	92 nM	US-9403833: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(2-oxaspiro[4.5]dec-7-en-8-yl)-1,2-oxazole-3-carboxamide	IC50	100 nM	US-9403810: Carboxamide derivatives
5-[(2S,4S,6R)-6-tert-butyl-4-methoxyoxan-2-yl]-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	100 nM	US-9403810: Carboxamide derivatives
5-[(2S,4R)-4-tert-butyl-1,3-dioxolan-2-yl]-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	160 nM	US-9403810: Carboxamide derivatives
5-[4-(2-bromopropan-2-yl)oxolan-2-yl]-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	160 nM	US-9403810: Carboxamide derivatives
A mixture of 5-((2R,4S)-4-(2-bromopropan-2-yl)tetrahydrofuran-2-yl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methylisoxazole-3-carboxamide and 5-((2S,4R)-4-(2-bromopropan-2-yl)tetrahydrofuran-2-yl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methylisoxazole-3-carboxamide	IC50	160 nM	US-10195181: Carboxamide derivatives
5-(4-tert-butyl-1,3-dioxolan-2-yl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	160 nM	US-10195181: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-[(2R,3S)-3,5,5-trimethyl-1,4-dioxan-2-yl]-1,2-oxazole-3-carboxamide	IC50	180 nM	US-9403810: Carboxamide derivatives
1-(4-chloro-2-cyclopropylphenyl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-methyltriazole-4-carboxamide	IC50	230 nM	US-9403833: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-[(2S,4S)-4-propan-2-yloxolan-2-yl]-1,2-oxazole-3-carboxamide	IC50	250 nM	US-9403810: Carboxamide derivatives
5-[(2R,4S,6S)-6-tert-butyl-4-methoxyoxan-2-yl]-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	290 nM	US-9403810: Carboxamide derivatives
5-[(2S,6R)-6-tert-butyloxan-2-yl]-N-(1-cyclobutyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	290 nM	US-9403810: Carboxamide derivatives
5-[(6S)-6-tert-butyloxan-2-yl]-N-(1-cyclobutyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	290 nM	US-10195181: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(4-propan-2-yloxycyclohexen-1-yl)-1,2-oxazole-3-carboxamide	IC50	310 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(4-propan-2-yloxolan-2-yl)-1,2-oxazole-3-carboxamide	IC50	340 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-[(2R,4R)-4-propan-2-yloxolan-2-yl]-1,2-oxazole-3-carboxamide	IC50	350 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(1,4-dioxaspiro[4.5]decan-8-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	420 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-[(2S,5S)-5-methyloxan-2-yl]-1,2-oxazole-3-carboxamide	IC50	420 nM	US-9403810: Carboxamide derivatives
1-(2-chloro-4-methoxyphenyl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-methyltriazole-4-carboxamide	IC50	440 nM	US-9403833: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(5-methyl-3,6-dihydro-2H-pyran-2-yl)-1,2-oxazole-3-carboxamide	IC50	490 nM	US-9403810: Carboxamide derivatives
1-[2-chloro-4-(trifluoromethoxy)phenyl]-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-methyltriazole-4-carboxamide	IC50	550 nM	US-9403833: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-1-(2,4-dichlorophenyl)-5-methyltriazole-4-carboxamide	IC50	570 nM	US-9403833: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(5-methyloxan-2-yl)-1,2-oxazole-3-carboxamide	IC50	570 nM	US-9403810: Carboxamide derivatives
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(5,5-dimethyl-1,3-dioxan-2-yl)-4-methyl-1,2-oxazole-3-carboxamide	IC50	580 nM	US-9403810: Carboxamide derivatives

ChEMBL bioactivities

172 potent at pChembl≥5 of 172 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.05	IC50	0.9	nM	CHEMBL3903549
8.85	IC50	1.4	nM	CHEMBL3949800
8.85	IC50	1.4	nM	CHEMBL3948610
8.74	IC50	1.8	nM	CHEMBL3918128
8.68	IC50	2.1	nM	CHEMBL3908757
8.66	IC50	2.2	nM	CHEMBL4584197
8.60	IC50	2.5	nM	CHEMBL3979914
8.59	IC50	2.6	nM	CHEMBL4559578
8.55	IC50	2.8	nM	CHEMBL3945602
8.49	IC50	3.2	nM	CHEMBL3959606
8.35	IC50	4.5	nM	CHEMBL4475920
8.24	IC50	5.7	nM	CHEMBL3922163
8.23	IC50	5.9	nM	CHEMBL4441459
8.22	IC50	6	nM	CHEMBL3923152
8.22	IC50	6	nM	CHEMBL3948012
8.10	IC50	8	nM	CHEMBL3963970
7.96	IC50	11	nM	CHEMBL5413507
7.85	IC50	14	nM	CHEMBL3936702
7.77	IC50	17	nM	CHEMBL4473531
7.72	IC50	19	nM	CHEMBL3896562
7.65	IC50	22.5	nM	CHEMBL4468431
7.64	IC50	23	nM	CHEMBL3971227
7.54	IC50	29.2	nM	CHEMBL4583928
7.54	IC50	29	nM	CHEMBL5440935
7.50	IC50	31.5	nM	CHEMBL4460342
7.48	IC50	33	nM	CHEMBL3937559
7.43	IC50	37	nM	CHEMBL3939778
7.43	IC50	37	nM	CHEMBL5968901
7.40	EC50	40	nM	CHEMBL5405373
7.34	IC50	46	nM	CHEMBL3977353
7.30	IC50	50	nM	CHEMBL3936863
7.26	IC50	55	nM	CHEMBL3975128
7.24	IC50	58	nM	CHEMBL3906702
7.24	IC50	58	nM	CHEMBL4466006
7.19	IC50	64	nM	CHEMBL3942689
7.13	IC50	74	nM	CHEMBL4113496
7.13	IC50	74	nM	CHEMBL5885418
7.12	IC50	75	nM	CHEMBL4111123
7.12	IC50	75	nM	CHEMBL5885418
7.04	IC50	92	nM	CHEMBL3933261
7.04	IC50	91	nM	CHEMBL3933097
7.04	IC50	91.8	nM	CHEMBL4585952
7.04	IC50	91	nM	CHEMBL5843881
7.01	IC50	98	nM	CHEMBL4461423
7.00	IC50	100	nM	CHEMBL3980364
7.00	IC50	100	nM	CHEMBL3953839
6.90	IC50	125	nM	CHEMBL4462198
6.88	IC50	132.5	nM	CHEMBL4547904
6.80	IC50	160	nM	CHEMBL3924296
6.80	IC50	160	nM	CHEMBL3897219

PubChem BioAssay actives

28 with measured affinity, of 31 total; 18 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
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(4,4-dimethylcyclohexen-1-yl)-4-methyl-1,2-oxazole-3-carboxamide	1317005: Inhibition of N-terminal Prolabel-tagged human Smurf-1 HECT domain expressed in HEK293 cells assessed as accumulation of Smurf-1 protein using chemiluminescent substrate after overnight incubation by beta-galactosidase complementation assay	ic50	0.0009	uM
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(5-methyloxan-2-yl)-1,2-oxazole-3-carboxamide	1317005: Inhibition of N-terminal Prolabel-tagged human Smurf-1 HECT domain expressed in HEK293 cells assessed as accumulation of Smurf-1 protein using chemiluminescent substrate after overnight incubation by beta-galactosidase complementation assay	ic50	0.0014	uM
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(4-ethylcyclohexen-1-yl)-4-methyl-1,2-oxazole-3-carboxamide	1317005: Inhibition of N-terminal Prolabel-tagged human Smurf-1 HECT domain expressed in HEK293 cells assessed as accumulation of Smurf-1 protein using chemiluminescent substrate after overnight incubation by beta-galactosidase complementation assay	ic50	0.0018	uM
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-5-(4-propan-2-ylcyclohexen-1-yl)-1,2-oxazole-3-carboxamide	1317005: Inhibition of N-terminal Prolabel-tagged human Smurf-1 HECT domain expressed in HEK293 cells assessed as accumulation of Smurf-1 protein using chemiluminescent substrate after overnight incubation by beta-galactosidase complementation assay	ic50	0.0028	uM
N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-(4,4-dimethylcyclohexyl)-4-methyl-1,2-oxazole-3-carboxamide	1317005: Inhibition of N-terminal Prolabel-tagged human Smurf-1 HECT domain expressed in HEK293 cells assessed as accumulation of Smurf-1 protein using chemiluminescent substrate after overnight incubation by beta-galactosidase complementation assay	ic50	0.0057	uM
5-(2-chloro-4-cyclopropylphenyl)-N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-4-methyl-1,2-oxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.0110	uM
5-(2,4-dichlorophenyl)-N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-4-methyl-1,2-oxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.0290	uM
5-(2-chloro-4-cyclopropylphenyl)-4-methyl-1,2-oxazole-3-carboxylic acid	1991369: Stabilization of SMURF1 (unknown origin) assessed as decrease in auto-ubiquitination by measuring increase in protein level by cell-based assay	ec50	0.0400	uM
5-(4-chlorophenyl)-N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-4-methyl-1,2-oxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.1800	uM
N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-5-(4-methoxy-2-methylphenyl)-4-methyl-1,2-oxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.1800	uM
N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-12-methoxy-3-oxa-4-azatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene-5-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.2000	uM
5-(2,5-dichlorophenyl)-N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-4-methyl-1,2-oxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.2800	uM
1-(2-chloro-4-cyclopropylphenyl)-N-(1-cyclohexyl-2,3-dimethyl-5-oxopyrazol-4-yl)-5-methyltriazole-4-carboxamide	1991369: Stabilization of SMURF1 (unknown origin) assessed as decrease in auto-ubiquitination by measuring increase in protein level by cell-based assay	ec50	0.3160	uM
N-(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-12-methoxy-3-oxa-4-azatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene-5-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.4000	uM
5-(4-chloro-2-fluorophenyl)-N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-4-methyl-1,2-oxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	0.7000	uM
N-[1-(2-fluorophenyl)-2,3-dimethyl-5-oxopyrazol-4-yl]-5-(4-methoxyphenyl)-4-methyl-1,2-oxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	1.0000	uM
5-(6-tert-butyl-4-methoxyoxan-2-yl)-N-(1-cyclobutyl-2,3-dimethyl-5-oxopyrazol-4-yl)-4-methyl-1,2-oxazole-3-carboxamide	1317005: Inhibition of N-terminal Prolabel-tagged human Smurf-1 HECT domain expressed in HEK293 cells assessed as accumulation of Smurf-1 protein using chemiluminescent substrate after overnight incubation by beta-galactosidase complementation assay	ic50	2.5000	uM
N-(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-7-methoxy-4,5-dihydrobenzo[g][1,2]benzoxazole-3-carboxamide	1991368: Inhibition of SMURF1 (unknown origin) assessed as self-ubiquitination by TR-FRET/biochemical assay	ic50	3.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
Benzo(a)pyrene	increases methylation, affects methylation	2
Cyclosporine	increases expression	2
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
vanadium pentoxide	decreases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases degradation	1
abrine	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Irinotecan	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Curcumin	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, decreases reaction, increases degradation, increases ubiquitination	1
Estradiol	affects cotreatment, increases expression	1
Fluorouracil	increases expression	1
Formaldehyde	increases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	increases expression	1
Selenium	increases expression	1
Silver	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3855890	Binding	Inhibition of N-terminal Prolabel-tagged human Smurf-1 HECT domain expressed in HEK293 cells assessed as accumulation of Smurf-1 protein using chemiluminescent substrate after overnight incubation by beta-galactosidase complementation assay	Therapeutic Potential of Smurf-1 Inhibitors for the Treatment of Pulmonary Arterial Hypertension (PAH). — ACS Med Chem Lett

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7ZG	Abcam Raji SMURF1 KO	Cancer cell line	Male
CVCL_C0A9	Abcam THP-1 SMURF1 KO	Cancer cell line	Male
CVCL_C7BX	Abcam PC-3 SMURF1 KO	Cancer cell line	Male
CVCL_D8B0	Ubigene A-549 SMURF1 KO	Cancer cell line	Male
CVCL_D8VQ	Ubigene HCT 116 SMURF1 KO	Cancer cell line	Male
CVCL_D9SE	Ubigene HEK293 SMURF1 KO	Transformed cell line	Female
CVCL_E0PG	Ubigene HeLa SMURF1 KO	Cancer cell line	Female
CVCL_XT57	HAP1 SMURF1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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