InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: SMAD3

Summary

InnateDB Protein

IDBP-18368.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

SMAD3

Protein Name

SMAD family member 3

Synonyms

HSPC193; HsT17436; JV15-2; LDS1C; LDS3; MADH3;

Species

Homo sapiens

Ensembl Protein

ENSP00000332973

InnateDB Gene

IDBG-18366 (SMAD3)

Protein Structure

UniProt Annotation

Function

Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF- mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269PubMed:10995748, ECO:0000269PubMed:15241418, ECO:0000269PubMed:15588252, ECO:0000269PubMed:16156666, ECO:0000269PubMed:16751101, ECO:0000269PubMed:16862174, ECO:0000269PubMed:17327236, ECO:0000269PubMed:19218245, ECO:0000269PubMed:19289081, ECO:0000269PubMed:9732876, ECO:0000269PubMed:9892009}.

Subcellular Localization

Cytoplasm. Nucleus. Note=Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4. Through the action of the phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1. Co-localizes with LEMD3 at the nucleus inner membrane. MAPK-mediated phosphorylation appears to have no effect on nuclear import. PDPK1 prevents its nuclear translocation in response to TGF-beta.

Disease Associations

Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry.Loeys-Dietz syndrome 3 (LDS3) [MIM:613795]: An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. {ECO:0000269PubMed:21217753, ECO:0000269PubMed:21778426}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource. {ECO:0000269PubMed:21778426}.

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 529 experimentally validated interaction(s) in this database.
They are also associated with 63 interaction(s) predicted by orthology.

Experimentally validated
Total	529 [view]
Protein-Protein	508 [view]
Protein-DNA	16 [view]
Protein-RNA	0
DNA-DNA	5 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	63 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000987	core promoter proximal region sequence-specific DNA binding
GO:0000988	protein binding transcription factor activity
GO:0001102	RNA polymerase II activating transcription factor binding
GO:0003677	DNA binding
GO:0003682	chromatin binding
GO:0003690	double-stranded DNA binding
GO:0003700	sequence-specific DNA binding transcription factor activity
GO:0005160	transforming growth factor beta receptor binding
GO:0005515	protein binding
GO:0005518	collagen binding
GO:0008013	beta-catenin binding
GO:0008134	transcription factor binding
GO:0008270	zinc ion binding
GO:0019899	enzyme binding
GO:0019901	protein kinase binding
GO:0019902	phosphatase binding
GO:0030618	transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity
GO:0031490	chromatin DNA binding
GO:0031625	ubiquitin protein ligase binding
GO:0035326	enhancer binding
GO:0042803	protein homodimerization activity
GO:0043130	ubiquitin binding
GO:0043425	bHLH transcription factor binding
GO:0043565	sequence-specific DNA binding
GO:0044212	transcription regulatory region DNA binding
GO:0046332	SMAD binding
GO:0070410	co-SMAD binding
GO:0070412	R-SMAD binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0001501	skeletal system development
GO:0001649	osteoblast differentiation
GO:0001657	ureteric bud development
GO:0001666	response to hypoxia
GO:0001701	in utero embryonic development
GO:0001707	mesoderm formation
GO:0001756	somitogenesis
GO:0001889	liver development
GO:0001933	negative regulation of protein phosphorylation
GO:0001947	heart looping
GO:0002076	osteoblast development
GO:0002520	immune system development
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006367	transcription initiation from RNA polymerase II promoter
GO:0006810	transport
GO:0006919	activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0006955	immune response
GO:0007050	cell cycle arrest
GO:0007179	transforming growth factor beta receptor signaling pathway
GO:0007183	SMAD protein complex assembly
GO:0007369	gastrulation
GO:0007492	endoderm development
GO:0008285	negative regulation of cell proliferation
GO:0009880	embryonic pattern specification
GO:0010467	gene expression
GO:0010694	positive regulation of alkaline phosphatase activity
GO:0010718	positive regulation of epithelial to mesenchymal transition
GO:0016202	regulation of striated muscle tissue development
GO:0017015	regulation of transforming growth factor beta receptor signaling pathway
GO:0019049	evasion or tolerance of host defenses by virus
GO:0023019	signal transduction involved in regulation of gene expression
GO:0030308	negative regulation of cell growth
GO:0030335	positive regulation of cell migration
GO:0030501	positive regulation of bone mineralization
GO:0030512	negative regulation of transforming growth factor beta receptor signaling pathway
GO:0030878	thyroid gland development
GO:0031053	primary miRNA processing
GO:0032332	positive regulation of chondrocyte differentiation
GO:0032731	positive regulation of interleukin-1 beta production
GO:0032909	regulation of transforming growth factor beta2 production
GO:0032916	positive regulation of transforming growth factor beta3 production
GO:0032924	activin receptor signaling pathway
GO:0033689	negative regulation of osteoblast proliferation
GO:0035413	positive regulation of catenin import into nucleus
GO:0035556	intracellular signal transduction
GO:0038092	nodal signaling pathway
GO:0042060	wound healing
GO:0042110	T cell activation
GO:0042177	negative regulation of protein catabolic process
GO:0042993	positive regulation of transcription factor import into nucleus
GO:0043066	negative regulation of apoptotic process
GO:0045087	innate immune response (InnateDB)
GO:0045216	cell-cell junction organization
GO:0045668	negative regulation of osteoblast differentiation
GO:0045893	positive regulation of transcription, DNA-templated
GO:0045930	negative regulation of mitotic cell cycle
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0048340	paraxial mesoderm morphogenesis
GO:0048589	developmental growth
GO:0048617	embryonic foregut morphogenesis
GO:0048701	embryonic cranial skeleton morphogenesis
GO:0050678	regulation of epithelial cell proliferation
GO:0050728	negative regulation of inflammatory response
GO:0050776	regulation of immune response
GO:0050821	protein stabilization
GO:0050927	positive regulation of positive chemotaxis
GO:0051098	regulation of binding
GO:0051496	positive regulation of stress fiber assembly
GO:0051894	positive regulation of focal adhesion assembly
GO:0060039	pericardium development
GO:0060290	transdifferentiation
GO:0061045	negative regulation of wound healing
GO:0070306	lens fiber cell differentiation
GO:0090263	positive regulation of canonical Wnt signaling pathway
GO:0097191	extrinsic apoptotic signaling pathway
GO:0097296	activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway
GO:1901313	positive regulation of gene expression involved in extracellular matrix organization

Cellular Component

GO:0000790	nuclear chromatin
GO:0005622	intracellular
GO:0005634	nucleus
GO:0005637	nuclear inner membrane
GO:0005654	nucleoplasm
GO:0005667	transcription factor complex
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0043234	protein complex
GO:0043235	receptor complex
GO:0071141	SMAD protein complex
GO:0071144	SMAD2-SMAD3 protein complex

Protein Structure and Domains

PDB ID

InterPro

IPR001132 SMAD domain, Dwarfin-type
IPR003619 MAD homology 1, Dwarfin-type
IPR008984 SMAD/FHA domain
IPR013019 MAD homology, MH1
IPR019471 Interferon regulatory factor-3

PFAM

PF03166
PF03165
PF10401

PRINTS

PIRSF

SMART

SM00524
SM00523

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt

P84022