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FLASH GENE

Symbol

SMAD3

contributors: mct/ - updated : 06-04-2018

HGNC name	SMAD family member 3
HGNC id	6769

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	LDS3 Loeys-Dietz syndrome, type 3 TAAD5 thoracic aortic aneurysm with aortic dissection 5
Location	15q22.33      Physical location : 67.358.194 - 67.487.532
Synonym name	MAD, mothers against decapentaplegic homolog 3 (Drosophila)
	SMAD, mothers against DPP homolog 3 (Drosophila)
	SMA- and MAD-related protein 3
	mad homolog JV15-2
Synonym symbol(s)	MADR3, JV15.2, MADH3, HsT17436, DKFZp586N0721, DKFZp686J10186, HSPC193, MGC60396, mad3

DNA

TYPE	functioning gene
STRUCTURE	129.34 kb     9 Exon(s)

regulatory sequence	Promoter
text structure	CACGTG E-boxes in its promoter

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005902 9 - 6256 NP_005893 48 425 - 2009 19289081 isoform 1 variant 5 - splicing 1148 isoform 5 - - higher in colon compared to stomach or thymus 2004 14980711 also called SMAD3 delta3 lacks exon 3 resulting in a truncated linker region having transcriptional and possessing functional transactivating properties NM_001145102 9 - 5997 NP_001138574 36 320 - 2009 19289081 isoform 2 NM_001145103 9 - 5808 NP_001138575 43.1 381 - 2009 19289081 isoform 3 NM_001145104 7 - 5441 NP_001138576 25.6 230 - 2009 19289081 isoform 4

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive liver           salivary gland       highly Endocrine pancreas           thyroid       highly Nervous brain         Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Epithelial secretory glandular exocrine

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	Dwarfin (DWA)/MH1 DNA binding domain including a nuclear localization-like signal (NLS-L)
	a double loop region, followed by a linker region
	a DWB/MH2 heterodimerization and transactivation domain
	two conserved polypeptide segments, the MH1 and MH2 domains, joined by a less conserved linker region (PMID

secondary structure

beta hairpin

mono polymer

complex

HOMOLOGY

interspecies

homolog to Drosophila Mad (mothers against dpp) gene JV15-1

Homologene

FAMILY

Dwarfin (DWA/B)/Smad family

CATEGORY

transcription factor , tumor suppressor , receptor nuclear

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,chromatin/chromosome
text	ligand induced nuclear translocation
	upon TGFB stimulation, SMAD3 is activated and translocated to nucleus where it binds to NKX2.5, which blocks NKX2.5 binding to the MYOCD promoter and thus inhibits the mRNA expression of MYOCD

basic FUNCTION	critical mediator of the TGFB signaling pathway
	sequence specific transcriptional activator, physically bound with AP1 family members : JUNB, JUNC and JUND and interacting with response elements to mediate transcriptional activation of target genes
	involved in TGFB dependent regulation of steroidogenesis and in T-cell response to TGFB
	primary transducer of male gonadal tumorigenesis, and potentially overlaps with SMAD2 function in the ovary
	playing a key role in the regulation of Cdc25A ubiquitination by SCFbeta-TrCP
	key intracellular signal transducer for TGF-beta signaling, and its transcriptional activity is controlled through reversible phosphorylation and nucleocytoplasmic shuttling
	plays an essential role in development and maintenance of self-tolerance
	involved in the increase of cell invasion ability induced by TGF-beta in cancer cells, in cooperation with S100A4
	regulates RHOA activation and cytoskeletal reorganization by controlling NET1 in TGF-beta1-induced retinal pigment epithelial cells
	a new role as a modulator of RHOA activation in the regulation of TGF-beta1-induced epithelial-mesenchymal transitions
	its expression in the normal colon is considered to contribute to the formation of a “proliferative zone” at the bottom of colonic crypts
	crucial role of SMAD3 reduction in tumor progression in colonic epithelium as well as in restitution of colonic epithelial cell crypts
	blocks NKX2.5 Binding to the MYOCD promoter and inhibits NKX2.5-mediated MYOCD promoter activation in a dose-dependent manner
	implication of SMAD3-mediated inhibition of MYOCD in the initiation phase of smooth muscle cells differentiation
	central role for SMAD3 in normal tendon formation and in the maintenance of mature tendon
	SMAD2 and SMAD3 were redundantly essential for TGFB1 signaling to induce histone modifications for IL9 transcription
	SMAD2 and SMAD3 cooperate and antagonize simultaneously in vertebrate neurogenesis
	SMAD2 and SMAD3 are both necessary for the formation of lens posterior capsular opacification (PCO)
	SMAD2/3 transcription factor plays a central role in differentiation and survival of erythroid cells
	SMAD3 is required for FSH synthesis
	in contrast to TCF21 which is protective toward coronary artery disease (CAD), SMAD3 expression in human coronary artery smooth muscle cells (HCASMC) was shown to be directly correlated with disease risk

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

TGFB

a component	forming a heterodimer with itself and SMAD4
	key component of the transforming growth factor-beta (TGF-beta) pathway , complexing with SNAI1
	forms a stable complex with the R-SMAD (SMAD3) and the Co-SMAD (SMAD4)

INTERACTION

DNA

binding

RNA

small molecule

protein	binding to AP1 members : JUNB, JUNC, JUND
	androgen receptor coregulator in prostate cancer cells
	binding activin receptor in associating with DOK1, triggered by activin stimulations and leading to apoptosis
	SARA, TGIF, RUNX3, SMURF2, SKIL
	interacting with XPO4 (XPO4 binds a conserved peptide sequence in the MH2 domain of SMAD3 in a Ran-dependent manner and is sufficient for carrying the nuclear export of SMAD3 in cooperation with RAN)
	interacting with ERBB2IP1 via its MH2 domain
	in the nucleus, binds to the TERT gene promoter directly and inhibits TERT gene transcription activity, acting as a repressor of the TERT gene
	interaction between SMAD3 and the CDC42 guanine nucleotide exchange factor, and Zizimin1, in response to TGF-beta1
	PP2R1A physically interacted with SMAD3 that occurred only in hypoxia (SMAD3-associated PP2R1A activity was found under hypoxic conditions)
	can phsycially and functionally interact with S100A4 in a Ca2+dependent manner
	physically interacts with DEDD (through its interaction with SMAD3, DEDD is a novel negative regulator of the TGF-B1 signaling pathway)
	ADP-ribosylation of SMAD proteins by PARP1 is a key step in controlling the strength and duration of SMAD-mediated transcription
	interacts with NKX2.5 (SMAD3-NKX2.5 interaction may lead to the blockade of MYOCD in the initiation phase of TGFB-induced smooth muscle cell differentiation)
	TRIB3 triggering the degradation of SMAD ubiquitin regulatory factor 2 (SMURF2), which resulted in a decrease in the degradation of SMAD2 and phosphorylated SMAD3
	SMAD3 is required for CDC7 function in inducing SMC promoter activities and marker gene expression
	SMAD3 is the critical intracellular link that mediates the effects of FST on MTOR signaling
	PPP5C modulates SMAD3 function in the TGFB pathway
	SMAD3, mediated TGFB1-induced epithelial–mesenchymal transition (EMT) in renal primary tubular epithelial cells
	TGFB1-induced transcriptional regulation is controlled by nuclear accumulation of SMAD3
	NANOG promotes liver cancer cell invasion by inducing epithelial-mesenchymal transition through NODAL/SMAD3 signaling pathway
	interplay between the inhibitory SMAD7 and the intracellular mediators SMAD2/3 is likely a control point for pancreatic endocrine development
	SMAD3 has the ability to physically interact with the critical transcriptional regulators SCX and MKX
	LEMD3 is an integral protein of the inner nuclear membrane, inhibiting TGFB1 signaling by binding to SMAD2 and SMAD3
	NFATC1 sequestering the SMAD3 prevents the proteasome mediated degradation of SKIL and SKIL has a role on the regulation of MMP2, MMP9 activity
	IRF4 was essential for the SMAD2/3-mediated IL9 promoter activation
	SMAD3 interacts with AHNAK through MH2 domain and AHNAK stimulates SMAD3 localization into nucleus leading to potentiating TGFB1-induced transcriptional activity of R-SMAD
	FOXO3 and SMAD3, converge to coordinately and directly regulate transcription of TRIM63
	SMAD2 and SMAD3 interact with each other to mediate transforming growth factor-beta (TGFB1)-triggered signaling transduction
	SMAD2 suppressed the phosphorylation and nuclear translocation of SMAD3, which may protect against SMAD3-mediated fibrotic response
	TCF3 is necessary to drive transcription of SMAD2/3 target genes, including critical regulators of dorsal cell fate and morphogenesis
	FSTL1 attenuates differentiation and survival of erythroid cells through SMAD2/3 signaling
	EXOC4 regulates CDH2 expression by controlling SMAD3 and SMAD4 expression at the basal transcriptional level, thereby modulating cell migration and adhesion
	ABL1 phosphorylates SKI-interacting protein (SNW1), a nuclear cofactor of the transcription factor SMAD3
	ZFYVE16 binds to SMAD4 and their binding affects the formation of SMAD2/3-SMAD4 complex in TGFB1 signaling
	interplay of WNT1-LEF1 and TGFB1-SMAD3 signaling activates canonical WNT1 target promoters in a manner that depends on CTNNB1 during myoblast proliferation but is independent of CTNNB1 during Skeletal muscle stem cells (MuSCs) quiescence
	ZNF165 and SMAD3 cooperate to modulate TGFB1-responsive gene expression
	ZNF165 is essential for recruitment of SMAD3 to shared target gene promoters and transcriptional activation

cell & other

REGULATION

activated by

in response to transforming growth factor-beta (TGF-beta)

inhibited by

inactivated by MEN1 (disruption of DNA binding)

Other	regulated by CDK4 and CDK2 for antiproliferative function
	is also regulated by phosphorylation at its linker region

ASSOCIATED DISORDERS

corresponding disease(s)

LDS3 , TAAD5

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral         in acute T-cell lymphoblastic leukemia and in gastric carcinoma in the early stage constitutional     --low   accelerates not only cutaneous wound healing and keratinocyte proliferation but also colonic epithelial cell proliferation constitutional     --over   upregulation of ZFYVE9 and SMAD3 in cortex neurons might be involved in the development of intractable temporal lobe epilepsy

Susceptibility

to osteoarthritis

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed diabete     inhibition of SMAD3 function has therapeutic potential for diabetic renal disease

ANIMAL & CELL MODELS

	Smad3 -/- mice showed an increased number of proliferating epithelial cells with activation of the Wnt/beta-catenin pathway in the colonic crypts
	mice lacking Smad3 are protected against tubulointerstitial fibrosis following unilateral ureteral obstruction as evidenced by blocking of EMT and abrogation of monocyte influx and collagen accumulation