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FLASH GENE

Symbol

SMAD4

contributors: mct/pgu - updated : 27-10-2012

HGNC name	SMAD family member 4
HGNC id	6770

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	JPHT juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome JPS juvenile polyposis syndrome MYHRS Myhre syndrome
Location	18q21.2      Physical location : 48.556.582 - 48.611.409
Synonym name	SMAD, mothers against DPP homolog 4 (Drosophila)
	transforming growth factor beta-inducible DNA binding protein carcinoma, locus 4, homeoprotein
	MAD, mothers against decapentaplegic homolog 4 (Drosophila)
	deleted in pancreatic cancer 4
	MAD homolog 4
Synonym symbol(s)	DPC4, MADH4, JIP

DNA

TYPE	functioning gene
STRUCTURE	54.83 kb     12 Exon(s)

regulatory sequence	Promoter
	Binding site
text structure	four promoters were identified, two of which had significant activity in several cell lines, while two others had minimal activity
	multiple potentially important transcription factor binding sites for each 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_005359 12 - 8789 NP_005350 60.31 552 - 2007 17724086

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 blood / hematopoietic thymus       highly Cardiovascular heart ventricle       Homo sapiens Respiratory lung       highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid         Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial Homo sapiens Cardiovascular endothelial cell

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	ubiquitous during testis development but becomes cell-specific in the adult

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	dwarfin (DWA)MH1 DNA binding domain, implicated in the interactions with Hox and regulating the transcription activity of Hox proteins
	a nuclear localization-like signal (NLS-L), non functional
	a double loop region
	a linker region and a DWB/MH2 heterodimerization
	transactivation domain

mono polymer

heteromer , trimer , complex

HOMOLOGY

interspecies	homolog to Drosophila Mad (mothers against dpp)
	homolog to murine Madh4
	homolog to C.elegans Sma2-3-4

Homologene

FAMILY

Dwarfin (DWA/B)/Smad family

CATEGORY

DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus
text	ligand induced nuclear translocation, nuclear when complexed with MADH5 or MADH2, cytoplasmic in the abscence of ligand

basic FUNCTION	sequence specific transcriptional activator
	critical mediator of TGFB and BMP signaling pathways
	corepressor for estrogen receptor (ER) alpha
	can repress the SMAD3-enhanced ER alpha (ESR1)transactivation in a dose dependent-manner
	central intracellular signal transducer for transforming growth factor-beta (TGF-beta) signaling
	involved in carcinogenesis mainly of the pancreas and colon
	in colon and pancreatic tumor cells, functioning as a positive transcriptional regulator of all three genes encoding LAMA5
	having function in the control of an essential basement membrane component
	having activity in the developing endothelial cells essential for blood vessel remodeling, maturation, and integrity
	required for the development and maintenance of the lens in addition to the proper development of the cornea, eyelids, and retina
	may affect lens survival and function by controlling lens differentiation
	likely functions as a signaling mediator downstream of Activinbeta B in regulating actin stress fiber assembly and eyelid epithelial movement
	key regulator of prostate cancer progression
	GATA4 and SMAD4 cooperatively activated the ID2 promoter
	its endocardial expression is required to promote normal cellularity in the developing endocardial cushion, and SMAD4 is required to promote proliferation during the activation process of the pre-endothelial-to-mesenchymal transformation endocardial cell
	plays a crucial role in regulating the interplay between TGFB/BMP and WNT signaling to ensure the proper cranial neural crest cell fate decision during organogenesis
	crucial role in TGFB/bone morphogenetic protein (BMP) signal transduction
	potentially required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors

CELLULAR PROCESS	nucleotide, transcription, regulation
	cell organization/biogenesis

PHYSIOLOGICAL PROCESS

text	suppression of angiogenesis

PATHWAY

metabolism

signaling

signal transduction

TGFB, BMP, SMAD pathway

a component	forming a ternary complex with LIP1 and serine-threonine kinase 11 (STK11)
	interacting with SMAD3 and forming a complex with SNA1
	transcriptional repressor complex that promotes TGFbeta-mediated epithelial-mesenchymal transition

INTERACTION

DNA

RNA

small molecule

protein	CREBBP/EP300, MSG1 (CITED1),LEF1
	binding to MADH1, MADH2, MADH3, MADH5
	cointeracting with FOXH1 through ASE (asymetric enhancers) of NODAL and LEFTY2
	interacting with ER alpha (ESR1 gene)
	interacts with TGFBRAP1
	SNIP1
	can interact directly with Hox proteins and suppress their DNA-binding activity
	interaction between the recombinant homeodomain (HD) of HOXC9 and MH1 domain of SMAD4 (SMAD4 inhibits HOXC9 transcription activity)
	interacting with USP9X (deubiquitinates mono-ubiquitinated SMAD4)
	ADP-ribosylation of SMAD proteins by PARP1 is a key step in controlling the strength and duration of SMAD-mediated transcription
	binding of the N-terminal portion of SMAD4 to the second zinc-finger domain of GATA4 (genetically cooperate in the endocardium during atrioventricular valve formation)

cell & other

REGULATION

activated by

activin receptors in the NODAL pathway (ACVR2)

Phosphorylated by

NLK

Other	COPS5 mediates its degradation
	protected by SUMO-1 modification from ubiquitin-dependent degradation and consequently enhancing the growth inhibitory and transcriptional responses of Smad4
	deubiquitination by USP9X is direct

ASSOCIATED DISORDERS

corresponding disease(s)

JPS , JPHT , MYHRS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   LOH     in cervical cancer constitutional germinal mutation       in juvenile polyposis with malformative vessels and with a more aggressive digestive phenotype tumoral   deletion     in juvenile polyposis in biliary and pancreatic cancer, and in juvenile polyposis (mutational hotspot) with gastric polyposis tumoral       loss of function in pancreas cancer cells lines and in colorectal cancer (in progression) constitutional       loss of function is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth tumoral     --low   is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age groups constitutional       loss of function inactivation in the lens/corneal ectoderm caused disruption in the development of the anterior segment constitutional     --over   sensitizes hematopoietic stem/progenitor cells to TGFB, resulting in growth arrest and apoptosis

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS