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SMAD4

Summary: This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasng blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, Aug 2017].

Name	OMIM ID	Ensembl ID	HGNC ID	PHARMGKB ID	Map Location
SMAD family member 4	MIM:600993	Ensembl:ENSG00000141646	HGNC:HGNC:6770	PA30527	18q21.2

Gene Categories:

HISTONE MODIFICATION TRANSCRIPTION FACTOR COMPLEX TRANSCRIPTION FACTOR BINDING CLINICALLY ACTIONABLE

GO terms in SMAD4

Term Type	Evidence Type	GO Term ID	GO Des.
MF	IDA	GO:0000978	RNA polymerase II proximal promoter sequence-specific DNA binding
MF	ISA	GO:0000981	RNA polymerase II transcription factor activity, sequence-specific DNA binding
MF	ISM	GO:0000981	RNA polymerase II transcription factor activity, sequence-specific DNA binding
MF	NAS	GO:0000981	RNA polymerase II transcription factor activity, sequence-specific DNA binding
MF	IDA	GO:0000987	proximal promoter sequence-specific DNA binding
MF	IDA	GO:0000989	transcription factor activity, transcription factor binding
MF	IDA	GO:0001077	transcriptional activator activity, RNA polymerase II proximal promoter sequence-specific DNA binding
MF	IEA	GO:0001085	RNA polymerase II transcription factor binding
MF	IDA	GO:0003677	DNA binding
MF	IEA	GO:0003682	chromatin binding
MF	IDA	GO:0003700	DNA-binding transcription factor activity
MF	IPI	GO:0005515	protein binding
MF	IEA	GO:0005518	collagen binding
MF	IDA	GO:0030616	transforming growth factor beta receptor, common-partner cytoplasmic mediator activity
MF	IMP	GO:0042802	identical protein binding
MF	IPI	GO:0042802	identical protein binding
MF	IPI	GO:0042803	protein homodimerization activity
MF	IMP	GO:0043199	sulfate binding
MF	IDA	GO:0043565	sequence-specific DNA binding
MF	IDA	GO:0044212	transcription regulatory region DNA binding
MF	IEA	GO:0046872	metal ion binding
MF	IEA	GO:0046982	protein heterodimerization activity
MF	IPI	GO:0070411	I-SMAD binding
MF	IPI	GO:0070412	R-SMAD binding
CC	IDA	GO:0000790	nuclear chromatin
CC	IDA	GO:0005634	nucleus
CC	IDA	GO:0005654	nucleoplasm
CC	TAS	GO:0005654	nucleoplasm
CC	IDA	GO:0005667	transcription factor complex
CC	IPI	GO:0005667	transcription factor complex
CC	IDA	GO:0005737	cytoplasm
CC	IDA	GO:0005813	centrosome
CC	IDA	GO:0005829	cytosol
CC	TAS	GO:0005829	cytosol
CC	IDA	GO:0032444	activin responsive factor complex
CC	IDA	GO:0071141	SMAD protein complex
CC	IMP	GO:0071141	SMAD protein complex
BP	ISS	GO:0000122	negative regulation of transcription by RNA polymerase II
BP	TAS	GO:0000122	negative regulation of transcription by RNA polymerase II
BP	IEA	GO:0001541	ovarian follicle development
BP	IEA	GO:0001658	branching involved in ureteric bud morphogenesis
BP	IMP	GO:0001666	response to hypoxia
BP	IEA	GO:0001701	in utero embryonic development
BP	IEA	GO:0001702	gastrulation with mouth forming second
BP	ISS	GO:0003148	outflow tract septum morphogenesis
BP	IEA	GO:0003190	atrioventricular valve formation
BP	IEA	GO:0003198	epithelial to mesenchymal transition involved in endocardial cushion formation
BP	ISS	GO:0003220	left ventricular cardiac muscle tissue morphogenesis
BP	IEA	GO:0003251	positive regulation of cell proliferation involved in heart valve morphogenesis
BP	IEA	GO:0003360	brainstem development
BP	ISS	GO:0006879	cellular iron ion homeostasis
BP	IDA	GO:0007179	transforming growth factor beta receptor signaling pathway
BP	ISS	GO:0007179	transforming growth factor beta receptor signaling pathway
BP	TAS	GO:0007179	transforming growth factor beta receptor signaling pathway
BP	IDA	GO:0007183	SMAD protein complex assembly
BP	IEA	GO:0007283	spermatogenesis
BP	IEA	GO:0007338	single fertilization
BP	IEA	GO:0007411	axon guidance
BP	IEA	GO:0007492	endoderm development
BP	IEA	GO:0007498	mesoderm development
BP	IEA	GO:0008283	cell proliferation
BP	IEA	GO:0008285	negative regulation of cell proliferation
BP	ISS	GO:0010614	negative regulation of cardiac muscle hypertrophy
BP	ISS	GO:0010718	positive regulation of epithelial to mesenchymal transition
BP	ISS	GO:0010862	positive regulation of pathway-restricted SMAD protein phosphorylation
BP	IEA	GO:0014033	neural crest cell differentiation
BP	TAS	GO:0016579	protein deubiquitination
BP	IMP	GO:0017015	regulation of transforming growth factor beta receptor signaling pathway
BP	IDA	GO:0030308	negative regulation of cell growth
BP	IDA	GO:0030509	BMP signaling pathway
BP	ISS	GO:0030509	BMP signaling pathway
BP	TAS	GO:0030509	BMP signaling pathway
BP	IDA	GO:0030511	positive regulation of transforming growth factor beta receptor signaling pathway
BP	IMP	GO:0030513	positive regulation of BMP signaling pathway
BP	IEA	GO:0032525	somite rostral/caudal axis specification
BP	IMP	GO:0032909	regulation of transforming growth factor beta2 production
BP	IEA	GO:0033686	positive regulation of luteinizing hormone secretion
BP	TAS	GO:0035019	somatic stem cell population maintenance
BP	IMP	GO:0035556	intracellular signal transduction
BP	IEA	GO:0036302	atrioventricular canal development
BP	IEA	GO:0042118	endothelial cell activation
BP	IEA	GO:0042733	embryonic digit morphogenesis
BP	IDA	GO:0045892	negative regulation of transcription, DNA-templated
BP	IDA	GO:0045893	positive regulation of transcription, DNA-templated
BP	IDA	GO:0045944	positive regulation of transcription by RNA polymerase II
BP	ISS	GO:0045944	positive regulation of transcription by RNA polymerase II
BP	TAS	GO:0045944	positive regulation of transcription by RNA polymerase II
BP	IEA	GO:0046881	positive regulation of follicle-stimulating hormone secretion
BP	IEA	GO:0048589	developmental growth
BP	IEA	GO:0048663	neuron fate commitment
BP	IEA	GO:0048733	sebaceous gland development
BP	IEA	GO:0048859	formation of anatomical boundary
BP	IEA	GO:0051098	regulation of binding
BP	ISS	GO:0051571	positive regulation of histone H3-K4 methylation
BP	IEA	GO:0051797	regulation of hair follicle development
BP	IEA	GO:0060065	uterus development
BP	ISS	GO:0060391	positive regulation of SMAD protein signal transduction
BP	IDA	GO:0060395	SMAD protein signal transduction
BP	ISS	GO:0060412	ventricular septum morphogenesis
BP	IEA	GO:0060548	negative regulation of cell death
BP	IEA	GO:0060956	endocardial cell differentiation
BP	IEA	GO:0061040	female gonad morphogenesis
BP	IEA	GO:0061614	pri-miRNA transcription by RNA polymerase II
BP	ISS	GO:0062009	secondary palate development
BP	ISS	GO:0070102	interleukin-6-mediated signaling pathway
BP	IMP	GO:0070207	protein homotrimerization
BP	ISS	GO:0070373	negative regulation of ERK1 and ERK2 cascade
BP	IDA	GO:0071559	response to transforming growth factor beta
BP	NAS	GO:0071773	cellular response to BMP stimulus
BP	IEA	GO:0072133	metanephric mesenchyme morphogenesis
BP	IEA	GO:0072134	nephrogenic mesenchyme morphogenesis
BP	IEA	GO:0072520	seminiferous tubule development
BP	TAS	GO:1901522	positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus
BP	ISS	GO:1905305	negative regulation of cardiac myofibril assembly
BP	ISS	GO:2000617	positive regulation of histone H3-K9 acetylation

Gene expression in normal tissue: SMAD4

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Gene-model tissue-cancer distribution: Bubble Plot

Gene-drug pathway distribution

Pathways in SMAD4

Database	Pathway ID	Pathway Des.
wikipathways	WP138	Androgen receptor signaling pathway
wikipathways	WP1425	Bone Morphogenic Protein (BMP) Signalling and Regulation
wikipathways	WP1591	Heart Development
wikipathways	WP179	Cell Cycle
wikipathways	WP2853	Endoderm Differentiation
wikipathways	WP2857	Mesodermal Commitment Pathway
wikipathways	WP2858	Ectoderm Differentiation
wikipathways	WP2870	Extracellular vesicle-mediated signaling in recipient cells
wikipathways	WP3646	Hepatitis C and Hepatocellular Carcinoma
wikipathways	WP3657	Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex
wikipathways	WP366	TGF-beta Signaling Pathway
wikipathways	WP3668	Hypothesized Pathways in Pathogenesis of Cardiovascular Disease
wikipathways	WP3859	TGF-B Signaling in Thyroid Cells for Epithelial-Mesenchymal Transition
wikipathways	WP3874	Canonical and Non-Canonical TGF-B signaling
wikipathways	WP3927	BMP Signaling Pathway in Eyelid Development
wikipathways	WP3931	ESC Pluripotency Pathways
wikipathways	WP4216	Chromosomal and microsatellite instability in colorectal cancer
wikipathways	WP4239	EMT transition in Colorectal Cancer
wikipathways	WP560	TGF-beta Receptor Signaling
wikipathways	WP615	Senescence and Autophagy in Cancer
wikipathways	WP710	DNA Damage Response (only ATM dependent)
netpath	Pathway_TGF_beta_Receptor	TGF_beta_Receptor
pid	alk1pathway	ALK1 signaling events
pid	alk2pathway	ALK2 signaling events
pid	bmppathway	BMP receptor signaling
pid	era_genomic_pathway	Validated nuclear estrogen receptor alpha network
pid	hif1_tfpathway	HIF-1-alpha transcription factor network
pid	lkb1_pathway	LKB1 signaling events
pid	myc_activpathway	Validated targets of C-MYC transcriptional activation
pid	myc_represspathway	Validated targets of C-MYC transcriptional repression
pid	smad2_3nuclearpathway	Regulation of nuclear SMAD2/3 signaling
pid	smad2_3pathway	Regulation of cytoplasmic and nuclear SMAD2/3 signaling
pid	tgfbrpathway	TGF-beta receptor signaling
kegg	hsa04068	FoxO signaling pathway - Homo sapiens (human)
kegg	hsa04110	Cell cycle - Homo sapiens (human)
kegg	hsa04310	Wnt signaling pathway - Homo sapiens (human)
kegg	hsa04350	TGF-beta signaling pathway - Homo sapiens (human)
kegg	hsa04371	Apelin signaling pathway - Homo sapiens (human)
kegg	hsa04390	Hippo signaling pathway - Homo sapiens (human)
kegg	hsa04520	Adherens junction - Homo sapiens (human)
kegg	hsa04550	Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
kegg	hsa04659	Th17 cell differentiation - Homo sapiens (human)
kegg	hsa04933	AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
kegg	hsa05161	Hepatitis B - Homo sapiens (human)
kegg	hsa05166	HTLV-I infection - Homo sapiens (human)
kegg	hsa05200	Pathways in cancer - Homo sapiens (human)
kegg	hsa05210	Colorectal cancer - Homo sapiens (human)
kegg	hsa05212	Pancreatic cancer - Homo sapiens (human)
kegg	hsa05220	Chronic myeloid leukemia - Homo sapiens (human)
kegg	hsa05225	Hepatocellular carcinoma - Homo sapiens (human)
kegg	hsa05226	Gastric cancer - Homo sapiens (human)
humancyc	PWY66-11	BMP Signalling Pathway
biocarta	alkpathway	alk in cardiac myocytes
biocarta	ctcfpathway	ctcf: first multivalent nuclear factor
biocarta	g1pathway	cell cycle: g1/s check point
biocarta	nthipathway	nfkb activation by nontypeable hemophilus influenzae
biocarta	tgfbpathway	tgf beta signaling pathway
biocarta	wntpathway	wnt signaling pathway
reactome	R-HSA-1181150	Signaling by NODAL
reactome	R-HSA-1266738	Developmental Biology
reactome	R-HSA-1502540	Signaling by Activin
reactome	R-HSA-162582	Signal Transduction
reactome	R-HSA-162582	Signal Transduction
reactome	R-HSA-1643685	Disease
reactome	R-HSA-170834	Signaling by TGF-beta Receptor Complex
reactome	R-HSA-170834	Signaling by TGF-beta Receptor Complex
reactome	R-HSA-201451	Signaling by BMP
reactome	R-HSA-212436	Generic Transcription Pathway
reactome	R-HSA-212436	Generic Transcription Pathway
reactome	R-HSA-2173789	TGF-beta receptor signaling activates SMADs
reactome	R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
reactome	R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
reactome	R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
reactome	R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
reactome	R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
reactome	R-HSA-3304347	Loss of Function of SMAD4 in Cancer
reactome	R-HSA-3304349	Loss of Function of SMAD2/3 in Cancer
reactome	R-HSA-3304351	Signaling by TGF-beta Receptor Complex in Cancer
reactome	R-HSA-3311021	SMAD4 MH2 Domain Mutants in Cancer
reactome	R-HSA-3315487	SMAD2/3 MH2 Domain Mutants in Cancer
reactome	R-HSA-392499	Metabolism of proteins
reactome	R-HSA-452723	Transcriptional regulation of pluripotent stem cells
reactome	R-HSA-5663202	Diseases of signal transduction
reactome	R-HSA-5688426	Deubiquitination
reactome	R-HSA-5689880	Ub-specific processing proteases
reactome	R-HSA-597592	Post-translational protein modification
reactome	R-HSA-73857	RNA Polymerase II Transcription
reactome	R-HSA-73857	RNA Polymerase II Transcription
reactome	R-HSA-74160	Gene expression (Transcription)
reactome	R-HSA-74160	Gene expression (Transcription)
reactome	R-HSA-8878159	Transcriptional regulation by RUNX3
reactome	R-HSA-8878166	Transcriptional regulation by RUNX2
reactome	R-HSA-8941326	RUNX2 regulates bone development
reactome	R-HSA-8941855	RUNX3 regulates CDKN1A transcription
reactome	R-HSA-8952158	RUNX3 regulates BCL2L11 (BIM) transcription
reactome	R-HSA-9006936	Signaling by TGF-beta family members
reactome	R-HSA-9006936	Signaling by TGF-beta family members

Gene-Drug: Aster Plot

Drug ID	Drug Name	Model Num.
iGMDRD190	Nilotinib	1
iGMDRD64	Parbendazole	7
iGMDRD524	ISX-9	4
iGMDRD399	Selumetinib	7
iGMDRD74	Idarubicin	1
iGMDRD188	Piperlongumine	1
iGMDRD780	PP-30	2
iGMDRD117	Docetaxel	2
iGMDRD284	Palbociclib	1
iGMDRD294	Batimastat	3
iGMDRD513	BML-259	2
iGMDRD316	N9-Isopropyl-olomoucine	2
iGMDRD427	ABT737	3
iGMDRD781	Sirolimus	1
iGMDRD283	Bosutinib	1
iGMDRD151	CHM-1	6
iGMDRD126	Tipifarnib	2
iGMDRD245	FH535	1
iGMDRD366	PI-103	1
iGMDRD705	Nakiterpiosin	4
iGMDRD461	VX-11e	1
iGMDRD594	AZD-8055	1
iGMDRD423	AT 7867	1
iGMDRD1036	X17AAG	1
iGMDRD405	PIK-75	1
iGMDRD564	GSK-650394	1
iGMDRD324	CI-1040	3
iGMDRD248	BRD4354	4
iGMDRD131	Erlotinib	2
iGMDRD60	Quinoclamine	2
iGMDRD312	Pelitinib	2
iGMDRD332	A-770041	1
iGMDRD398	Sepantronium	4
iGMDRD562	Navitoclax	7
iGMDRD577	BIX01294	3
iGMDRD782	DC-45-A2	2
iGMDRD441	TW 37	1
iGMDRD491	TAE-684	1
iGMDRD255	SB225002	3
iGMDRD673	LSM-1215	1
iGMDRD401	Afatinib	4
iGMDRD608	Refametinib	3
iGMDRD519	GDC-0941	1
iGMDRD193	Fqi1	2
iGMDRD239	Dasatinib	1
iGMDRD678	Tubastatin A	2
iGMDRD313	Axitinib	1
iGMDRD136	Nutlin-3	1
iGMDRD112	Methotrexate	1
iGMDRD659	Avagacestat (BMS-708163)	1
iGMDRD1008	SR-II-138A	1
iGMDRD505	Pevonedistat	6
iGMDRD472	PF-562271	1
iGMDRD353	PD0325901	2
iGMDRD872	BRD7137	3
iGMDRD68	Paclitaxel	1
iGMDRD459	RO-3306	1
iGMDRD271	Brefeldin A	1
iGMDRD139	Fumagillol	2
iGMDRD901	ELCPK	5
iGMDRD351	GW843682X	4
iGMDRD456	Crizotinib	1
iGMDRD486	Tosedostat	1
iGMDRD382	CEP-701	1
iGMDRD23	Gossypol	3
iGMDRD356	PNU-74654	1
iGMDRD133	Lapatinib	2
iGMDRD146	Elesclomol	1
iGMDRD187	BRD9876	2
iGMDRD260	FQI-2	3
iGMDRD159	3-Chloro-L-alanine	4
iGMDRD407	Sotrastaurin	1
iGMDRD748	PHA-665752	1
iGMDRD21	Fluorouracil	1
iGMDRD639	YK 4-279	4
iGMDRD670	ML 210	2
iGMDRD397	Pazopanib	1
iGMDRD409	Saracatinib	1
iGMDRD433	Lexibulin	4
iGMDRD749	ZINC6718453	1
iGMDRD889	Compound 7d-cis	1
iGMDRD12	Bicalutamide	2
iGMDRD147	Prima-1	1
iGMDRD421	AZD7762	1
iGMDRD871	BRD6368	3
iGMDRD993	QL-XII-61	1
iGMDRD662	JQ-1	2
iGMDRD221	Tamoxifen	1
iGMDRD158	NSC141540	4
iGMDRD293	Bleomycin	1
iGMDRD103	SN-38	2
iGMDRD5	Tyrphostin AG 1478	1
iGMDRD123	Isoevodiamine	3
iGMDRD154	NSC23766	3
iGMDRD775	NCGC00346967-01	1
iGMDRD237	ABT-751	3
iGMDRD352	PD-0325901	2
iGMDRD698	Neratinib	1
iGMDRD15	Tacedinaline	1
iGMDRD276	AS 605240	2
iGMDRD533	HSCI1_000270	1
iGMDRD444	Tivantinib	1
iGMDRD451	Serdemetan	1
iGMDRD887	Compound 23 citrate	2
iGMDRD309	17AAG	2
iGMDRD138	PX 12	1
iGMDRD134	Sorafenib	1
iGMDRD33	Entinostat	1
iGMDRD802	4-methylfasudil	7
iGMDRD280	CYTOCHALASIN B	2
iGMDRD776	QL-XI-92	1
iGMDRD253	Vincaleukoblastine	2
iGMDRD446	LY 2183240	2
iGMDRD718	Pyrvinium pamoate	1
iGMDRD144	NSC95397	2
iGMDRD494	Neopeltolide	1
iGMDRD400	A-443654	1
iGMDRD42	Vorinostat	2
iGMDRD967	Panitumumab	1
iGMDRD192	CIL56	3
iGMDRD434	BMS-536924	1
iGMDRD6	AM-580	2
iGMDRD551	Ponatinib	1
iGMDRD481	Dactolisib	2
iGMDRD177	Teniposide	4
iGMDRD357	AG 14361	2
iGMDRD435	BI-2536	1
iGMDRD317	CCT 018159	1
iGMDRD765	BRD-K51490254	1
iGMDRD536	PLX-4720	1
iGMDRD84	Lovastatin acid	1
iGMDRD792	Cetuximab	2

Gene in drug-gene network: Network Plot

Gene-drug targets distribution

Gene Structure: PDB

Models in SMAD4

SITE

DATATYPES

CLASSFICATION

Disclaimer: iGMDR is intended for research purposes only. Its information cannot be used for emergencies or medical or professional advice.