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].

NameOMIM IDEnsembl IDHGNC IDPHARMGKB IDMap Location
SMAD family member 4MIM:600993Ensembl:ENSG00000141646HGNC:HGNC:6770PA3052718q21.2

GO terms in SMAD4


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

Gene expression in normal tissue: SMAD4

Gene-model tissue-cancer distribution: Bubble Plot

Gene-drug pathway distribution

Pathways in SMAD4


DatabasePathway IDPathway Des.
wikipathwaysWP138Androgen receptor signaling pathway
wikipathwaysWP1425Bone Morphogenic Protein (BMP) Signalling and Regulation
wikipathwaysWP1591Heart Development
wikipathwaysWP179Cell Cycle
wikipathwaysWP2853Endoderm Differentiation
wikipathwaysWP2857Mesodermal Commitment Pathway
wikipathwaysWP2858Ectoderm Differentiation
wikipathwaysWP2870Extracellular vesicle-mediated signaling in recipient cells
wikipathwaysWP3646Hepatitis C and Hepatocellular Carcinoma
wikipathwaysWP3657Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex
wikipathwaysWP366TGF-beta Signaling Pathway
wikipathwaysWP3668Hypothesized Pathways in Pathogenesis of Cardiovascular Disease
wikipathwaysWP3859TGF-B Signaling in Thyroid Cells for Epithelial-Mesenchymal Transition
wikipathwaysWP3874Canonical and Non-Canonical TGF-B signaling
wikipathwaysWP3927BMP Signaling Pathway in Eyelid Development
wikipathwaysWP3931ESC Pluripotency Pathways
wikipathwaysWP4216Chromosomal and microsatellite instability in colorectal cancer
wikipathwaysWP4239EMT transition in Colorectal Cancer
wikipathwaysWP560TGF-beta Receptor Signaling
wikipathwaysWP615Senescence and Autophagy in Cancer
wikipathwaysWP710DNA Damage Response (only ATM dependent)
netpathPathway_TGF_beta_ReceptorTGF_beta_Receptor
pidalk1pathwayALK1 signaling events
pidalk2pathwayALK2 signaling events
pidbmppathwayBMP receptor signaling
pidera_genomic_pathwayValidated nuclear estrogen receptor alpha network
pidhif1_tfpathwayHIF-1-alpha transcription factor network
pidlkb1_pathwayLKB1 signaling events
pidmyc_activpathwayValidated targets of C-MYC transcriptional activation
pidmyc_represspathwayValidated targets of C-MYC transcriptional repression
pidsmad2_3nuclearpathwayRegulation of nuclear SMAD2/3 signaling
pidsmad2_3pathwayRegulation of cytoplasmic and nuclear SMAD2/3 signaling
pidtgfbrpathwayTGF-beta receptor signaling
kegghsa04068FoxO signaling pathway - Homo sapiens (human)
kegghsa04110Cell cycle - Homo sapiens (human)
kegghsa04310Wnt signaling pathway - Homo sapiens (human)
kegghsa04350TGF-beta signaling pathway - Homo sapiens (human)
kegghsa04371Apelin signaling pathway - Homo sapiens (human)
kegghsa04390Hippo signaling pathway - Homo sapiens (human)
kegghsa04520Adherens junction - Homo sapiens (human)
kegghsa04550Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
kegghsa04659Th17 cell differentiation - Homo sapiens (human)
kegghsa04933AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
kegghsa05161Hepatitis B - Homo sapiens (human)
kegghsa05166HTLV-I infection - Homo sapiens (human)
kegghsa05200Pathways in cancer - Homo sapiens (human)
kegghsa05210Colorectal cancer - Homo sapiens (human)
kegghsa05212Pancreatic cancer - Homo sapiens (human)
kegghsa05220Chronic myeloid leukemia - Homo sapiens (human)
kegghsa05225Hepatocellular carcinoma - Homo sapiens (human)
kegghsa05226Gastric cancer - Homo sapiens (human)
humancycPWY66-11BMP Signalling Pathway
biocartaalkpathwayalk in cardiac myocytes
biocartactcfpathwayctcf: first multivalent nuclear factor
biocartag1pathwaycell cycle: g1/s check point
biocartanthipathwaynfkb activation by nontypeable hemophilus influenzae
biocartatgfbpathwaytgf beta signaling pathway
biocartawntpathwaywnt signaling pathway
reactomeR-HSA-1181150Signaling by NODAL
reactomeR-HSA-1266738Developmental Biology
reactomeR-HSA-1502540Signaling by Activin
reactomeR-HSA-162582Signal Transduction
reactomeR-HSA-162582Signal Transduction
reactomeR-HSA-1643685Disease
reactomeR-HSA-170834Signaling by TGF-beta Receptor Complex
reactomeR-HSA-170834Signaling by TGF-beta Receptor Complex
reactomeR-HSA-201451Signaling by BMP
reactomeR-HSA-212436Generic Transcription Pathway
reactomeR-HSA-212436Generic Transcription Pathway
reactomeR-HSA-2173789TGF-beta receptor signaling activates SMADs
reactomeR-HSA-2173793Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
reactomeR-HSA-2173793Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
reactomeR-HSA-2173795Downregulation of SMAD2/3:SMAD4 transcriptional activity
reactomeR-HSA-2173795Downregulation of SMAD2/3:SMAD4 transcriptional activity
reactomeR-HSA-2173796SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
reactomeR-HSA-3304347Loss of Function of SMAD4 in Cancer
reactomeR-HSA-3304349Loss of Function of SMAD2/3 in Cancer
reactomeR-HSA-3304351Signaling by TGF-beta Receptor Complex in Cancer
reactomeR-HSA-3311021SMAD4 MH2 Domain Mutants in Cancer
reactomeR-HSA-3315487SMAD2/3 MH2 Domain Mutants in Cancer
reactomeR-HSA-392499Metabolism of proteins
reactomeR-HSA-452723Transcriptional regulation of pluripotent stem cells
reactomeR-HSA-5663202Diseases of signal transduction
reactomeR-HSA-5688426Deubiquitination
reactomeR-HSA-5689880Ub-specific processing proteases
reactomeR-HSA-597592Post-translational protein modification
reactomeR-HSA-73857RNA Polymerase II Transcription
reactomeR-HSA-73857RNA Polymerase II Transcription
reactomeR-HSA-74160Gene expression (Transcription)
reactomeR-HSA-74160Gene expression (Transcription)
reactomeR-HSA-8878159Transcriptional regulation by RUNX3
reactomeR-HSA-8878166Transcriptional regulation by RUNX2
reactomeR-HSA-8941326RUNX2 regulates bone development
reactomeR-HSA-8941855RUNX3 regulates CDKN1A transcription
reactomeR-HSA-8952158RUNX3 regulates BCL2L11 (BIM) transcription
reactomeR-HSA-9006936Signaling by TGF-beta family members
reactomeR-HSA-9006936Signaling by TGF-beta family members

Gene-Drug: Aster Plot


Drug IDDrug NameModel Num.
iGMDRD190Nilotinib1
iGMDRD64Parbendazole7
iGMDRD524ISX-94
iGMDRD399Selumetinib7
iGMDRD74Idarubicin1
iGMDRD188Piperlongumine1
iGMDRD780PP-302
iGMDRD117Docetaxel2
iGMDRD284Palbociclib1
iGMDRD294Batimastat3
iGMDRD513BML-2592
iGMDRD316N9-Isopropyl-olomoucine2
iGMDRD427ABT7373
iGMDRD781Sirolimus1
iGMDRD283Bosutinib1
iGMDRD151CHM-16
iGMDRD126Tipifarnib2
iGMDRD245FH5351
iGMDRD366PI-1031
iGMDRD705Nakiterpiosin4
iGMDRD461VX-11e1
iGMDRD594AZD-80551
iGMDRD423AT 78671
iGMDRD1036X17AAG1
iGMDRD405PIK-751
iGMDRD564GSK-6503941
iGMDRD324CI-10403
iGMDRD248BRD43544
iGMDRD131Erlotinib2
iGMDRD60Quinoclamine2
iGMDRD312Pelitinib2
iGMDRD332A-7700411
iGMDRD398Sepantronium4
iGMDRD562Navitoclax7
iGMDRD577BIX012943
iGMDRD782DC-45-A22
iGMDRD441TW 371
iGMDRD491TAE-6841
iGMDRD255SB2250023
iGMDRD673LSM-12151
iGMDRD401Afatinib4
iGMDRD608Refametinib3
iGMDRD519GDC-09411
iGMDRD193Fqi12
iGMDRD239Dasatinib1
iGMDRD678Tubastatin A2
iGMDRD313Axitinib1
iGMDRD136Nutlin-31
iGMDRD112Methotrexate1
iGMDRD659Avagacestat (BMS-708163)1
iGMDRD1008SR-II-138A1
iGMDRD505Pevonedistat6
iGMDRD472PF-5622711
iGMDRD353PD03259012
iGMDRD872BRD71373
iGMDRD68Paclitaxel1
iGMDRD459RO-33061
iGMDRD271Brefeldin A1
iGMDRD139Fumagillol2
iGMDRD901ELCPK5
iGMDRD351GW843682X4
iGMDRD456Crizotinib1
iGMDRD486Tosedostat1
iGMDRD382CEP-7011
iGMDRD23Gossypol3
iGMDRD356PNU-746541
iGMDRD133Lapatinib2
iGMDRD146Elesclomol1
iGMDRD187BRD98762
iGMDRD260FQI-23
iGMDRD1593-Chloro-L-alanine4
iGMDRD407Sotrastaurin1
iGMDRD748PHA-6657521
iGMDRD21Fluorouracil1
iGMDRD639YK 4-2794
iGMDRD670ML 2102
iGMDRD397Pazopanib1
iGMDRD409Saracatinib1
iGMDRD433Lexibulin4
iGMDRD749ZINC67184531
iGMDRD889Compound 7d-cis1
iGMDRD12Bicalutamide2
iGMDRD147Prima-11
iGMDRD421AZD77621
iGMDRD871BRD63683
iGMDRD993QL-XII-611
iGMDRD662JQ-12
iGMDRD221Tamoxifen1
iGMDRD158NSC1415404
iGMDRD293Bleomycin1
iGMDRD103SN-382
iGMDRD5Tyrphostin AG 14781
iGMDRD123Isoevodiamine3
iGMDRD154NSC237663
iGMDRD775NCGC00346967-011
iGMDRD237ABT-7513
iGMDRD352PD-03259012
iGMDRD698Neratinib1
iGMDRD15Tacedinaline1
iGMDRD276AS 6052402
iGMDRD533HSCI1_0002701
iGMDRD444Tivantinib1
iGMDRD451Serdemetan1
iGMDRD887Compound 23 citrate2
iGMDRD30917AAG2
iGMDRD138PX 121
iGMDRD134Sorafenib1
iGMDRD33Entinostat1
iGMDRD8024-methylfasudil7
iGMDRD280CYTOCHALASIN B2
iGMDRD776QL-XI-921
iGMDRD253Vincaleukoblastine2
iGMDRD446LY 21832402
iGMDRD718Pyrvinium pamoate1
iGMDRD144NSC953972
iGMDRD494Neopeltolide1
iGMDRD400A-4436541
iGMDRD42Vorinostat2
iGMDRD967Panitumumab1
iGMDRD192CIL563
iGMDRD434BMS-5369241
iGMDRD6AM-5802
iGMDRD551Ponatinib1
iGMDRD481Dactolisib2
iGMDRD177Teniposide4
iGMDRD357AG 143612
iGMDRD435BI-25361
iGMDRD317CCT 0181591
iGMDRD765BRD-K514902541
iGMDRD536PLX-47201
iGMDRD84Lovastatin acid1
iGMDRD792Cetuximab2

Gene in drug-gene network: Network Plot

Gene-drug targets distribution

Gene Structure: PDB

Models in SMAD4

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