| Tag | Content |
|---|---|
| Uniprot ID | P97471; Q6GTP6; Q9CW56; |
| Entrez ID | 17128 |
| Genbank protein ID | AAB57905.1; EDL09560.1; BAB23576.1; AAH46584.1; |
| Genbank nucleotide ID | NM_008540.2 |
| Ensembl protein ID | ENSMUSP00000025393; ENSMUSP00000110589; |
| Ensembl nucleotide ID | ENSMUSG00000024515 |
| Gene name | Mothers against decapentaplegic homolog 4 |
| Gene symbol | Smad4 |
| Organism | Mus musculus |
| NCBI taxa ID | 10090 |
| Cleft type | CPO |
| Developmental stage | E12.5, E13.5, E14.5 |
| Data sources | Manually collected |
| Reference | 25523394; 23406900; |
| Functional description | Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator (By similarity). Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (PubMed:15329343). Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (PubMed:15329343). In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. |
| Sequence | MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK KDELDSLITA 60 ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR WPDLHKNELK HVKYCQYAFD 120 LKCDSVCVNP YHYERVVSPG IDLSGLTLQS NAPSMLVKDE YVHDFEGQPS LPTEGHSIQT 180 IQHPPSNRAS TETYSAPALL APAESNATST TNFPNIPVAS TSQPASILAG SHSEGLLQIA 240 SGPQPGQQQN GFTAQPATYH HNSTTTWTGS RTAPYTPNLP HHQNGHLQHH PPMPPHPGHY 300 WPVHNELAFQ PPISNHPAPE YWCSIAYFEM DVQVGETFKV PSSCPVVTVD GYVDPSGGDR 360 FCLGQLSNVH RTEAIERARL HIGKGVQLEC KGEGDVWVRC LSDHAVFVQS YYLDREAGRA 420 PGDAVHKIYP SAYIKVFDLR QCHRQMQQQA ATAQAAAAAQ AAAVAGNIPG PGSVGGIAPA 480 ISLSAAAGIG VDDLRRLCIL RMSFVKGWGP DYPRQSIKET PCWIEIHLHR ALQLLDEVLH 540 TMPIADPQPL D 551 |
Abbreviation :
CLO : cleft lip only. CPO : cleft palate only.
CLP : cleft lip and palate. CL/P : cleft lip with/without cleft palate.
For humans: CL/P, CLO, CPO, and CLP. For mice: CLO, CLP, and CPO.
| Relation | Gene symbol | Entrez ID | UniProt ID | Cleft type | Developmental stage | Species | Evidence | Details |
|---|---|---|---|---|---|---|---|---|
| 1:1 ortholog | SMAD4 | 540248 | B0JYL0 | Bos taurus | Prediction | More>> | ||
| 1:1 ortholog | SMAD4 | A0A5F4CED2 | Canis lupus familiaris | Prediction | More>> | |||
| 1:1 ortholog | SMAD4 | A0A452F8L3 | Capra hircus | Prediction | More>> | |||
| 1:1 ortholog | SMAD4 | A0A3Q2GWH9 | Equus caballus | Prediction | More>> | |||
| 1:1 ortholog | SMAD4 | 4089 | Q13485 | Homo sapiens | Prediction | More>> | ||
| 1:1 ortholog | Smad4 | 17128 | P97471 | CPO | E12.5, E13.5, E14.5 | Mus musculus | Publication | More>> |
| 1:1 ortholog | SMAD4 | A0A2I3S6S5 | Pan troglodytes | Prediction | More>> | |||
| 1:1 ortholog | A0A4X1UID5 | Sus scrofa | Prediction | More>> | ||||
| 1:1 ortholog | SMAD4 | 100342294 | G1SKR1 | Oryctolagus cuniculus | Prediction | More>> | ||
| 1:1 ortholog | Smad4 | A0A0G2K970 | Rattus norvegicus | Prediction | More>> |
| GO ID | GO Term | Evidence |
|---|---|---|
| GO:0000977 | RNA polymerase II regulatory region sequence-specific DNA binding | IGI |
| GO:0000977 | RNA polymerase II regulatory region sequence-specific DNA binding | IDA |
| GO:0000978 | RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISO |
| GO:0000978 | RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA |
| GO:0000987 | cis-regulatory region sequence-specific DNA binding | ISO |
| GO:0001085 | RNA polymerase II transcription factor binding | IPI |
| GO:0001223 | transcription coactivator binding | ISO |
| GO:0001228 | DNA-binding transcription activator activity, RNA polymerase II-specific | ISO |
| GO:0001228 | DNA-binding transcription activator activity, RNA polymerase II-specific | IDA |
| GO:0001228 | DNA-binding transcription activator activity, RNA polymerase II-specific | IGI |
| GO:0003677 | DNA binding | ISO |
| GO:0003677 | DNA binding | IDA |
| GO:0003682 | chromatin binding | IDA |
| GO:0003700 | DNA-binding transcription factor activity | IDA |
| GO:0003712 | transcription coregulator activity | ISO |
| GO:0005515 | protein binding | IPI |
| GO:0005518 | collagen binding | IPI |
| GO:0030616 | transforming growth factor beta receptor, common-partner cytoplasmic mediator activity | ISO |
| GO:0031005 | filamin binding | ISO |
| GO:0042802 | identical protein binding | ISO |
| GO:0042803 | protein homodimerization activity | ISO |
| GO:0043199 | sulfate binding | ISO |
| GO:0044212 | transcription regulatory region DNA binding | ISO |
| GO:0046332 | SMAD binding | ISO |
| GO:0046872 | metal ion binding | IEA |
| GO:0070411 | I-SMAD binding | ISO |
| GO:0070412 | R-SMAD binding | ISO |
| GO:0098772 | molecular function regulator | IMP |
| GO:0003700 | DNA-binding transcription factor activity | ISO |
| GO:0043565 | sequence-specific DNA binding | ISO |
| GO ID | GO Term | Evidence |
|---|---|---|
| GO:0000122 | negative regulation of transcription by RNA polymerase II | IMP |
| GO:0001541 | ovarian follicle development | IGI |
| GO:0001541 | ovarian follicle development | IMP |
| GO:0001649 | osteoblast differentiation | ISO |
| GO:0001658 | branching involved in ureteric bud morphogenesis | IGI |
| GO:0001666 | response to hypoxia | ISO |
| GO:0001701 | in utero embryonic development | IMP |
| GO:0001702 | gastrulation with mouth forming second | IMP |
| GO:0001822 | kidney development | IMP |
| GO:0003148 | outflow tract septum morphogenesis | IGI |
| GO:0003190 | atrioventricular valve formation | IGI |
| GO:0003198 | epithelial to mesenchymal transition involved in endocardial cushion formation | IMP |
| GO:0003220 | left ventricular cardiac muscle tissue morphogenesis | IMP |
| GO:0003251 | positive regulation of cell proliferation involved in heart valve morphogenesis | IMP |
| GO:0003279 | cardiac septum development | IGI |
| GO:0003360 | brainstem development | IMP |
| GO:0006357 | regulation of transcription by RNA polymerase II | IDA |
| GO:0006879 | cellular iron ion homeostasis | IMP |
| GO:0007179 | transforming growth factor beta receptor signaling pathway | ISO |
| GO:0007179 | transforming growth factor beta receptor signaling pathway | IMP |
| GO:0007179 | transforming growth factor beta receptor signaling pathway | IGI |
| GO:0007183 | SMAD protein complex assembly | ISO |
| GO:0007283 | spermatogenesis | IMP |
| GO:0007338 | single fertilization | IGI |
| GO:0007369 | gastrulation | IMP |
| GO:0007411 | axon guidance | IMP |
| GO:0007492 | endoderm development | IMP |
| GO:0007498 | mesoderm development | IMP |
| GO:0008283 | cell population proliferation | IMP |
| GO:0008285 | negative regulation of cell population proliferation | IGI |
| GO:0008584 | male gonad development | IMP |
| GO:0008585 | female gonad development | IGI |
| GO:0009653 | anatomical structure morphogenesis | IMP |
| GO:0009952 | anterior/posterior pattern specification | IMP |
| GO:0010614 | negative regulation of cardiac muscle hypertrophy | IMP |
| GO:0010666 | positive regulation of cardiac muscle cell apoptotic process | ISO |
| GO:0010718 | positive regulation of epithelial to mesenchymal transition | IMP |
| GO:0010862 | positive regulation of pathway-restricted SMAD protein phosphorylation | IMP |
| GO:0014033 | neural crest cell differentiation | IMP |
| GO:0017015 | regulation of transforming growth factor beta receptor signaling pathway | ISO |
| GO:0030154 | cell differentiation | IMP |
| GO:0030308 | negative regulation of cell growth | ISO |
| GO:0030509 | BMP signaling pathway | ISO |
| GO:0030509 | BMP signaling pathway | IMP |
| GO:0030511 | positive regulation of transforming growth factor beta receptor signaling pathway | ISO |
| GO:0030513 | positive regulation of BMP signaling pathway | ISO |
| GO:0032525 | somite rostral/caudal axis specification | IMP |
| GO:0032909 | regulation of transforming growth factor beta2 production | ISO |
| GO:0033686 | positive regulation of luteinizing hormone secretion | IGI |
| GO:0033686 | positive regulation of luteinizing hormone secretion | IMP |
| GO:0035556 | intracellular signal transduction | ISO |
| GO:0036302 | atrioventricular canal development | IGI |
| GO:0042060 | wound healing | ISO |
| GO:0042118 | endothelial cell activation | IMP |
| GO:0042127 | regulation of cell population proliferation | IGI |
| GO:0042127 | regulation of cell population proliferation | IMP |
| GO:0042177 | negative regulation of protein catabolic process | ISO |
| GO:0042733 | embryonic digit morphogenesis | IMP |
| GO:0045892 | negative regulation of transcription, DNA-templated | ISO |
| GO:0045893 | positive regulation of transcription, DNA-templated | ISO |
| GO:0045893 | positive regulation of transcription, DNA-templated | IDA |
| GO:0045944 | positive regulation of transcription by RNA polymerase II | ISO |
| GO:0045944 | positive regulation of transcription by RNA polymerase II | IMP |
| GO:0045944 | positive regulation of transcription by RNA polymerase II | IDA |
| GO:0045944 | positive regulation of transcription by RNA polymerase II | IGI |
| GO:0046881 | positive regulation of follicle-stimulating hormone secretion | IGI |
| GO:0046881 | positive regulation of follicle-stimulating hormone secretion | IMP |
| GO:0048382 | mesendoderm development | IMP |
| GO:0048589 | developmental growth | IMP |
| GO:0048663 | neuron fate commitment | IMP |
| GO:0048729 | tissue morphogenesis | IMP |
| GO:0048733 | sebaceous gland development | IMP |
| GO:0048859 | formation of anatomical boundary | IMP |
| GO:0051098 | regulation of binding | IDA |
| GO:0051571 | positive regulation of histone H3-K4 methylation | IMP |
| GO:0051797 | regulation of hair follicle development | IMP |
| GO:0060065 | uterus development | IGI |
| GO:0060391 | positive regulation of SMAD protein signal transduction | IMP |
| GO:0060395 | SMAD protein signal transduction | ISO |
| GO:0060412 | ventricular septum morphogenesis | IMP |
| GO:0060548 | negative regulation of cell death | IMP |
| GO:0060956 | endocardial cell differentiation | IMP |
| GO:0061040 | female gonad morphogenesis | IMP |
| GO:0061614 | pri-miRNA transcription by RNA polymerase II | IMP |
| GO:0062009 | secondary palate development | IMP |
| GO:0070102 | interleukin-6-mediated signaling pathway | IDA |
| GO:0070207 | protein homotrimerization | ISO |
| GO:0070371 | ERK1 and ERK2 cascade | ISO |
| GO:0070373 | negative regulation of ERK1 and ERK2 cascade | IMP |
| GO:0071333 | cellular response to glucose stimulus | ISO |
| GO:0071559 | response to transforming growth factor beta | ISO |
| GO:0072133 | metanephric mesenchyme morphogenesis | IMP |
| GO:0072134 | nephrogenic mesenchyme morphogenesis | IMP |
| GO:0072520 | seminiferous tubule development | IMP |
| GO:1905305 | negative regulation of cardiac myofibril assembly | IMP |
| GO:2000617 | positive regulation of histone H3-K9 acetylation | IMP |
| GO ID | GO Term | Evidence |
|---|---|---|
| GO:0000790 | nuclear chromatin | ISO |
| GO:0005623 | cell | IEA |
| GO:0005634 | nucleus | ISO |
| GO:0005634 | nucleus | IDA |
| GO:0005654 | nucleoplasm | ISO |
| GO:0005654 | nucleoplasm | TAS |
| GO:0005667 | transcription factor complex | ISO |
| GO:0005667 | transcription factor complex | IPI |
| GO:0005737 | cytoplasm | ISO |
| GO:0005737 | cytoplasm | IDA |
| GO:0005813 | centrosome | ISO |
| GO:0005829 | cytosol | ISO |
| GO:0032444 | activin responsive factor complex | ISO |
| GO:0032991 | protein-containing complex | ISO |
| GO:0071141 | SMAD protein complex | ISO |
| GO:0090575 | RNA polymerase II transcription factor complex | IDA |
| Reactome ID | Reactome Term | Evidence |
|---|---|---|
| R-MMU-1181150 | Signaling by NODAL | IEA |
| R-MMU-1266738 | Developmental Biology | IEA |
| R-MMU-1502540 | Signaling by Activin | IEA |
| R-MMU-162582 | Signal Transduction | IEA |
| R-MMU-170834 | Signaling by TGF-beta Receptor Complex | IEA |
| R-MMU-201451 | Signaling by BMP | IEA |
| R-MMU-212436 | Generic Transcription Pathway | IEA |
| R-MMU-2173789 | TGF-beta receptor signaling activates SMADs | IEA |
| R-MMU-2173793 | Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer | IEA |
| R-MMU-2173795 | Downregulation of SMAD2/3:SMAD4 transcriptional activity | IEA |
| R-MMU-2173796 | SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription | IEA |
| R-MMU-392499 | Metabolism of proteins | IEA |
| R-MMU-5688426 | Deubiquitination | IEA |
| R-MMU-5689880 | Ub-specific processing proteases | IEA |
| R-MMU-597592 | Post-translational protein modification | IEA |
| R-MMU-73857 | RNA Polymerase II Transcription | IEA |
| R-MMU-74160 | Gene expression (Transcription) | IEA |
| R-MMU-8878159 | Transcriptional regulation by RUNX3 | IEA |
| R-MMU-8878166 | Transcriptional regulation by RUNX2 | IEA |
| R-MMU-8941326 | RUNX2 regulates bone development | IEA |
| R-MMU-8941855 | RUNX3 regulates CDKN1A transcription | IEA |
| R-MMU-9006936 | Signaling by TGF-beta family members | IEA |
| R-MMU-9614085 | FOXO-mediated transcription | IEA |
| R-MMU-9617828 | FOXO-mediated transcription of cell cycle genes | IEA |