======= SMAD4 =======
== Gene Information ==
* **Official Symbol**: SMAD4
* **Official Name**: SMAD family member 4
* **Aliases and Previous Symbols**: N/A
* **Entrez ID**: [[https://www.ncbi.nlm.nih.gov/gene/?term=4089|4089]]
* **UniProt**: [[https://www.uniprot.org/uniprot/Q13485|Q13485]]
* **Interactions**: [[https://thebiogrid.org/search.php?search=SMAD4&organism=9606|BioGRID]]
* **PubMed articles**: [[https://www.ncbi.nlm.nih.gov/pubmed/?term=gene%20SMAD4|Open PubMed]]
* **OMIM**: [[https://omim.org/entry/600993|Open OMIM]]
== Function Summary ==
* **Entrez 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].
* **UniProt Summary**: 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. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). 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. {ECO:0000250, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:9389648}.
|MH1|
|MH2|
|transforming growth factor beta receptor, common-partner cytoplasmic mediator activity|
|regulation of cardiac myofibril assembly|
|female gonad morphogenesis|
|positive regulation of cell proliferation involved in heart valve morphogenesis|
|negative regulation of cardiac myofibril assembly|
|left ventricular cardiac muscle tissue morphogenesis|
|gonad morphogenesis|
|nephrogenic mesenchyme morphogenesis|
|kidney mesenchyme morphogenesis|
|nephrogenic mesenchyme development|
|regulation of cell proliferation involved in heart valve morphogenesis|
|metanephric mesenchyme morphogenesis|
|activin responsive factor complex|
|molecular function regulator|
|positive regulation of luteinizing hormone secretion|
|sulfate binding|
|formation of anatomical boundary|
|positive regulation of cell proliferation involved in heart morphogenesis|
|positive regulation of follicle-stimulating hormone secretion|
|regulation of follicle-stimulating hormone secretion|
|SMAD protein complex assembly|
|atrioventricular canal development|
|regulation of luteinizing hormone secretion|
|SMAD protein complex|
|positive regulation of gonadotropin secretion|
|brainstem development|
|pri-miRNA transcription by RNA polymerase II|
|endocardial cell differentiation|
|regulation of transforming growth factor beta2 production|
|atrioventricular valve formation|
|sebaceous gland development|
|positive regulation of histone H3-K9 acetylation|
|cardiac endothelial cell differentiation|
|mesendoderm development|
|endothelial cell activation|
|somite rostral/caudal axis specification|
|regulation of gonadotropin secretion|
|I-SMAD binding|
|positive regulation of SMAD protein signal transduction|
|seminiferous tubule development|
|epithelial to mesenchymal transition involved in endocardial cushion formation|
|heart valve formation|
|endocardium development|
|metanephric mesenchyme development|
|cardiac left ventricle morphogenesis|
|regulation of histone H3-K9 acetylation|
|interleukin-6-mediated signaling pathway|
|positive regulation of histone H3-K4 methylation|
|negative regulation of cardiac muscle cell differentiation|
|regulation of cell proliferation involved in heart morphogenesis|
|kidney mesenchyme development|
|endocardial cushion formation|
|regulation of hair follicle development|
|negative regulation of cardiocyte differentiation|
|positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus|
|uterus development|
|regulation of SMAD protein signal transduction|
|R-SMAD binding|
|secondary palate development|
|atrioventricular valve morphogenesis|
|negative regulation of cardiac muscle hypertrophy|
|atrioventricular valve development|
|regulation of histone H3-K4 methylation|
|gastrulation with mouth forming second|
|negative regulation of muscle hypertrophy|
|outflow tract septum morphogenesis|
|cardiac epithelial to mesenchymal transition|
|regulation of hair cycle|
|positive regulation of cellular response to transforming growth factor beta stimulus|
|positive regulation of transforming growth factor beta receptor signaling pathway|
|positive regulation of histone acetylation|
|proximal promoter sequence-specific DNA binding|
|protein homotrimerization|
|negative regulation of cardiac muscle tissue development|
|positive regulation of BMP signaling pathway|
|cellular response to interleukin-6|
|positive regulation of peptidyl-lysine acetylation|
|endocardial cushion morphogenesis|
|regulation of transforming growth factor beta production|
|regulation of cardiac muscle cell differentiation|
|response to interleukin-6|
|embryonic axis specification|
|negative regulation of striated muscle cell differentiation|
|negative regulation of organelle assembly|
|positive regulation of histone methylation|
|regulation of heart morphogenesis|
|ventricular septum morphogenesis|
|positive regulation of protein acetylation|
|endocardial cushion development|
|regulation of endocrine process|
|branching involved in ureteric bud morphogenesis|
|positive regulation of epithelial to mesenchymal transition|
|positive regulation of pathway-restricted SMAD protein phosphorylation|
|negative regulation of striated muscle tissue development|
|ventricular cardiac muscle tissue morphogenesis|
|negative regulation of muscle organ development|
|regulation of cardiocyte differentiation|
|anterior/posterior axis specification|
|mesenchyme morphogenesis|
|negative regulation of muscle tissue development|
|ovarian follicle development|
|heart valve morphogenesis|
|ureteric bud morphogenesis|
|mesonephric tubule morphogenesis|
|protein trimerization|
|negative regulation of muscle cell differentiation|
|ventricular cardiac muscle tissue development|
|regulation of cardiac muscle hypertrophy|
|regulation of histone acetylation|
|SMAD protein signal transduction|
|regulation of muscle hypertrophy|
|embryonic digit morphogenesis|
|regulation of pathway-restricted SMAD protein phosphorylation|
|heart valve development|
|regulation of peptidyl-lysine acetylation|
|cellular iron ion homeostasis|
|embryonic pattern specification|
|RNA polymerase II transcription factor binding|
|neuron fate commitment|
|collagen binding|
|nephron tubule morphogenesis|
|regulation of histone methylation|
|somitogenesis|
|somatic stem cell population maintenance|
|nephron epithelium morphogenesis|
|negative regulation of ERK1 and ERK2 cascade|
|nephron morphogenesis|
|cardiac muscle tissue morphogenesis|
|renal tubule morphogenesis|
|epithelial to mesenchymal transition|
|regulation of protein acetylation|
|ventricular septum development|
|endoderm development|
|cardiac septum morphogenesis|
|outflow tract morphogenesis|
|cardiac ventricle morphogenesis|
|nephron tubule development|
|regulation of cardiac muscle tissue development|
|renal tubule development|
|muscle tissue morphogenesis|
|iron ion homeostasis|
|positive regulation of animal organ morphogenesis|
|somite development|
|transcription coregulator activity|
|endothelial cell differentiation|
|metanephros development|
|regulation of epithelial to mesenchymal transition|
|kidney morphogenesis|
|regulation of muscle adaptation|
|axis specification|
|regulation of epidermis development|
|ureteric bud development|
|muscle organ morphogenesis|
|mesonephric epithelium development|
|mesonephric tubule development|
|regulation of BMP signaling pathway|
|female gonad development|
|neural crest cell differentiation|
|regulation of actomyosin structure organization|
|BMP signaling pathway|
|roof of mouth development|
|positive regulation of histone modification|
|mesonephros development|
|development of primary female sexual characteristics|
|endothelium development|
|segmentation|
|nephron epithelium development|
|regulation of striated muscle cell differentiation|
|transforming growth factor beta receptor signaling pathway|
|positive regulation of chromatin organization|
|positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway|
|response to BMP|
|cellular response to BMP stimulus|
|cellular transition metal ion homeostasis|
|female sex differentiation|
|cardiac septum development|
|regulation of transforming growth factor beta receptor signaling pathway|
|cardiocyte differentiation|
|regulation of cellular response to transforming growth factor beta stimulus|
|mesoderm development|
|nephron development|
|embryonic appendage morphogenesis|
|embryonic limb morphogenesis|
|cardiac chamber morphogenesis|
|positive regulation of hormone secretion|
|cardiac ventricle development|
|kidney epithelium development|
|transition metal ion homeostasis|
|negative regulation of supramolecular fiber organization|
|branching morphogenesis of an epithelial tube|
|regulation of striated muscle tissue development|
|male gonad development|
|development of primary male sexual characteristics|
|regulation of muscle tissue development|
|stem cell population maintenance|
|regulation of muscle organ development|
|maintenance of cell number|
|single fertilization|
|negative regulation of cytoskeleton organization|
|regulation of histone modification|
|limb morphogenesis|
|appendage morphogenesis|
|regulation of muscle cell differentiation|
|cellular response to transforming growth factor beta stimulus|
|male sex differentiation|
|mesenchymal cell differentiation|
|stem cell differentiation|
|morphogenesis of a branching epithelium|
|gastrulation|
|cardiac muscle tissue development|
|response to transforming growth factor beta|
|negative regulation of MAPK cascade|
|morphogenesis of a branching structure|
|cardiac chamber development|
|fertilization|
|positive regulation of chromosome organization|
|limb development|
|appendage development|
|negative regulation of cell growth|
|regulation of chromatin organization|
|transmembrane receptor protein serine/threonine kinase signaling pathway|
|transcription factor complex|
|gonad development|
|development of primary sexual characteristics|
|anterior/posterior pattern specification|
|transcription regulatory region DNA binding|
|regulation of organelle assembly|
|mesenchyme development|
|regulation of muscle system process|
|regulation of transmembrane receptor protein serine/threonine kinase signaling pathway|
|nuclear chromatin|
|negative regulation of growth|
|cell fate commitment|
|heart morphogenesis|
|regulation of animal organ morphogenesis|
|axon guidance|
|neuron projection guidance|
|sex differentiation|
|kidney development|
|regulation of hormone secretion|
|regulation of cellular response to growth factor stimulus|
|protein deubiquitination|
|striated muscle tissue development|
|renal system development|
|regulation of ERK1 and ERK2 cascade|
|muscle organ development|
|muscle tissue development|
|protein modification by small protein removal|
|epithelial tube morphogenesis|
|urogenital system development|
|regionalization|
|negative regulation of cell development|
|protein homooligomerization|
|response to hypoxia|
|regulation of actin cytoskeleton organization|
|regulation of chromosome organization|
|regulation of supramolecular fiber organization|
|response to decreased oxygen levels|
|axonogenesis|
|negative regulation of organelle organization|
|regulation of binding|
|in utero embryonic development|
|response to oxygen levels|
|skin development|
|regulation of actin filament-based process|
|developmental growth|
|growth|
|chromatin binding|
|positive regulation of secretion by cell|
|negative regulation of protein phosphorylation|
|axon development|
|gland development|
|regulation of cell growth|
|sequence-specific DNA binding|
|reproductive structure development|
|reproductive system development|
|cell morphogenesis involved in neuron differentiation|
|morphogenesis of an epithelium|
|positive regulation of secretion|
|pattern specification process|
|negative regulation of phosphorylation|
|DNA-binding transcription activator activity, RNA polymerase II-specific|
|muscle structure development|
|neuron projection morphogenesis|
|transcription by RNA polymerase II|
|plasma membrane bounded cell projection morphogenesis|
|protein heterodimerization activity|
|cell projection morphogenesis|
|centrosome|
|cellular response to growth factor stimulus|
|RNA polymerase II proximal promoter sequence-specific DNA binding|
|negative regulation of intracellular signal transduction|
|cell part morphogenesis|
|protein complex oligomerization|
|heart development|
|response to growth factor|
|regulation of hormone levels|
|regulation of cytoskeleton organization|
|spermatogenesis|
|chemotaxis|
|taxis|
|cell population proliferation|
|cell morphogenesis involved in differentiation|
|cellular metal ion homeostasis|
|negative regulation of phosphate metabolic process|
|negative regulation of phosphorus metabolic process|
|male gamete generation|
|tissue morphogenesis|
|embryonic morphogenesis|
|regulation of system process|
|negative regulation of protein modification process|
|positive regulation of organelle organization|
|metal ion homeostasis|
|cellular cation homeostasis|
|chordate embryonic development|
|transcription, DNA-templated|
|nucleic acid-templated transcription|
|cellular ion homeostasis|
|embryo development ending in birth or egg hatching|
|RNA biosynthetic process|
|tube morphogenesis|
|neuron projection development|
|developmental process involved in reproduction|
|regulation of growth|
|cytokine-mediated signaling pathway|
|DNA-binding transcription factor activity|
|negative regulation of cell population proliferation|
|epithelial cell differentiation|
|gamete generation|
|regulation of cytokine production|
|negative regulation of cellular component organization|
|cation homeostasis|
|negative regulation of cell differentiation|
|enzyme linked receptor protein signaling pathway|
|inorganic ion homeostasis|
|cell morphogenesis|
|cellular chemical homeostasis|
|regulation of secretion by cell|
|regulation of MAPK cascade|
|ion homeostasis|
|regulation of secretion|
|neuron development|
|cellular component morphogenesis|
|multicellular organismal reproductive process|
|sexual reproduction|
|cellular protein-containing complex assembly|
|multicellular organism reproduction|
|tube development|
|negative regulation of transcription by RNA polymerase II|
|circulatory system development|
|protein homodimerization activity|
|anatomical structure formation involved in morphogenesis|
|cellular homeostasis|
|positive regulation of cell population proliferation|
|regulation of cell development|
|negative regulation of developmental process|
|animal organ morphogenesis|
|regulation of cellular component biogenesis|
|positive regulation of cell differentiation|
|embryo development|
|protein modification by small protein conjugation or removal|
|positive regulation of transport|
|multi-organism reproductive process|
|negative regulation of cell death|
|cellular response to cytokine stimulus|
|neuron differentiation|
|positive regulation of protein phosphorylation|
|negative regulation of cellular protein metabolic process|
|positive regulation of phosphorylation|
|regulation of anatomical structure morphogenesis|
|identical protein binding|
|cell activation|
|nucleobase-containing compound biosynthetic process|
|response to cytokine|
|negative regulation of protein metabolic process|
|chemical homeostasis|
|epithelium development|
|plasma membrane bounded cell projection organization|
|positive regulation of phosphorus metabolic process|
|positive regulation of phosphate metabolic process|
|cell projection organization|
|response to abiotic stimulus|
|heterocycle biosynthetic process|
|aromatic compound biosynthetic process|
|negative regulation of transcription, DNA-templated|
|negative regulation of multicellular organismal process|
|positive regulation of cellular component organization|
|positive regulation of transcription by RNA polymerase II|
|cellular response to endogenous stimulus|
|positive regulation of protein modification process|
|negative regulation of nucleic acid-templated transcription|
|negative regulation of RNA biosynthetic process|
|negative regulation of signal transduction|
|proteolysis|
|regulation of organelle organization|
|organic cyclic compound biosynthetic process|
|locomotion|
|negative regulation of RNA metabolic process|
|negative regulation of cell communication|
|negative regulation of signaling|
|positive regulation of developmental process|
|negative regulation of cellular macromolecule biosynthetic process|
|reproductive process|
|reproduction|
|negative regulation of nucleobase-containing compound metabolic process|
|regulation of protein phosphorylation|
|DNA binding|
|negative regulation of macromolecule biosynthetic process|
|response to endogenous stimulus|
|negative regulation of cellular biosynthetic process|
|generation of neurons|
|positive regulation of transcription, DNA-templated|
|negative regulation of biosynthetic process|
|movement of cell or subcellular component|
|protein-containing complex assembly|
|DNA-binding transcription factor activity, RNA polymerase II-specific|
|regulation of phosphorylation|
|positive regulation of cellular protein metabolic process|
|regulation of cell population proliferation|
|negative regulation of response to stimulus|
|neurogenesis|
|cellular nitrogen compound biosynthetic process|
|positive regulation of nucleic acid-templated transcription|
|positive regulation of RNA biosynthetic process|
|homeostatic process|
|cell development|
|positive regulation of signal transduction|
|RNA metabolic process|
|regulation of cell death|
|intracellular signal transduction|
|positive regulation of protein metabolic process|
|cellular macromolecule biosynthetic process|
|negative regulation of gene expression|
|positive regulation of RNA metabolic process|
|positive regulation of multicellular organismal process|
|tissue development|
|macromolecule biosynthetic process|
|regulation of phosphate metabolic process|
|regulation of phosphorus metabolic process|
|regulation of cell differentiation|
|positive regulation of cell communication|
|positive regulation of signaling|
|regulation of intracellular signal transduction|
|regulation of protein modification process|
|protein-containing complex subunit organization|
|regulation of transport|
|positive regulation of nucleobase-containing compound metabolic process|
|positive regulation of macromolecule biosynthetic process|
|positive regulation of cellular biosynthetic process|
|positive regulation of gene expression|
|gene expression|
|positive regulation of biosynthetic process|
\\
=== CRISPR Data ===
^Screen^Score^
|[[:results:exp146|Quinacrine 2.5μM R03 exp146]]|-1.82|
|[[:results:exp303|39°C R06 exp303]]|-1.73|
No correlation found to any other genes in chemogenomics.
Global Fraction of Cell Lines Where Essential: 0/726
^Tissue^Fraction Of Cell Lines Where Essential^
|1290807.0|0/1|
|909776.0|0/1|
|bile duct|0/28|
|blood|0/28|
|bone|0/25|
|breast|0/33|
|central nervous system|0/56|
|cervix|0/4|
|colorectal|0/17|
|esophagus|0/13|
|fibroblast|0/1|
|gastric|0/15|
|kidney|0/21|
|liver|0/20|
|lung|0/75|
|lymphocyte|0/14|
|ovary|0/26|
|pancreas|0/24|
|peripheral nervous system|0/16|
|plasma cell|0/15|
|prostate|0/1|
|skin|0/24|
|soft tissue|0/7|
|thyroid|0/2|
|upper aerodigestive|0/22|
|urinary tract|0/29|
|uterus|0/5|
== Essentiality in NALM6 ==
* **Essentiality Rank**: 7804
* **Expression level (log2 read counts)**: 6.42
{{:chemogenomics:nalm6 dist.png?nolink |}}