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Gene Ontology Classifications
SMAD family member 4

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GO curators for mouse genes have assigned the following annotations to the gene product of Smad4. (This text reflects annotations as of Tuesday, May 26, 2015.)
Summary from NCBI RefSeq

[Summary is not available for the mouse gene. This summary is for the human ortholog.] 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 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 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, Oct 2009]
Summary text based on GO annotations supported by experimental evidence in mouse
Summary text based on GO annotations supported by experimental evidence in other organisms
Summary text based on GO annotations supported by structural data
Summary text for additional MGI annotations
  1. Baburajendran N et al. (2011) Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers. Nucleic Acids Res, 39:8213-22. (PubMed:21724602)
  2. Bailey JS et al. (2004) Activin regulation of the follicle-stimulating hormone beta-subunit gene involves Smads and the TALE homeodomain proteins Pbx1 and Prep1. Mol Endocrinol, 18:1158-70. (PubMed:14764653)
  3. Brugger SM et al. (2004) A phylogenetically conserved cis-regulatory module in the Msx2 promoter is sufficient for BMP-dependent transcription in murine and Drosophila embryos. Development, 131:5153-65. (PubMed:15459107)
  4. Chen X et al. (1997) Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature, 389:85-9. (PubMed:9288972)
  5. Chu GC et al. (2004) Differential requirements for Smad4 in TGFbeta-dependent patterning of the early mouse embryo. Development, 131:3501-12. (PubMed:15215210)
  6. Collart C et al. (2005) Smicl is a novel Smad interacting protein and cleavage and polyadenylation specificity factor associated protein. Genes Cells, 10:897-906. (PubMed:16115198)
  7. da Silva S et al. (2011) Proper formation of whisker barrelettes requires periphery-derived Smad4-dependent TGF-{beta} signaling. Proc Natl Acad Sci U S A, 108:3395-400. (PubMed:21300867)
  8. Ellis LR et al. (2003) Interaction of Smads with collagen types I, III, and V. Biochem Biophys Res Commun, 310:1117-23. (PubMed:14559231)
  9. Ellsworth BS et al. (2003) The gonadotropin releasing hormone (GnRH) receptor activating sequence (GRAS) is a composite regulatory element that interacts with multiple classes of transcription factors including Smads, AP-1 and a forkhead DNA binding protein. Mol Cell Endocrinol, 206:93-111. (PubMed:12943993)
  10. Hartwig S et al. (2005) Glypican-3 modulates inhibitory Bmp2-Smad signaling to control renal development in vivo. Mech Dev, 122:928-38. (PubMed:15925496)
  11. Hodge LK et al. (2007) Retrograde BMP signaling regulates trigeminal sensory neuron identities and the formation of precise face maps. Neuron, 55:572-86. (PubMed:17698011)
  12. Hsu LJ et al. (2009) Transforming growth factor beta1 signaling via interaction with cell surface Hyal-2 and recruitment of WWOX/WOX1. J Biol Chem, 284:16049-59. (PubMed:19366691)
  13. Izzi L et al. (2007) Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development. EMBO J, 26:3132-43. (PubMed:17568773)
  14. Labbe E et al. (1998) Smad2 and Smad3 positively and negatively regulate TGF beta-dependent transcription through the forkhead DNA-binding protein FAST2. Mol Cell, 2:109-20. (PubMed:9702197)
  15. Lin EA et al. (2009) miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1. J Biol Chem, 284:11326-35. (PubMed:19251704)
  16. Morikawa Y et al. (2009) BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways. Development, 136:3575-84. (PubMed:19793887)
  17. Moskowitz IP et al. (2011) Cardiac-specific transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. Proc Natl Acad Sci U S A, 108:4006-11. (PubMed:21330551)
  18. Mullen AC et al. (2011) Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell, 147:565-76. (PubMed:22036565)
  19. Nawshad A et al. (2003) TGF{beta}3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development. J Cell Biol, 163:1291-1301. (PubMed:14691138)
  20. Nishiyama A et al. (2009) Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. Cell Stem Cell, 5:420-33. (PubMed:19796622)
  21. Owens P et al. (2008) Smad4-dependent desmoglein-4 expression contributes to hair follicle integrity. Dev Biol, 322:156-66. (PubMed:18692037)
  22. Oxburgh L et al. (2004) TGFbeta superfamily signals are required for morphogenesis of the kidney mesenchyme progenitor population. Development, 131:4593-605. (PubMed:15342483)
  23. Seno H et al. (2002) Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps. Cancer Res, 62:506-11. (PubMed:11809702)
  24. Sharff KA et al. (2009) Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. J Biol Chem, 284:649-59. (PubMed:18986983)
  25. Sirard C et al. (1998) The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev, 12:107-19. (PubMed:9420335)
  26. Subramanian SV et al. (2004) Induction of vascular smooth muscle alpha-actin gene transcription in transforming growth factor beta1-activated myofibroblasts mediated by dynamic interplay between the Pur repressor proteins and Sp1/Smad coactivators. Mol Biol Cell, 15:4532-43. (PubMed:15282343)
  27. Takaku K et al. (1998) Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell, 92:645-56. (PubMed:9506519)
  28. Takaku K et al. (1999) Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res, 59:6113-7. (PubMed:10626800)
  29. Taketo MM et al. (2000) Gastrointestinal tumorigenesis in Smad4 (Dpc4) mutant mice. Hum Cell, 13:85-95. (PubMed:11197776)
  30. Taketo MM et al. (2000) Gastro-intestinal tumorigenesis in Smad4 mutant mice. Cytokine Growth Factor Rev, 11:147-57. (PubMed:10708962)
  31. Tang LY et al. (2011) Ablation of Smurf2 reveals an inhibition in TGF-beta signalling through multiple mono-ubiquitination of Smad3. EMBO J, 30:4777-89. (PubMed:22045334)
  32. Tang Y et al. (2003) Disruption of transforming growth factor-beta signaling in ELF beta-spectrin-deficient mice. Science, 299:574-7. (PubMed:12543979)
  33. Wilkinson DS et al. (2008) Chromatin-bound p53 anchors activated Smads and the mSin3A corepressor to confer transforming-growth-factor-beta-mediated transcription repression. Mol Cell Biol, 28:1988-98. (PubMed:18212064)
  34. Wilkinson DS et al. (2005) A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol, 25:1200-12. (PubMed:15657445)
  35. Xiao C et al. (2003) Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. Genes Dev, 17:2933-49. (PubMed:14633973)
  36. Yang L et al. (2006) Isl1Cre reveals a common Bmp pathway in heart and limb development. Development, 133:1575-85. (PubMed:16556916)
  37. Zhang J et al. (2007) Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons. Nat Neurosci, 10:77-86. (PubMed:17159989)
  38. Zhang W et al. (2002) Regulation of Hex Gene Expression by a Smads-dependent Signaling Pathway. J Biol Chem, 277:45435-41. (PubMed:12270938)
  39. Zieba A et al. (2012) Intercellular variation in signaling through the TGF-beta pathway and its relation to cell density and cell cycle phase. Mol Cell Proteomics, 11:M111.013482. (PubMed:22442258)

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Gene Ontology Evidence Code Abbreviations:

  EXP Inferred from experiment
  IAS Inferred from ancestral sequence
  IBA Inferred from biological aspect of ancestor
  IBD Inferred from biological aspect of descendant
  IC Inferred by curator
  IDA Inferred from direct assay
  IEA Inferred from electronic annotation
  IGI Inferred from genetic interaction
  IKR Inferred from key residues
  IMP Inferred from mutant phenotype
  IMR Inferred from missing residues
  IPI Inferred from physical interaction
  IRD Inferred from rapid divergence
  ISS Inferred from sequence or structural similarity
  ISO Inferred from sequence orthology
  ISA Inferred from sequence alignment
  ISM Inferred from sequence model
  NAS Non-traceable author statement
  ND No biological data available
  RCA Reviewed computational analysis
  TAS Traceable author statement


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