TGF-beta signaling by Smad proteins.
Members of the transforming growth factor-beta (TGF-beta) family bind to type II and type I serine/threonine kinase receptors, which initiate intracellular signals through activation of Smad proteins. Receptor-regulated Smads (R-Smads) are anchored to the cell membrane by interaction with membrane-bound proteins, including Smad anchor for receptor activation (SARA). Upon ligand stimulation, R-Smads are phosphorylated by the receptors and form oligomeric complexes with common-partner Smads (Co-Smads). The oligomeric Smad complexes then translocate into the nucleus, where they regulate the transcription of target genes by direct binding to DNA, interaction with various DNA-binding proteins, and recruitment of transcriptional coactivators or corepressors. A third class of Smads, inhibitory Smads (I-Smads), inhibits the signals from the serine/threonine kinase receptors. Since the expression of I-Smads is induced by the TGF-beta superfamily proteins, Smads constitute an autoinhibitory signaling pathway. The functions of Smads are regulated by other signaling pathways, such as the MAP kinase pathway. Moreover, Smads interact with and modulate the functions of various transcription factors which are downstream targets of other signaling pathways. Loss of function of certain Smads is involved in tumorigenesis, e.g., pancreatic and colorectal cancers. Analyses by gene targeting revealed pivotal roles of Smads in early embryogenesis, angiogenesis, and immune functions in vivo.
Miyazono
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K
Department of Biochemistry, Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan.
ten Dijke
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Heldin
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CH
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D004331:Drosophila melanogaster / Q000378:metabolism; D005314:Embryonic and Fetal Development; D005326:Fetal Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D015801:Helminth Proteins / Q000502:physiology; D006801:Humans; D019476:Insect Proteins / Q000502:physiology; D020935:MAP Kinase Signaling System; D046911:Macromolecular Substances; D008954:Models, Biological; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017434:Protein Structure, Tertiary; D020239:Receptor Cross-Talk; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000145:classification / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000502:physiology*; D014981:Xenopus / Q000378:metabolism
D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D015801:Helminth Proteins; D019476:Insect Proteins; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases