Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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TGFB Transforming growth factor-beta (TGF-beta) family

SMART accession number:	SM00204
Description:	Family members are active as disulphide-linked homo- or heterodimers. TGFB is a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types.
Interpro abstract (IPR001839):	Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. TGF-beta-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein [(PUBMED:8679613)]. A number of proteins are known to be related to TGF-beta-1 [(PUBMED:1575734), (PUBMED:8199356)]. Proteins from the TGF-beta family are only active as homo- or heterodimer; the two chains being linked by a single disulphide bond. From X-ray studies of TGF-beta-2 [(PUBMED:1631557)], it is known that all the other cysteines are involved in intrachain disulphide bonds. There are four disulphide bonds in the TGF-beta's and in inhibin beta chains, while the other members of this family lack the first bond. The regulatory cytokine TGFbeta exerts tumour-suppressive effects, but also modulates cell invasion and immune regulation [(PUBMED:18662538)]. Misregulation of the TGF-beta signalling pathway can result in tumour development.
GO function:	growth factor activity (GO:0008083)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 1864 TGFB domains in 1864 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a TGFB domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with TGFB domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Hoodless PA, Wrana JL
  • Mechanism and function of signaling by the TGF beta superfamily.
  • Curr Top Microbiol Immunol. 1998; 228: 235-72

  • Padgett RW, Savage C, Das P
  • Genetic and biochemical analysis of TGF beta signal transduction.
  • Cytokine Growth Factor Rev. 1997; 8: 1-9
  • Display abstract

  • TGF beta-like ligands are involved in many different developmental processes that pattern a variety of tissues in invertebrates and vertebrates. In the last few years, rapid progress has been made toward elucidating the developmental roles of the TGF beta-like pathways and identifying the novel components involved in transducing their signals, particularly the newly discovered Smads. This rapid progress has been the result of a synergy between classical genetic approaches and biochemical approaches, and this combined approach is likely to propel future understanding of the signaling pathway used by TGF beta.

  • Moses HL, Serra R
  • Regulation of differentiation by TGF-beta.
  • Curr Opin Genet Dev. 1996; 6: 581-6
  • Display abstract

  • Recent experiments in neural, skeletal, endothelial, and hematopoietic tissues have provided new insights into the way members of the transforming growth factor-beta (TGF-beta) superfamily regulate cellular differentiation. TGF-betas regulate the fate of multipotential stem cells instructively (in the neural crest) by regulating the expression or function of tissue-specific transcription factors, as well as selectively (in the mesenchyme) by regulating the expression of required growth factors and their receptors. During skeletal development, TGF-betas have unique functions and act sequentially to modulate chondrocyte and osteoblast differentiation. Responsiveness to TGF-betas changes as cells differentiate and evidence now suggests that changes in TGF-beta receptor profile may account for some of these differences. Drosophila and transgenic mouse models are now providing useful insights into mechanisms of TGF-beta action in vivo.

  • Derynck R et al.
  • Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells.
  • Nature. 1985; 316: 701-5
  • Display abstract

  • The partial amino-acid sequence of purified human transforming growth factor-beta (TGF-beta) was used to identify a series of cDNA clones encoding the protein. The cDNA sequence indicates that the 112-amino acid monomeric form of the natural TGF-beta homodimer is derived proteolytically from a much longer precursor polypeptide which may be secreted. TGF-beta messenger RNA is synthesized in various normal and transformed cells.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the TGFB domain.

  Protein	Disease
  Left-right determination factor 2 (O00292) (SMART)	OMIM:601877: Left-right axis malformation
  Muellerian-inhibiting factor (P03971) (SMART)	OMIM:600957: Persistent Mullerian duct syndrome, type I OMIM:261550:
  Glial cell line-derived neurotrophic factor (P39905) (SMART)	OMIM:600837: Hirschsprung disease OMIM:142623:

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 30.64 map04350 TGF-beta signaling pathway 25.89 map04060 Cytokine-cytokine receptor interaction 9.98 map04340 Hedgehog signaling pathway 4.99 map05217 Basal cell carcinoma 4.75 map05210 Colorectal cancer 4.75 map05211 Renal cell carcinoma 4.75 map04110 Cell cycle 4.75 map04010 MAPK signaling pathway 4.75 map05212 Pancreatic cancer 4.75 map05220 Chronic myeloid leukemia This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with TGFB domain which could be assigned to a KEGG orthologous group, and not all proteins containing TGFB domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of TGFB domains in PDB

  PDB code	Main view	Title
  1agq		Glial cell-derived neurotrophic factor from rat
  1bmp		Bone morphogenetic protein-7
  1es7		Complex between bmp-2 and two bmp receptor ia ectodomains
  1kla		Solution structure of tgf-b1, nmr, models 1-17 of 33 structures
  1klc		Solution structure of tgf-b1, nmr, minimized average structure
  1kld		Solution structure of tgf-b1, nmr, models 18-33 of 33 structures
  1ktz		Crystal structure of the human tgf-beta type ii receptor extracellular domain in complex with tgf-beta3
  1lx5		Crystal structure of the bmp7/actrii extracellular domain complex
  1lxi		Refinement of bmp7 crystal structure
  1m4u		Crystal structure of bone morphogenetic protein-7 (bmp-7) in complex with the secreted antagonist noggin
  1nys		Crystal structure of activin a bound to the ecd of actriib p41
  1nyu		Crystal structure of activin a bound to the ecd of actriib
  1reu		Structure of the bone morphogenetic protein 2 mutant l51p
  1rew		Structural refinement of the complex of bone morphogenetic protein 2 and its type ia receptor
  1s4y		Crystal structure of the activin/actriib extracellular domain
  1tfg		An unusual feature revealed by the crystal structure at 2.2 angstroms resolution of human transforming growth factor- beta2
  1tgj		Human transforming growth factor-beta 3, crystallized from dioxane
  1tgk		Human transforming growth factor beta 3, crystallized from peg 4000
  1waq		Crystal structure of human growth and differentiation factor 5 (gdf-5)
  1zkz		Crystal structure of bmp9
  2arp		Activin a in complex with fs12 fragment of follistatin
  2arv		Structure of human activin a
  2ask		Structure of human artemin
  2b0u		The structure of the follistatin:activin complex
  2bhk		Crystal structure of human growth and differentiation factor (gdf5)
  2gh0		Growth factor/receptor complex
  2goo		Ternary complex of bmp-2 bound to bmpr-ia-ecd and actrii-ecd
  2gyr		Crystal structure of human artemin
  2gyz		Crystal structure of human artemin
  2h62		Crystal structure of a ternary ligand-receptor complex of bmp-2
  2h64		Crystal structure of a ternary ligand-receptor complex of bmp-2
  2p6a		The structure of the activin:follistatin 315 complex
  2pjy		Structural basis for cooperative assembly of the tgf-beta signaling complex
  2qcq		Crystal structure of bone morphogenetic protein-3 (bmp-3)
  2qcw		Crystal structure of bone morphogenetic protein-6 (bmp-6)
  2qj9		Crystal structure analysis of bmp-2 in complex with bmpr-ia variant b1
  2qja		Crystal structure analysis of bmp-2 in complex with bmpr-ia variant b12
  2qjb		Crystal structure analysis of bmp-2 in complex with bmpr-ia variant ia/ib
  2r52		Crystal structure analysis of bone morphogenetic protein-6 (bmp-6)
  2r53		Crystal structure analysis of bone morphogenetic protein-6 variant b2 (b2-bmp-6)
  2tgi		Crystal structure of transforming growth factor-beta2: an unusual fold for the superfamily
  2v5e		The structure of the gdnf\:coreceptor complex\: insights into ret signalling and heparin binding.
  3b4v		X-ray structure of activin in complex with fstl3
  3bk3		Crystal structure of the complex of bmp-2 and the first von willebrand domain type c of crossveinless-2
  3bmp		Human bone morphogenetic protein-2 (bmp-2)
  3eo1		Structure of the fab fragment of gc-1008 in complex with transforming growth factor-beta 3
  3evs		Crystal structure of the gdf-5:bmp receptor ib complex.
  3fub		Crystal structure of gdnf-gfralpha1 complex
  3hh2		Crystal structure of the myostatin:follistatin 288 complex

• Links (links to other resources describing this domain)

• BLOCKS	TGF_BETA
  PFAM	TGF-beta
  INTERPRO	IPR001839
  PROSITE	TGFB_DOMAIN

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