TGF beta 2901165 221995564 2008-06-27T01:34:18Z Nbauman 2419261 Autocrine signalling. Clarify. [[Image:SMAD apoptosis.svg|thumb|right|200px|The SMAD Pathway]] [[Image:DAXX Pathway.svg|thumb|right|200px|The DAXX Pathway]] '''[[Transforming growth factor]] beta''' (TGF-β) controls [[cell growth|proliferation]], [[cellular differentiation]], and other functions in most cells. It plays a role in immunity, cancer, and heart disease. Some cells secrete TGF-β, and also have receptors for TGF-β. This is known as [[autocrine signalling]]. Cancerous cells increase their production of TGF-β, which also acts on surrounding cells. TGF-β is a secreted [[protein]] that exists in three [[isoform]]s called, [[TGF beta 1|TGF-β1]], [[TGF beta 2|TGF-β2]] and [[TGF beta 3|TGF-β3]]. It was also the original name for TGF-β1, which was the founding member of this family. The TGF-β family is part of a superfamily of proteins known as the [[transforming growth factor beta superfamily]], which includes [[inhibin]]s, [[activin]], [[anti-müllerian hormone]], [[bone morphogenetic protein]], [[decapentaplegic]] and [[Vg-1]]. ==The Structure of TGF-β== The peptide structures of the three members of the TGF-β family are highly similar. They are all encoded as large [[protein precursor]]s; TGF-β1 contains 390 [[amino acid]]s and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal [[signal peptide]] of 20-30 amino acids that they require for secretion from a cell, a pro-region (called [[latency associated peptide]] or LAP), and a 112-114 amino acid [[C-terminal]] region that becomes the ''mature'' TGF-β molecule following its release from the pro-region by [[proteolysis|proteolytic]] cleavage.<ref>{{cite journal |author=Khalil N |title=TGF-beta: from latent to active |journal=Microbes Infect |volume=1 |issue=15 |pages=1255–63 |year=1999 |pmid=10611753 |doi=10.1016/S1286-4579(99)00259-2}}</ref> The mature TGF-β protein dimerizes to produce a 25 KDa active molecule with many conserved structural motifs.<ref>{{cite journal |author=Herpin A, Lelong C, Favrel P |title=Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans |journal=Dev Comp Immunol |volume=28 |issue=5 |pages=461–85 |year=2004 |pmid=15062644 |doi=10.1016/j.dci.2003.09.007}}</ref> TGF-β has nine [[cysteine]] residues that are conserved among its family; eight form disulfide bonds within the molecule to create a [[cysteine knot]] structure characteristic of the TGF-β superfamily while the ninth cysteine forms a bond with the ninth cysteine of another TGF-β molecule to produce the dimer.<ref>{{cite journal |author=Daopin S, Piez K, Ogawa Y, Davies D |title=Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily |journal=Science |volume=257 |issue=5068 |pages=369–73 |year=1992 |pmid=1631557 |doi=10.1126/science.1631557}}</ref> Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β molecules that is exposed at the surface of the molecule and is implicated in receptor binding and specificity of TGF-β. ==Functions== ===Role in apoptosis=== Cells can die in two ways: Through [[apoptosis]], when the cell self-destructs through programmed cell death as a result of "death signals", and through necrosis, which is death from other causes, such as lack of oxygen or toxins. TGF-β induces [[apoptosis]] in numerous cell types. TGF-β can induce apoptosis in two ways: The [[SMAD (protein)|SMAD]] pathway or the [[DAXX]] pathway. ====SMAD pathway==== The SMAD pathway is the classical [[TGF-beta signaling pathway|signaling pathway]] that TGF-β family members signal through. In this pathway, TGF-β dimers bind to a type II receptor which recruits and phosphorylates a type I receptor. The type I receptor then recruits and phosphorylates a [[receptor regulated SMAD]] (R-SMAD). [[SMAD3]], an R-SMAD, has been implicated in inducing apoptosis. The R-SMAD then binds to the common SMAD (coSMAD) [[SMAD4]] and forms a heterodimeric complex. This complex then enters the [[cell nucleus]] where it acts as a transcription factor for various genes, including those to activate the [[mitogen-activated protein kinase]] 8 pathway, which triggers apoptosis. ====DAXX pathway==== TGF-β may also trigger apoptosis via the [[death associated protein 6]] (DAXX adapter protein). DAXX has been shown to associate with and bind to the type II TGF-β receptor kinase. ===Role in cell cycle=== TGF-β plays a crucial role in the regulation of the [[cell cycle]]. ===Role in cancer === In normal cells, TGF-ß, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-ß signaling pathway are mutated, and TGF-ß no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-ß. This TGF-ß acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive.<ref>[http://content.nejm.org/cgi/content/full/342/18/1350 Blobe, GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000 May 4;342(18):1350-8.]</ref> TGF-ß also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction. ===Role in heart disease=== A study at the [[Saint Louis University]] School of Medicine has found that [[cholesterol]] suppresses the responsiveness of cardiovascular cells to TGF-β and its protective qualities, thus allowing atherosclerosis to develop. It was also found that [[statin]]s, drugs that lower cholesterol levels, enhance the responsiveness of cardiovascular cells to the protective actions of TGF-ß, thus helping prevent the development of [[atherosclerosis]] and [[heart disease]]. [http://www.slu.edu/x17685.xml] ==Types== The primary three are: * [[TGF beta 1]] - TGFB1 {{OMIM|190180}} * [[TGF beta 2]] - TGFB2 {{OMIM|190220}} * [[TGF beta 3]] - TGFB3 {{OMIM|190230}} * TGFβ4 precursor was discovered as a gene upregulated during [[menstruation|pre-menstrual]] phase in the [[endometrium|endometrail]] stroma(Kothapalli et al. 1997) and called EBAF ('''endometrial bleeding associated factor'''). Later independently discovered to be involved in vertebrate embryonic [[left right asymmetry]] determination, and given the name '''[[Lefty (protein)|lefty2]]''' (also called ''Lefty A''). ==See also== * [[Anita Roberts]] ==References== {{Reflist}} ==External links== *[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=7040 Description of the TGF beta producing genes at ncbi.nlm.nih.gov] *[http://www.genome.ad.jp/dbget-bin/get_pathway?org_name=hsa&mapno=04350 Diagram of the TGF beta signaling pathway at genome.ad.jp] *{{MeshName|TGF-beta}} {{TGF beta signaling}} {{Cytokines}} {{Signaling proteins}} [[Category:TGFβ domain]] [[pl:TGF-β]] [[zh:转化生长因子-β]]