View source for Transforming growth factor beta

{{short description|Cytokine}}
[[File:Computer graphic of tgf-beta.jpg|thumb|300x300px|Computer graphic of TGF-beta. TGF-beta is a cytokine with three different [[Protein isoform|isoforms]], which regulates many cellular functions including cell proliferation, differentiation, adhesion and migration]]
'''Transforming growth factor beta''' ('''TGF-β''') is a multifunctional [[cytokine]] belonging to the [[Transforming growth factor beta family|transforming growth factor superfamily]] that includes three<ref>{{cite journal |last1=Meng |first1=Xiao-ming |last2=Nikolic-Paterson |first2=David J. |last3=Lan |first3=Hui Yao |title=TGF-β: the master regulator of fibrosis |journal=Nature Reviews Nephrology |date=June 2016 |volume=12 |issue=6 |pages=325–338 |doi=10.1038/nrneph.2016.48 |pmid=27108839 |s2cid=25871413 }}</ref> different mammalian isoforms (TGF-β 1 to 3, [[HUGO Gene Nomenclature Committee|HGNC]] symbols [[TGFB1]], [[TGFB2]], [[TGFB3]]) and many other [[cell signaling|signaling proteins]]. TGFB proteins are produced by all [[white blood cell]] lineages.

Activated TGF-β complexes with other factors to form a [[serine/threonine kinase]] complex that binds to [[TGF beta receptors|TGF-β receptors]]. TGF-β receptors are composed of both type 1 and type 2 receptor subunits. After the binding of TGF-β, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade.<ref name="Massagué 616–630">{{cite journal | vauthors = Massagué J | title = TGFβ signalling in context | journal = Nature Reviews. Molecular Cell Biology | volume = 13 | issue = 10 | pages = 616–30 | date = October 2012 | pmid = 22992590 | pmc = 4027049 | doi = 10.1038/nrm3434 }}</ref> This leads to the activation of different downstream substrates and regulatory proteins, inducing transcription of different target genes that function in differentiation, [[chemotaxis]], proliferation, and activation of many immune cells.<ref name="Massagué 616–630" /><ref>{{cite journal | vauthors = Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P | display-authors = 6 | title = Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling | journal = Nature | volume = 389 | issue = 6651 | pages = 631–5 | date = October 1997 | pmid = 9335507 | doi = 10.1038/39369 | bibcode = 1997Natur.389..631N | s2cid = 4311145 }}</ref>

TGF-β is secreted by many cell types, including [[Macrophage|macrophages]], in a latent form in which it is complexed with two other [[polypeptides]], [[latent TGF-beta binding protein]] (LTBP) and latency-associated peptide (LAP). Serum [[proteinase]]s such as [[plasmin]] catalyze the release of active TGF-β from the complex. This often occurs on the surface of macrophages where the latent TGF-β complex is bound to [[CD36]] via its ligand, [[thrombospondin-1]] (TSP-1). Inflammatory stimuli that activate macrophages enhance the release of active TGF-β by promoting the activation of plasmin. Macrophages can also endocytose IgG-bound latent TGF-β complexes that are secreted by plasma cells and then release active TGF-β into the extracellular fluid.<ref>[http://www.signaling-gateway.org/data/cgi-bin/ligand_desc_display.cgi?ligandabbr=TGF AfCS signaling gateway – data center – ligand description<!-- Bot generated title -->]</ref> Among its key functions is [[Macrophage|regulation of inflammatory processes]], particularly in the gut.<ref name="ReferenceA">{{cite journal | vauthors = Letterio JJ, Roberts AB | title = Regulation of immune responses by TGF-beta | journal = Annual Review of Immunology | volume = 16 | issue = 1 | pages = 137–61 | date = April 1998 | pmid = 9597127 | doi = 10.1146/annurev.immunol.16.1.137 | url = https://zenodo.org/record/1234983 }}</ref> TGF-β also plays a crucial role in stem cell differentiation as well as T-cell regulation and differentiation.<ref>{{cite journal | vauthors = Massagué J, Xi Q | title = TGF-β control of stem cell differentiation genes | journal = FEBS Letters | volume = 586 | issue = 14 | pages = 1953–8 | date = July 2012 | pmid = 22710171 | pmc = 3466472 | doi = 10.1016/j.febslet.2012.03.023 }}</ref><ref>{{cite journal | vauthors = Li MO, Flavell RA | title = TGF-beta: a master of all T cell trades | journal = Cell | volume = 134 | issue = 3 | pages = 392–404 | date = August 2008 | pmid = 18692464 | pmc = 3677783 | doi = 10.1016/j.cell.2008.07.025 }}</ref>

Because of its role in immune and [[stem cell]] regulation and differentiation, it is a highly researched [[cytokine]] in the fields of cancer, auto-immune diseases, and [[infectious disease]].

The [[Transforming growth factor beta family|TGF-β superfamily]] includes endogenous growth inhibiting proteins; an increase in expression of TGF-β often correlates with the malignancy of many cancers and a defect in the cellular growth inhibition response to TGF-β. Its immunosuppressive functions then come to dominate, contributing to oncogenesis.<ref>{{cite journal | vauthors = Massagué J, Blain SW, Lo RS | title = TGFbeta signaling in growth control, cancer, and heritable disorders | journal = Cell | volume = 103 | issue = 2 | pages = 295–309 | date = October 2000 | pmid = 11057902 | doi = 10.1016/S0092-8674(00)00121-5 | s2cid = 15482063 | doi-access = free }}</ref> The dysregulation of its immunosuppressive functions is also implicated in the pathogenesis of autoimmune diseases, although their effect is mediated by the environment of other cytokines present.<ref name="ReferenceA" /><ref>{{Cite journal |last1=Lichtman |first1=Michael K. |last2=Otero-Vinas |first2=Marta |last3=Falanga |first3=Vincent |date=March 2016 |title=Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis |url=https://pubmed.ncbi.nlm.nih.gov/26704519/ |journal=Wound Repair and Regeneration |volume=24 |issue=2 |pages=215–222 |doi=10.1111/wrr.12398 |issn=1524-475X |pmid=26704519|s2cid=4967954 }}</ref>

== Structure ==
The primary 3 mammalian types are:
* [[TGF beta 1]] – TGFB1<ref>{{OMIM|190180}}</ref><ref>{{UniProt Full|P01137}}</ref>
* [[TGF beta 2]] – TGFB2<ref>{{OMIM|190220}}</ref><ref>{{UniProt Full|P61812}}</ref>
* [[TGF beta 3]] – TGFB3<ref>{{OMIM|190230}}</ref><ref>{{UniProt Full|P10600}}</ref>

A fourth member of the subfamily, TGFB4, has been identified in birds and a fifth, TGFB5, only in frogs.<ref name="Multiple forms of TGF-beta: distinc">{{cite book |last1=Roberts |first1=Anita B. |title=Ciba Foundation Symposium 157 - Clinical Applications of TGF-β |last2=Kim |first2=Seong-Jin |last3=Noma |first3=Takafumi |last4=Glick |first4=Adam B. |last5=Lafyatis |first5=Robert |last6=Lechleider |first6=Robert |last7=Jakowlew |first7=Sonia B. |last8=Geiser |first8=Andrew |last9=O'Reilly |first9=Michael A. |year=2007 |isbn=978-0-470-51406-1 |series=Novartis Foundation Symposia |volume=157 |pages=7–28 |chapter=Multiple Forms of TGF-β: Distinct Promoters and Differential Expression |doi=10.1002/9780470514061.ch2 |pmid=1906395 |last10=Danielpour |first10=David |last11=Sporn |first11=Michael B.}}</ref>

The peptide structures of the TGF-β isoforms are highly similar (homologies on the order of 70–80%). 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 (LAP - Alias: Pro-TGF beta 1, LAP/TGF beta 1), and a 112-114 amino acid [[C-terminus|C-terminal]] region that becomes the mature TGF-β molecule following its release from the pro-region by [[proteolysis|proteolytic]] cleavage.<ref>{{cite journal | vauthors = Khalil N | title = TGF-beta: from latent to active | journal = Microbes and Infection | volume = 1 | issue = 15 | pages = 1255–63 | date = December 1999 | pmid = 10611753 | doi = 10.1016/S1286-4579(99)00259-2 }}</ref> The mature TGF-β protein dimerizes to produce a 25 KDa active protein with many conserved structural motifs.<ref>{{cite journal | vauthors = Herpin A, Lelong C, Favrel P | title = Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans | journal = Developmental and Comparative Immunology | volume = 28 | issue = 5 | pages = 461–85 | date = May 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 bond]]s within the protein to create a [[cystine knot|cysteine knot]] structure characteristic of the TGF-β superfamily. The ninth cysteine forms a [[disulfide bond]] with the ninth cysteine of another TGF-β protein to produce a dimer.<ref>{{cite journal | vauthors = Daopin S, Piez KA, Ogawa Y, Davies DR | title = Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily | journal = Science | volume = 257 | issue = 5068 | pages = 369–73 | date = July 1992 | pmid = 1631557 | doi = 10.1126/science.1631557 | bibcode = 1992Sci...257..369D | url = https://zenodo.org/record/1230942 }}</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 proteins that is exposed at the surface of the protein and is implicated in receptor binding and specificity of TGF-β.

== Latent TGF-β complex ==
All three TGF-βs are synthesized as precursor molecules containing a propeptide region in addition to the TGF-β homodimer.<ref>{{cite journal | vauthors = Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV | display-authors = 6 | title = Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells | journal = Nature | volume = 316 | issue = 6030 | pages = 701–5 | year = 1985 | pmid = 3861940 | doi = 10.1038/316701a0 | bibcode = 1985Natur.316..701D | url = https://zenodo.org/record/1233037 | s2cid = 4245501 }}</ref> After it is synthesized, the TGF-β homodimer interacts with a Latency-Associated Peptide (LAP), a protein derived from the N-terminal region of the TGF-β gene product, forming a complex called Small Latent Complex (SLC). This complex remains in the cell until it is bound by another protein called Latent TGF-β-Binding Protein (LTBP), forming a larger complex called Large Latent Complex (LLC). It is this LLC that gets secreted to the [[extracellular matrix]] (ECM).<ref>{{cite journal | vauthors = Rifkin DB | title = Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability | journal = The Journal of Biological Chemistry | volume = 280 | issue = 9 | pages = 7409–12 | date = March 2005 | pmid = 15611103 | doi = 10.1074/jbc.R400029200 | doi-access = free }}</ref>

In most cases, before the LLC is secreted, the TGF-β precursor is cleaved from the propeptide but remains attached to it by noncovalent bonds.<ref>{{cite journal | vauthors = Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R | title = Processing of transforming growth factor beta 1 precursor by human furin convertase | journal = The Journal of Biological Chemistry | volume = 270 | issue = 18 | pages = 10618–24 | date = May 1995 | pmid = 7737999 | doi = 10.1074/jbc.270.18.10618 | doi-access = free }}</ref> After its secretion, it remains in the extracellular matrix as an in [[activated complex]] containing both the LTBP and the LAP which need to be further processed in order to release active TGF-β.<ref name="Annes03" /> The attachment of TGF-β to the LTBP is by disulfide bond which allows it to remain inactive by preventing it from binding to its receptors {{Citation needed|date=January 2014}}. Because different cellular mechanisms require distinct levels of TGF-β signaling, the inactive complex of this cytokine gives opportunity for a proper mediation of TGF-β signaling.<ref name="Annes03" />

There are four different LTBP isoforms known, LTBP-1, LTBP-2, LTBP-3 and LTBP-4.<ref>{{cite journal | vauthors = Saharinen J, Hyytiäinen M, Taipale J, Keski-Oja J | title = Latent transforming growth factor-beta binding proteins (LTBPs)--structural extracellular matrix proteins for targeting TGF-beta action | journal = Cytokine & Growth Factor Reviews | volume = 10 | issue = 2 | pages = 99–117 | date = June 1999 | pmid = 10743502 | doi = 10.1016/S1359-6101(99)00010-6 }}</ref> Mutation or alteration of LAP or LTBP can result in improper TGF-β signaling. Mice lacking LTBP-3 or LTBP-4 demonstrate phenotypes consistent to phenotypes seen in mice with altered TGF-β signaling.<ref>{{cite journal | vauthors = Sterner-Kock A, Thorey IS, Koli K, Wempe F, Otte J, Bangsow T, Kuhlmeier K, Kirchner T, Jin S, Keski-Oja J, von Melchner H | display-authors = 6 | title = Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer | journal = Genes & Development | volume = 16 | issue = 17 | pages = 2264–73 | date = September 2002 | pmid = 12208849 | pmc = 186672 | doi = 10.1101/gad.229102 }}</ref> Furthermore, specific LTBP isoforms have a propensity to associate with specific LAP•TGF-β isoforms. For example, LTBP-4 is reported to bind only to TGF-β1,<ref>{{cite journal | vauthors = Saharinen J, Keski-Oja J | title = Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta | journal = Molecular Biology of the Cell | volume = 11 | issue = 8 | pages = 2691–704 | date = August 2000 | pmid = 10930463 | pmc = 14949 | doi = 10.1091/mbc.11.8.2691 }}</ref> thus, mutation in LTBP-4 can lead to TGF-β associated complications which are specific to tissues that predominantly involves TGF-β1. Moreover, the structural differences within the LAP's provide different latent TGF-β complexes which are selective but to specific stimuli generated by specific activators.

== Activation ==
Although TGF-β is important in regulating crucial cellular activities, only a few TGF-β activating pathways are currently known, and the full mechanism behind the suggested activation pathways is not yet well understood. Some of the known activating pathways are cell or tissue specific, while some are seen in multiple cell types and tissues.<ref name="Annes03">{{cite journal | vauthors = Annes JP, Munger JS, Rifkin DB | title = Making sense of latent TGFbeta activation | journal = Journal of Cell Science | volume = 116 | issue = Pt 2 | pages = 217–24 | date = January 2003 | pmid = 12482908 | doi = 10.1242/jcs.00229 | doi-access = free }}</ref><ref>{{cite journal | vauthors = ten Dijke P, Hill CS | title = New insights into TGF-beta-Smad signalling | journal = Trends in Biochemical Sciences | volume = 29 | issue = 5 | pages = 265–73 | date = May 2004 | pmid = 15130563 | doi = 10.1016/j.tibs.2004.03.008 }}</ref> Proteases, integrins, pH, and reactive oxygen species are just few of the currently known factors that can activate TGF-β, as discussed below.<ref name="Stetler-Stevenson W.G. 1993">{{cite journal | vauthors = Stetler-Stevenson WG, Aznavoorian S, Liotta LA | title = Tumor cell interactions with the extracellular matrix during invasion and metastasis | journal = Annual Review of Cell Biology | volume = 9 | pages = 541–73 | year = 1993 | pmid = 8280471 | doi = 10.1146/annurev.cb.09.110193.002545 | url = https://zenodo.org/record/1234947 }}</ref><ref name="Barcellos-Hoff, M. H 1996">{{cite journal | vauthors = Barcellos-Hoff MH, Dix TA | title = Redox-mediated activation of latent transforming growth factor-beta 1 | journal = Molecular Endocrinology | volume = 10 | issue = 9 | pages = 1077–83 | date = September 1996 | doi = 10.1210/mend.10.9.8885242 | pmid = 8885242 | doi-access = free }}</ref><ref name="Wipff08">{{cite journal | vauthors = Wipff PJ, Hinz B | title = Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship | journal = European Journal of Cell Biology | volume = 87 | issue = 8–9 | pages = 601–15 | date = September 2008 | pmid = 18342983 | doi = 10.1016/j.ejcb.2008.01.012 }}</ref> It is well known that perturbations of these activating factors can lead to unregulated TGF-β signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts.<ref name="yu">{{cite journal | vauthors = Yu Q, Stamenkovic I | title = Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis | journal = Genes & Development | volume = 14 | issue = 2 | pages = 163–76 | date = January 2000 | doi = 10.1101/gad.14.2.163 | pmid = 10652271 | pmc = 316345 }}</ref><ref name="Taipale, J. 1994">{{cite journal | vauthors = Taipale J, Miyazono K, Heldin CH, Keski-Oja J | title = Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein | journal = The Journal of Cell Biology | volume = 124 | issue = 1–2 | pages = 171–81 | date = January 1994 | pmid = 8294500 | pmc = 2119892 | doi = 10.1083/jcb.124.1.171 }}</ref> In most cases, an activated TGF-β ligand will initiate the TGF-β signaling cascade as long as TGF-β receptors I and II are available for binding. This is due to a high affinity between TGF-β and its receptors, suggesting why the TGF-β signaling recruits a latency system to mediate its signaling.<ref name="Annes03" />

== Integrin-independent activation ==
=== Activation by protease and metalloprotease ===
[[Plasmin]] and a number of [[matrix metalloproteinase]]s (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components.<ref name="Stetler-Stevenson W.G. 1993" /> The TGF-β activation process involves the release of the LLC from the matrix, followed by further proteolysis of the LAP to release TGF-β to its receptors. [[MMP-9]] and [[MMP-2]] are known to cleave latent TGF-β.<ref name="yu" /> The LAP complex contains a protease-sensitive hinge region which can be the potential target for this liberation of TGF-β.<ref name="Taipale, J. 1994" /> Despite the fact that MMPs have been proven to play a key role in activating TGF-β, mice with mutations in MMP-9 and MMP-2 genes can still activate TGF-β and do not show any TGF-β deficiency phenotypes, this may reflect redundancy among the activating enzymes<ref name="Annes03" /> suggesting that other unknown proteases might be involved.

===Activation by pH===
Acidic conditions can denature the LAP. Treatment of the medium with extremes of pH (1.5 or 12) resulted in significant activation of TGF-β as shown by radio-receptor assays, while mild acid treatment (pH 4.5) yielded only 20-30% of the activation achieved by pH 1.5.<ref>{{cite journal | vauthors = Lyons RM, Keski-Oja J, Moses HL | title = Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium | journal = The Journal of Cell Biology | volume = 106 | issue = 5 | pages = 1659–65 | date = May 1988 | pmid = 2967299 | pmc = 2115066 | doi = 10.1083/jcb.106.5.1659 }}</ref>

===Activation by reactive oxygen species (ROS)===
The structure of LAP is important in maintaining its function. Structure modification of LAP can lead to disturb the interaction between LAP and TGF-β and thus activating it. Factors that may cause such modification may include hydroxyl radicals from reactive oxygen species (ROS). TGF-β was rapidly activated after ''in vivo'' radiation exposure ROS.<ref name="Barcellos-Hoff, M. H 1996" />

===Activation by thrombospondin-1===
[[Thrombospondin 1|Thrombospondin-1]] (TSP-1) is a matricellular glycoprotein found in plasma of healthy patients with levels in the range of 50–250&nbsp;ng/ml.<ref>{{cite journal | vauthors = Booth WJ, Berndt MC | title = Thrombospondin in clinical disease states | journal = Seminars in Thrombosis and Hemostasis | volume = 13 | issue = 3 | pages = 298–306 | date = July 1987 | pmid = 3317840 | doi = 10.1055/s-2007-1003505 | s2cid = 28212659 }}</ref> TSP-1 levels are known to increase in response to injury and during development.<ref>{{cite journal | vauthors = Raugi GJ, Olerud JE, Gown AM | title = Thrombospondin in early human wound tissue | journal = The Journal of Investigative Dermatology | volume = 89 | issue = 6 | pages = 551–4 | date = December 1987 | pmid = 3680981 | doi = 10.1111/1523-1747.ep12461198 | doi-access = free }}</ref> TSP-1 activates latent TGF-beta<ref>{{cite journal | vauthors = Schultz-Cherry S, Murphy-Ullrich JE | title = Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism | journal = The Journal of Cell Biology | volume = 122 | issue = 4 | pages = 923–32 | date = August 1993 | pmid = 8349738 | pmc = 2119591 | doi = 10.1083/jcb.122.4.923 }}</ref> by forming direct interactions with the latent TGF-β complex and induces a conformational rearrangement preventing it from binding to the matured TGF-β.<ref>{{cite journal | vauthors = Murphy-Ullrich JE, Poczatek M | title = Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology | journal = Cytokine & Growth Factor Reviews | volume = 11 | issue = 1–2 | pages = 59–69 | year = 2000 | pmid = 10708953 | doi = 10.1016/S1359-6101(99)00029-5 }}</ref>

== Activation by Alpha(V) containing integrins ==
The general theme of integrins participating in latent TGF-β1 activation arose from studies that examined mutations/knockouts of β6 integrin,<ref>{{cite journal | vauthors = Huang XZ, Wu JF, Cass D, Erle DJ, Corry D, Young SG, Farese RV, Sheppard D | display-authors = 6 | title = Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin | journal = The Journal of Cell Biology | volume = 133 | issue = 4 | pages = 921–8 | date = May 1996 | pmid = 8666675 | pmc = 2120829 | doi = 10.1083/jcb.133.4.921 }}</ref> αV integrin,<ref>{{cite journal | vauthors = Bader BL, Rayburn H, Crowley D, Hynes RO | title = Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins | journal = Cell | volume = 95 | issue = 4 | pages = 507–19 | date = November 1998 | pmid = 9827803 | doi = 10.1016/S0092-8674(00)81618-9 | s2cid = 13076974 | doi-access = free }}</ref> β8 integrin and in LAP. These mutations produced phenotypes that were similar to phenotypes seen in TGF-β1 knockout mice.<ref>{{cite journal | vauthors = Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D | display-authors = 6 | title = Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease | journal = Nature | volume = 359 | issue = 6397 | pages = 693–9 | date = October 1992 | pmid = 1436033 | pmc = 3889166 | doi = 10.1038/359693a0 | bibcode = 1992Natur.359..693S }}</ref> Currently there are two proposed models of how αV containing integrins can activate latent TGF-β1; the first proposed model is by inducing conformational change to the latent TGF-β1 complex and hence releasing the active TGF-β1 and the second model is by a protease-dependent mechanism.<ref name="Wipff08" />

===Conformation change mechanism pathway (without proteolysis)===
αVβ6 integrin was the first integrin to be identified as TGF-β1 activator.<ref name="Annes03" /> LAPs contain an RGD motif which is recognized by vast majority of αV containing integrins,<ref>{{cite journal | vauthors = Munger JS, Harpel JG, Giancotti FG, Rifkin DB | title = Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1 | journal = Molecular Biology of the Cell | volume = 9 | issue = 9 | pages = 2627–38 | date = September 1998 | pmid = 9725916 | pmc = 25536 | doi = 10.1091/mbc.9.9.2627 | citeseerx = 10.1.1.492.5809 }}</ref> and αVβ6 integrin can activate TGF-β1 by binding to the RGD motif present in LAP-β1 and LAP-β3.<ref>{{cite journal | vauthors = Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D | display-authors = 6 | title = The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis | journal = Cell | volume = 96 | issue = 3 | pages = 319–28 | date = February 1999 | pmid = 10025398 | doi = 10.1016/S0092-8674(00)80545-0 | doi-access = free }}</ref> Upon binding, it induces adhesion-mediated cell forces that are translated into biochemical signals which can lead to liberation/activation of TGFb from its latent complex.<ref name="Transforming growth factor beta 1 n">{{cite journal | vauthors = Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S | display-authors = 6 | title = Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 2 | pages = 770–4 | date = January 1993 | pmid = 8421714 | pmc = 45747 | doi = 10.1073/pnas.90.2.770 | bibcode = 1993PNAS...90..770K | doi-access = free }}</ref> This pathway has been demonstrated for activation of TGF-β in epithelial cells and does not associate MMPs.<ref>{{cite journal | vauthors = Taylor AW | title = Review of the activation of TGF-beta in immunity | journal = Journal of Leukocyte Biology | volume = 85 | issue = 1 | pages = 29–33 | date = January 2009 | pmid = 18818372 | pmc = 3188956 | doi = 10.1189/jlb.0708415 }}</ref>

===Integrin protease-dependent activation mechanism===
Because MMP-2 and MMP-9 can activate TGF-β through [[proteolytic degradation]] of the latent TGF beta complex,<ref name="yu" /> αV containing integrins activate TGF-β1 by creating a close connection between the latent TGF-β complex and MMPs. Integrins αVβ6 and αVβ3 are suggested to simultaneously bind the latent TGF-β1 complex and proteinases, simultaneous inducing conformational changes of the LAP and sequestering proteases to close proximity. Regardless of involving MMPs, this mechanism still necessitates the association of integrins and that makes it a non proteolytic pathway.<ref name="Wipff08" /><ref>{{cite journal | vauthors = Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL | display-authors = 6 | title = The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1 | journal = The Journal of Cell Biology | volume = 157 | issue = 3 | pages = 493–507 | date = April 2002 | pmid = 11970960 | pmc = 2173277 | doi = 10.1083/jcb.200109100 }}</ref>

== Signaling pathways ==
[[File:SMAD apoptosis.svg|thumb|right|200px|The SMAD Pathway]]

[[File:DAXX Pathway.svg|thumb|right|200px|The DAXX Pathway]]

=== Canonical signaling: The SMAD pathway ===
[[SMAD (protein)|Smads]] are a class of intracellular signalling proteins and transcription factors for the TGF-β family of signalling molecules. This pathway conceptually resembles the [[JAK-STAT signaling pathway|Jak-STAT signal transduction pathway]] characterized in the activation of cytokine receptors implicated, for example, in the B cell isotype switching pathway. As previously stated, the binding of the TGF-β ligand to the TGF-β receptor, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade. In the case of Smad, receptor-activated Smads are phosphorylated by the type 1 TGF-β receptor kinase, and these go on to complex with other Smads, which is able to translocate into the cell nucleus to induce transcription of different effectors.<ref>{{cite journal | vauthors = Derynck R, Zhang Y, Feng XH | title = Smads: transcriptional activators of TGF-beta responses | language = en | journal = Cell | volume = 95 | issue = 6 | pages = 737–40 | date = December 1998 | pmid = 9865691 | doi = 10.1016/S0092-8674(00)81696-7 | s2cid = 17711163 | doi-access = free }}</ref>

More specifically, activated TGF-β complexes bind to the type 2 domain of the TGF-β receptor which then recruits and phosphorylates a type 1 receptor. The type 1 receptor then recruits and phosphorylates a [[r-SMAD|receptor regulated SMAD]] (R-SMAD). The R-SMAD then binds to the common SMAD (coSMAD) [[Mothers against decapentaplegic homolog 4|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]]. The SMAD pathway is regulated by feedback inhibition. SMAD6 and SMAD7 may block type I receptors.<ref>{{cite journal | vauthors = Derynck R, Zhang YE | title = Smad-dependent and Smad-independent pathways in TGF-beta family signalling | journal = Nature | volume = 425 | issue = 6958 | pages = 577–84 | date = October 2003 | pmid = 14534577 | doi = 10.1038/nature02006 | bibcode = 2003Natur.425..577D | s2cid = 4419607 }}</ref> There is also substantial evidence that TGF-β-dependent signaling via the SMAD-3 pathway is responsible for many of the inhibitory functions of TGF-β discussed in later sections and thus it is implicated in oncogenesis.<ref>{{cite journal | vauthors = Letterio JJ | title = TGF-beta signaling in T cells: roles in lymphoid and epithelial neoplasia | journal = Oncogene | volume = 24 | issue = 37 | pages = 5701–12 | date = August 2005 | pmid = 16123803 | doi = 10.1038/sj.onc.1208922 | doi-access = free }}</ref>

The Smads are not the only TGF-β-regulated signaling pathways. Non-Smad signaling proteins can initiate parallel signaling that eventually cooperate with the Smads or crosstalk with other major signaling pathways. Among them, the mitogen-activated protein kinase (MAPK) family that include the extracellular-regulated kinases (ERK1 and 2), Jun N-terminal kinases (JNKs) and p38 MAPK play an important role in the TGF-β signaling.<ref name="pmid27864313">{{cite journal | vauthors = Zhang YE | title = Non-Smad Signaling Pathways of the TGF-β Family | journal = Cold Spring Harbor Perspectives in Biology | volume = 9 | issue = 2 | date = February 2017 | pages = a022129 | pmid = 27864313 | pmc = 5287080 | doi = 10.1101/cshperspect.a022129 }}</ref> ERK 1 and 2 are activated via the Raf-Ras-MEK1/2 pathway induced by mitogenic stimuli such as epidermal growth factor,<ref name="pmid22569528">{{cite journal | vauthors = Roskoski R | title = ERK1/2 MAP kinases: structure, function, and regulation | journal = Pharmacological Research | volume = 66 | issue = 2 | pages = 105–43 | date = August 2012 | pmid = 22569528 | doi = 10.1016/j.phrs.2012.04.005 }}</ref> whereas the JNK and p38 MAPK are activated by the MAPK kinase, activated themselves by the TGF-β-activated kinase-1 (TAK1) upon stress stimuli.<ref name="pmid26189595">{{cite journal | vauthors = Chen IT, Hsu PH, Hsu WC, Chen NJ, Tseng PH | title = Polyubiquitination of Transforming Growth Factor β-activated Kinase 1 (TAK1) at Lysine 562 Residue Regulates TLR4-mediated JNK and p38 MAPK Activation | journal = Scientific Reports | volume = 5 | pages = 12300 | date = July 2015 | pmid = 26189595 | pmc = 4507259 | doi = 10.1038/srep12300 | bibcode = 2015NatSR...512300C }}</ref>

=== Apoptosis via the DAXX pathway ===
TGF-β induces apoptosis, or programmed cell death, in human lymphocytes and hepatocytes. The importance of this function is clear in TGF-β deficient mice which experience hyperproliferation and unregulated autoimmunity.<ref name="Transforming growth factor beta 1 n"/> In a separate apoptotic pathway from the association of [[death-associated protein 6]] (DAXX) with the death receptor [[Fas receptor|Fas]], there is evidence of association and binding between DAXX and type 2 TGF-β receptor kinase, wherein DAXX binds to the C-terminal region of the type 2 TGF-β receptor.<ref>{{cite journal | vauthors = Yang X, Khosravi-Far R, Chang HY, Baltimore D | title = Daxx, a novel Fas-binding protein that activates JNK and apoptosis | language = en | journal = Cell | volume = 89 | issue = 7 | pages = 1067–76 | date = June 1997 | pmid = 9215629 | pmc = 2989411 | doi = 10.1016/S0092-8674(00)80294-9 }}</ref> The exact molecular mechanism is unknown, but as a general overview, DAXX is then phosphorylated by homeodomain-interacting protein kinase 2 (HIPK2), which then activates [[ASK1|apoptosis signal-inducing kinase 1]] (ASK1), which goes on to activate the [[C-Jun N-terminal kinases|Jun amino-terminal kinase]] (JNK) pathway and thus apoptosis as seen in the left panel of the adjacent image.<ref>{{cite journal | vauthors = Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA | title = TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation | journal = Nature Cell Biology | volume = 3 | issue = 8 | pages = 708–14 | date = August 2001 | pmid = 11483955 | doi = 10.1038/35087019 | s2cid = 20435808 }}</ref><ref>{{cite journal | vauthors = Hofmann TG, Stollberg N, Schmitz ML, Will H | title = HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells | journal = Cancer Research | volume = 63 | issue = 23 | pages = 8271–7 | date = December 2003 | pmid = 14678985 }}</ref>

== TGFβ receptor inhibitors ==
[[Galunisertib]] is the selective and potent TGFβRI kinase inhibitor.<ref>{{cite journal |last1=Yingling |first1=Jonathan M. |last2=McMillen |first2=William T. |last3=Yan |first3=Lei |last4=Huang |first4=Huocong |last5=Sawyer |first5=J. Scott |last6=Graff |first6=Jeremy |last7=Clawson |first7=David K. |last8=Britt |first8=Karen S. |last9=Anderson |first9=Bryan D. |last10=Beight |first10=Douglas W. |last11=Desaiah |first11=Durisala |last12=Lahn |first12=Michael M. |last13=Benhadji |first13=Karim A. |last14=Lallena |first14=Maria J. |last15=Holmgaard |first15=Rikke B. |last16=Xu |first16=Xiaohong |last17=Zhang |first17=Faming |last18=Manro |first18=Jason R. |last19=Iversen |first19=Philip W. |last20=Iyer |first20=Chandrasekar V. |last21=Brekken |first21=Rolf A. |last22=Kalos |first22=Michael D. |last23=Driscoll |first23=Kyla E. |title=Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor |journal=Oncotarget |date=23 January 2018 |volume=9 |issue=6 |pages=6659–6677 |doi=10.18632/oncotarget.23795 |pmid=29467918 |pmc=5805504 }}{{Creative Commons text attribution notice|cc=by3|from this source=yes}}</ref>

== TGF-β mimic ==
The parasitic roundworm ''[[Heligmosomoides polygyrus]]'' secretes a molecule that mimics the ability of mammalian TGF-β to bind to the TGFβR complex and trigger downstream signalling pathways.<ref>{{cite journal |last1=Johnston |first1=Chris J. C. |last2=Smyth |first2=Danielle J. |last3=Kodali |first3=Ravindra B. |last4=White |first4=Madeleine P. J. |last5=Harcus |first5=Yvonne |last6=Filbey |first6=Kara J. |last7=Hewitson |first7=James P. |last8=Hinck |first8=Cynthia S. |last9=Ivens |first9=Alasdair |last10=Kemter |first10=Andrea M. |last11=Kildemoes |first11=Anna O. |last12=Le Bihan |first12=Thierry |last13=Soares |first13=Dinesh C. |last14=Anderton |first14=Stephen M. |last15=Brenn |first15=Thomas |last16=Wigmore |first16=Stephen J. |last17=Woodcock |first17=Hannah V. |last18=Chambers |first18=Rachel C. |last19=Hinck |first19=Andrew P. |last20=McSorley |first20=Henry J. |last21=Maizels |first21=Rick M. |title=A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells |journal=Nature Communications |date=December 2017 |volume=8 |issue=1 |pages=1741 |doi=10.1038/s41467-017-01886-6 |pmid=29170498|pmc=5701006 |bibcode=2017NatCo...8.1741J }}</ref> This molecule, termed ''Hp''-TGM, shares no sequence homology to TGF-β and is secreted by ''H. polygyrus'' in a biologically active form. ''Hp''-TGM consists of 5 domains, with the first three shown to crucial for interaction with the TGFβR complex, with functions for domains 4 and 5 not yet known.<ref>{{cite journal |last1=Smyth |first1=Danielle J. |last2=Harcus |first2=Yvonne |last3=White |first3=Madeleine P.J. |last4=Gregory |first4=William F. |last5=Nahler |first5=Janina |last6=Stephens |first6=Ian |last7=Toke-Bjolgerud |first7=Edward |last8=Hewitson |first8=James P. |last9=Ivens |first9=Alasdair |last10=McSorley |first10=Henry J. |last11=Maizels |first11=Rick M. |title=TGF-β mimic proteins form an extended gene family in the murine parasite Heligmosomoides polygyrus |journal=International Journal for Parasitology |date=April 2018 |volume=48 |issue=5 |pages=379–385 |doi=10.1016/j.ijpara.2017.12.004 |pmid=29510118|pmc=5904571 }}</ref><ref>{{cite journal |last1=Mukundan |first1=Ananya |last2=Byeon |first2=Chang-Hyeock |last3=Hinck |first3=Cynthia S. |last4=Smyth |first4=Danielle J. |last5=Maizels |first5=Rick M. |last6=Hinck |first6=Andrew P. |title=Structure-based mapping of the TβRI and TβRII receptor binding sites of the parasitic TGF-β mimic, Hp-TGM |date=2020-12-09 |doi=10.1101/2020.12.08.416701|s2cid=229293860 }}</ref> Importantly, ''Hp''-TGM shows promise as a novel therapeutic as it induces less fibrosis than TGF-β ''in vivo'' in mice and can be used to induce populations of human [[FOXP3|FOXP3<sup>+</sup>]] regulatory T&nbsp;cells that had much greater stability than those induced by TGF-β.<ref>{{cite journal |last1=Cook |first1=Laura |last2=Reid |first2=Kyle T |last3=Häkkinen |first3=Elmeri |last4=de Bie |first4=Brett |last5=Tanaka |first5=Shigeru |last6=Smyth |first6=Danielle J |last7=White |first7=Madeleine PJ |last8=Wong |first8=May Q |last9=Huang |first9=Qing |last10=Gillies |first10=Jana K |last11=Zeigler |first11=Steven F |last12=Maizels |first12=Rick M |last13=Levings |first13=Megan K |title=Induction of stable human FOXP3<sup>+</sup> Tregs by a parasite-derived TGF-β mimic |journal=Immunology & Cell Biology |date=2021-04-30 |volume=99 |issue=8 |pages=833–847 |doi=10.1111/imcb.12475 |pmc=8453874 |pmid=33929751|doi-access=free }}</ref>

== Effects on immune cells ==
=== T lymphocytes ===
TGF-β1 plays a role in the induction from CD4<sup>+</sup> T&nbsp;cells of both [[Regulatory T cell#Induced regulatory T cells|induced T<sub>reg</sub>&nbsp;cells]] (iT<sub>reg</sub>&nbsp;cells), which have a regulatory function, and [[T helper 17 cell|T<sub>h</sub>17&nbsp;cells]], which secrete pro-inflammatory cytokines.<ref name=":3">{{cite journal | vauthors = Eisenstein EM, Williams CB | title = The T(reg)/Th17 cell balance: a new paradigm for autoimmunity | journal = Pediatric Research | volume = 65 | issue = 5 Pt 2 | pages = 26R–31R | date = May 2009 | pmid = 19218879 | doi = 10.1203/PDR.0b013e31819e76c7 | s2cid = 1778541 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Morishima N, Mizoguchi I, Takeda K, Mizuguchi J, Yoshimoto T | title = TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23 | journal = Biochemical and Biophysical Research Communications | volume = 386 | issue = 1 | pages = 105–10 | date = August 2009 | pmid = 19501566 | doi = 10.1016/j.bbrc.2009.05.140 }}</ref>

TGF-β1 alone precipitates the expression of FOXP3 and T<sub>reg</sub> differentiation from activated T helper cells, and the mechanism for this differentiation is unknown for both induced T regulatory cells as well as natural T regulatory cells. In mouse models, the effect of TGF-β1 appears to be age-dependent.<ref name=":1" />

Studies show that neutralization of TGF-β1 in vitro inhibits the differentiation of helper T&nbsp;cells into T<sub>h</sub>17&nbsp;cells. The role of TGF-β1 in the generation of T<sub>h</sub>17 cells goes against its dominant conceptualization as an anti-inflammatory cytokine; however, the shared requirement between inflammatory and anti-inflammatory immune cells suggests that an imbalance between these two cell types can be an important link to autoimmunity.<ref name=":3" /> Co-activation by IL-6 from activated dendritic cells, which serves to activate the transcription factor [[STAT3]], is required in addition to TGF-β1 for the differentiation of T<sub>h</sub>17 cells. However, the molecular mechanism of T<sub>h</sub>17 differentiation is not well understood.<ref name=":1">{{cite journal | vauthors = Li MO, Flavell RA | title = TGF-beta: a master of all T cell trades | language = en | journal = Cell | volume = 134 | issue = 3 | pages = 392–404 | date = August 2008 | pmid = 18692464 | pmc = 3677783 | doi = 10.1016/j.cell.2008.07.025 }}</ref> Because T<sub>h</sub>17 cells are distinct from T<sub>h</sub>1 and T<sub>h</sub>2 lineages in that they have been shown to be capable of regulatory functions, this is further evidence of TGF-β1's regulatory function in the immune system.<ref>{{cite journal | vauthors = O'Connor W, Zenewicz LA, Flavell RA | title = The dual nature of T(H)17 cells: shifting the focus to function | journal = Nature Immunology | volume = 11 | issue = 6 | pages = 471–6 | date = June 2010 | pmid = 20485275 | doi = 10.1038/ni.1882 | s2cid = 2980102 }}</ref>

=== B lymphocytes ===
TGF-β has mainly inhibitory effects on B lymphocytes. TGF-β inhibits B cell proliferation. The exact mechanism is unknown, but there is evidence that TGF-β inhibits B&nbsp;cell proliferation by inducing the transcription factor Id3, inducing expression of cyclin-dependent kinase inhibitor 21 (a regulator of cell cycle progression through the G1 and S phase), and repressing other key regulatory genes such as c-myc and ATM.<ref name=":0">{{cite journal | vauthors = Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA | title = Transforming growth factor-beta regulation of immune responses | journal = Annual Review of Immunology | volume = 24 | issue = 1 | pages = 99–146 | date = 2006-01-01 | pmid = 16551245 | doi = 10.1146/annurev.immunol.24.021605.090737 }}</ref><ref>{{cite journal | vauthors = Roes J, Choi BK, Cazac BB | title = Redirection of B cell responsiveness by transforming growth factor beta receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 12 | pages = 7241–6 | date = June 2003 | pmid = 12773615 | pmc = 165860 | doi = 10.1073/pnas.0731875100 | bibcode = 2003PNAS..100.7241R | doi-access = free }}</ref> CD40, a key surface molecule in the activation of the innate immune response, can induce Smad7 expression to reverse the growth inhibition of B cells induced by TGF-β.<ref>{{cite journal | vauthors = Patil S, Wildey GM, Brown TL, Choy L, Derynck R, Howe PH | title = Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta -induced growth inhibition and apoptosis | journal = The Journal of Biological Chemistry | volume = 275 | issue = 49 | pages = 38363–70 | date = December 2000 | pmid = 10995749 | doi = 10.1074/jbc.M004861200 | doi-access = free }}</ref> TGF-β also blocks B cell activation and promotes class switching [[IgA]] in both human and mouse B cells and has an otherwise inhibitory function for antibody production.<ref name=":0" />

TGF-β also induces apoptosis of immature or resting B&nbsp;cells; the mechanism is unknown, but may overlap with its anti-proliferation pathway. TGF-β has been shown to downregulate c-myc as it does in the inhibition of B cell proliferation. It is also known to induce NF-κB inhibitor IKBa, inhibiting NF-κB activation.<ref>{{cite journal | vauthors = Arsura M, Wu M, Sonenshein GE | title = TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha | language = en | journal = Immunity | volume = 5 | issue = 1 | pages = 31–40 | date = July 1996 | pmid = 8758892 | doi = 10.1016/S1074-7613(00)80307-6 | doi-access = free }}</ref> NF-κB is a transcription factor that regulates the production of cytokines like IL-1, TNF-a, and defensins, although its function in apoptosis may be separate from this function.

=== Macrophages ===
The general consensus in the literature is that TGF-β stimulates resting monocytes and inhibits activated macrophages. For monocytes, TGF-β has been shown to function as a chemoattractant as well as an upregulator of anti-inflammatory response.<ref>{{cite journal | vauthors = Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S | title = TGF-β - an excellent servant but a bad master | language = En | journal = Journal of Translational Medicine | volume = 10 | issue = 1 | pages = 183 | date = September 2012 | pmid = 22943793 | pmc = 3494542 | doi = 10.1186/1479-5876-10-183 | doi-access = free }}</ref> However, TGF-β has also been shown to downregulate inflammatory cytokine production in monocytes and macrophages, likely by the aforementioned inhibition of NF-κB.<ref>{{cite journal | vauthors = Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, Orenstein JM, Smith PD | display-authors = 6 | title = Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity | journal = The Journal of Clinical Investigation | volume = 115 | issue = 1 | pages = 66–75 | date = January 2005 | pmid = 15630445 | pmc = 539188 | doi = 10.1172/JCI19229 }}</ref> This contradiction may be due to the fact that the effect of TGF-β has been shown to be highly context-dependent.<ref>{{cite journal | vauthors = Wahl SM | title = Transforming growth factor-beta: innately bipolar | journal = Current Opinion in Immunology | volume = 19 | issue = 1 | pages = 55–62 | date = February 2007 | pmid = 17137775 | doi = 10.1016/j.coi.2006.11.008 | url = https://zenodo.org/record/1258845 }}</ref>

TGF-β is thought to play a role in alternative macrophage activation seen in lean mice, and these macrophages maintain an anti-inflammatory phenotype. This phenotype is lost in obese mice, who have not only more macrophages than lean mice but also classically activated macrophages which release TNF-α and other pro-inflammatory cytokines that contribute to a chronically pro-inflammatory milieu.<ref name=":2">{{cite journal | vauthors = Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM | display-authors = 6 | title = Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis | journal = Science | volume = 332 | issue = 6026 | pages = 243–7 | date = April 2011 | pmid = 21436399 | pmc = 3144160 | doi = 10.1126/science.1201475 | bibcode = 2011Sci...332..243W }}</ref>

=== Cell cycle ===
TGF-β plays a crucial role in the regulation of the [[cell cycle]] by blocking progress through [[G1 phase|G<sub>1</sub> phase]]. TGF-β causes synthesis of p15 and p21 proteins, which block the cyclin:CDK complex responsible for [[retinoblastoma protein]] (Rb) phosphorylation. Thus, TGF-β blocks advancement through the G<sub>1</sub> phase of the cycle.<ref name="Hanahan00">{{cite journal | vauthors = Hanahan D, Weinberg RA | title = The hallmarks of cancer | journal = Cell | volume = 100 | issue = 1 | pages = 57–70 | date = January 2000 | pmid = 10647931 | doi = 10.1016/S0092-8674(00)81683-9 | s2cid = 1478778 | doi-access = free }}</ref> In doing so, TGF-β suppresses expression of [[c-myc]], a gene which is involved in G<sub>1</sub> cell cycle progression.<ref name="Hanahan00" />

== Clinical significance ==
=== Cancer ===
In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. In many cancer cells, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β 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>{{cite journal | vauthors = Blobe GC, Schiemann WP, Lodish HF | title = Role of transforming growth factor beta in human disease | journal = The New England Journal of Medicine | volume = 342 | issue = 18 | pages = 1350–8 | date = May 2000 | pmid = 10793168 | doi = 10.1056/NEJM200005043421807 }}</ref> TGF-β1 has been implicated in the process of activating Hepatic Stellate Cells (HSCs) with the magnitude of hepatic fibrosis being in proportion to increase in TGF-β levels. Studies have shown that ACTA2 is associated with TGF-β pathway that enhances contractile properties of HSCs leading to Liver fibrosis.<ref>{{cite journal |last1=Hassan |first1=Sobia |last2=Shah |first2=Hussain |last3=Shawana |first3=Summayya |title=Dysregulated epidermal growth factor and tumor growth factor-beta receptor signaling through GFAP-ACTA2 protein interaction in liver fibrosis |journal=Pakistan Journal of Medical Sciences |date=2020 |volume=36 |issue=4 |pages=782–787 |doi=10.12669/pjms.36.4.1845 |pmid=32494274 |pmc=7260937 }}</ref> TGF-β 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.
Normal tissue integrity is preserved by feedback interactions between different cell types that express adhesion molecules and secrete cytokines. Disruption of these feedback mechanisms in cancer damages a tissue. When TGF-β signaling fails to control NF-κB activity in cancer cells, this has at least two potential effects: first, it enables the malignant tumor to persist in the presence of activated immune cells, and second, the cancer cell outlasts immune cells because it survives in the presence of apoptotic, and anti-inflammatory mediators.<ref>{{cite journal | vauthors = Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, Adamaki M, Bacopoulou F, Copland JA, Boldogh I, Karin M, Chrousos GP | display-authors = 6 | title = Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment | journal = Cytokine & Growth Factor Reviews | volume = 26 | issue = 4 | pages = 389–403 | date = August 2015 | pmid = 26119834 | pmc = 4526340 | doi = 10.1016/j.cytogfr.2015.06.001 }}</ref>

Furthermore, [[FOXP3|forkhead box protein 3]] (FOXP3) as a transcription factor is an essential molecular marker of regulatory T ([[Regulatory T cell|T<sub>reg</sub>]]) cells. [[FOXP3]] polymorphism (rs3761548) might be involved in cancer progression like [[gastric cancer]] through influencing Tregs function and the secretion of immunomodulatory cytokines such as [[Interleukin 10|IL-10]], [[IL-35]], and [[TGF-β]].<ref>{{cite journal | vauthors = Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, Eftekharsadat AT, Sadighi Moghaddam B, Salek Farrokhi A | title = Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients | journal = Cytokine | volume = 138 | issue = | pages = 155351 | date = February 2021 | pmid = 33127257 | doi = 10.1016/j.cyto.2020.155351 | s2cid = 226218796 | url = https://www.sciencedirect.com/science/article/pii/S1043466620303677| issn =1043-4666 | url-access = subscription }}</ref>

=== Tuberculosis ===
''[[Mycobacterium tuberculosis]]'' infection, or tuberculosis, has been shown to result in increased levels of active TGF-β within the lung.<ref>{{cite journal |last1=Bonecini-Almeida |first1=M. Glória |last2=Ho |first2=John L. |last3=Boéchat |first3=Neio |last4=Huard |first4=Richard C. |last5=Chitale |first5=Sadhana |last6=Doo |first6=Howard |last7=Geng |first7=Jiayuan |last8=Rego |first8=Lorena |last9=Lazzarini |first9=Luiz Claudio Oliveira |last10=Kritski |first10=Afrânio L. |last11=Johnson |first11=Warren D. |last12=McCaffrey |first12=Timothy A. |last13=Silva |first13=José R. Lapa e |title=Down-Modulation of Lung Immune Responses by Interleukin-10 and Transforming Growth Factor β (TGF-β) and Analysis of TGF-β Receptors I and II in Active Tuberculosis |journal=Infection and Immunity |date=May 2004 |volume=72 |issue=5 |pages=2628–2634 |doi=10.1128/IAI.72.5.2628-2634.2004|pmid=15102771 |pmc=387880 }}</ref><ref>{{cite journal |last1=Rook |first1=Graham A. W. |last2=Lowrie |first2=Douglas B. |last3=Hernàndez-Pando |first3=Rogelio |title=Immunotherapeutics for Tuberculosis in Experimental Animals: Is There a Common Pathway Activated by Effective Protocols? |journal=The Journal of Infectious Diseases |date=15 July 2007 |volume=196 |issue=2 |pages=191–198 |doi=10.1086/518937|pmid=17570105 |doi-access=free }}</ref> Due to the broad range of suppressive effects of TGF-β on immune cells, computer modeling has predicted that TGF-β blockade may improve immune responses and infection outcome.<ref>{{cite journal |last1=Warsinske |first1=Hayley C. |last2=Pienaar |first2=Elsje |last3=Linderman |first3=Jennifer J. |last4=Mattila |first4=Joshua T. |last5=Kirschner |first5=Denise E.|author5-link=Denise Kirschner |title=Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model |journal=Frontiers in Immunology |date=20 December 2017 |volume=8 |pages=1843 |doi=10.3389/fimmu.2017.01843|pmid=29326718 |pmc=5742530 |doi-access=free }}</ref> Research in animal models has further shown that TGF-β impairs immune responses and elimination of TGF-β signaling results in an enhanced T cell response and lower bacterial burdens.<ref>{{cite journal |last1=Gern |first1=Benjamin H. |last2=Adams |first2=Kristin N. |last3=Plumlee |first3=Courtney R. |last4=Stoltzfus |first4=Caleb R. |last5=Shehata |first5=Laila |last6=Moguche |first6=Albanus O. |last7=Busman-Sahay |first7=Kathleen |last8=Hansen |first8=Scott G. |last9=Axthelm |first9=Michael K. |last10=Picker |first10=Louis J. |last11=Estes |first11=Jacob D. |last12=Urdahl |first12=Kevin B. |last13=Gerner |first13=Michael Y. |title=TGFβ restricts expansion, survival, and function of T cells within the tuberculous granuloma |journal=Cell Host & Microbe |date=March 2021 |volume=29 |issue=4 |pages=594–606.e6 |doi=10.1016/j.chom.2021.02.005|pmid=33711270 |pmc=8624870 |s2cid=232217715 }}</ref><ref>{{cite journal |last1=Jayaswal |first1=Shilpi |last2=Kamal |first2=Md. Azhar |last3=Dua |first3=Raina |last4=Gupta |first4=Shashank |last5=Majumdar |first5=Tanmay |last6=Das |first6=Gobardhan |last7=Kumar |first7=Dhiraj |last8=Rao |first8=Kanury V. S. |title=Identification of Host-Dependent Survival Factors for Intracellular Mycobacterium tuberculosis through an siRNA Screen |journal=PLOS Pathogens |date=15 April 2010 |volume=6 |issue=4 |pages=e1000839 |doi=10.1371/journal.ppat.1000839|pmid=20419122 |pmc=2855445 |s2cid=1769658 |doi-access=free }}</ref><ref>{{cite journal |last1=Rosas-Taraco |first1=Adrian G. |last2=Higgins |first2=David M. |last3=Sánchez-Campillo |first3=Joaquín |last4=Lee |first4=Eric J. |last5=Orme |first5=Ian M. |last6=González-Juarrero |first6=Mercedes |title=Local pulmonary immunotherapy with siRNA targeting TGFβ1 enhances antimicrobial capacity in Mycobacterium tuberculosis infected mice |journal=Tuberculosis |date=January 2011 |volume=91 |issue=1 |pages=98–106 |doi=10.1016/j.tube.2010.11.004|pmid=21195670 |pmc=7238550 }}</ref> Thus, therapies which block TGF-β may have the potential to improve therapy for tuberculosis.

=== Heart disease ===
One animal study suggests that [[cholesterol]] suppresses the responsiveness of cardiovascular cells to TGF-β and its protective qualities, thus allowing [[atherosclerosis]] and [[heart disease]] to develop, while [[statin]]s, drugs that lower cholesterol levels, may enhance the responsiveness of cardiovascular cells to the protective actions of TGF-β.<ref>[http://www.slu.edu/x17685.xml Understanding Heart Disease: Research Explains Link Between Cholesterol and Heart Disease] {{Webarchive|url=https://web.archive.org/web/20071112041943/http://www.slu.edu/x17685.xml |date=2007-11-12 }}</ref>

TGF-β is involved in regeneration of zebrafish heart.

=== Marfan syndrome ===
TGF-β signaling also likely plays a major role in the pathogenesis of [[Marfan syndrome]],<ref name="tgf2beta">{{Cite web|url=https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=gene&dopt=full_report&list_uids=7048|title=TGFBR2 transforming growth factor, beta receptor II|access-date=January 11, 2007|year=2007|author=Entrez Gene|format=Entrez gene entry}}</ref> a disease characterized by disproportionate height, [[arachnodactyly]], [[ectopia lentis]] and heart complications such as [[mitral valve prolapse]] and aortic enlargement increasing the likelihood of [[aortic dissection]]. While the underlying defect in Marfan syndrome is faulty synthesis of the [[glycoprotein]] [[fibrillin]] I, normally an important component of [[elastic fibers]], it has been shown that the Marfan syndrome phenotype can be relieved by addition of a TGF-β antagonist in affected mice.<ref>{{cite journal | vauthors = Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC | display-authors = 6 | title = Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome | journal = Science | volume = 312 | issue = 5770 | pages = 117–21 | date = April 2006 | pmid = 16601194 | pmc = 1482474 | doi = 10.1126/science.1124287 | bibcode = 2006Sci...312..117H }}</ref> This suggests that while the symptoms of Marfan syndrome may seem consistent with a connective tissue disorder, the mechanism is more likely related to reduced sequestration of TGF-β by fibrillin.<ref>{{cite journal | vauthors = Robinson PN, Arteaga-Solis E, Baldock C, Collod-Béroud G, Booms P, De Paepe A, Dietz HC, Guo G, Handford PA, Judge DP, Kielty CM, Loeys B, Milewicz DM, Ney A, Ramirez F, Reinhardt DP, Tiedemann K, Whiteman P, Godfrey M | display-authors = 6 | title = The molecular genetics of Marfan syndrome and related disorders | journal = Journal of Medical Genetics | volume = 43 | issue = 10 | pages = 769–87 | date = October 2006 | pmid = 16571647 | pmc = 2563177 | doi = 10.1136/jmg.2005.039669 }}</ref>

===Loeys–Dietz syndrome===
TGF-β signaling is also disturbed in [[Loeys–Dietz syndrome]] which is caused by mutations in the TGF-β receptor.

===Obesity and diabetes===
TGF-β/SMAD3 signaling pathway is important in regulating glucose and energy homeostasis and might play a role in [[diabetic nephropathy]].

As noted above in the section about macrophages, loss of TGF-β signaling in obesity is one contributor to the inflammatory milieu generated in the case of obesity.<ref name=":2" />

===Multiple Sclerosis===
Induced T regulatory cells (iTreg), stimulated by TGF-β in the presence of [[Interleukin 2|IL-2]], suppressed the development of [[experimental autoimmune encephalomyelitis]] (EAE), an animal model of [[multiple sclerosis]] (MS) via a [[FOXP3]] and [[Interleukin 10|IL-10]] mediated response. This suggests a possible role for TGF-β and iTreg in the regulation and treatment of MS.<ref>{{cite journal | vauthors = Selvaraj RK, Geiger TL | title = Mitigation of experimental allergic encephalomyelitis by TGF-β induced FOXP3<sup>+</sup> regulatory T&nbsp;cells through the induction of anergy and infectious tolerance | journal = Journal of Immunology | volume = 180 | issue = 5 | pages = 2830–8 | date = March 2008 | pmid = 18292504 | doi = 10.4049/jimmunol.180.5.2830 | doi-access = free }}</ref>

Decreased levels of TGF-β have been observed in patients diagnosed with multiple sclerosis.<ref name="Dobolyi_2012">{{cite journal | vauthors = Dobolyi A, Vincze C, Pál G, Lovas G | title = The neuroprotective functions of transforming growth factor beta proteins | journal = International Journal of Molecular Sciences | volume = 13 | issue = 7 | pages = 8219–58 | date = July 2012 | pmid = 22942700 | pmc = 3430231 | doi = 10.3390/ijms13078219 | doi-access = free }}</ref> Its role in multiple sclerosis can be explained due to TGF-β role in regulating apoptosis of [[T helper 17 cell|T<sub>h</sub>17 cells]].<ref name="Dobolyi_2012" /> When TGF-β levels decrease, they are unable to induce T<sub>h</sub>17 cells apoptosis.<ref name="Dobolyi_2012" /> T<sub>h</sub>17 cells secretes TNF-α, which induces demyelination of the oligodendroglial via TNF receptor 1.<ref name="Nakahara_2012">{{cite journal | vauthors = Nakahara J, Maeda M, Aiso S, Suzuki N | title = Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy | journal = Clinical Reviews in Allergy & Immunology | volume = 42 | issue = 1 | pages = 26–34 | date = February 2012 | pmid = 22189514 | doi = 10.1007/s12016-011-8287-6 | s2cid = 21058811 }}</ref> The decreased TGF-β levels lead to increased T<sub>h</sub>17 cells and subsequently increased TNFα levels.<ref name="Dobolyi_2012" /> As a result, demyelination of neurons occurs.<ref name="Dobolyi_2012" /> TGF-β have also been observed to induce [[oligodendrocyte]] ([[myelin sheath]] producing cells) growth.<ref name="Dobolyi_2012" /> Hence, the decreased TGF-β levels during MS may also prevent remyelination of neurons.<ref name="Dobolyi_2012" />

=== Neurological ===
Higher concentrations of TGF-β are found in the blood and cerebrospinal fluid of patients with [[Alzheimer's disease]] as compared to control subjects,<ref>{{cite journal | vauthors = Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N | title = A meta-analysis of cytokines in Alzheimer's disease | journal = Biological Psychiatry | volume = 68 | issue = 10 | pages = 930–41 | date = November 2010 | pmid = 20692646 | doi = 10.1016/j.biopsych.2010.06.012 | s2cid = 6544784 }}</ref> suggesting a possible role in the neurodegenerative cascade leading to Alzheimer's disease symptoms and pathology.
The role of TGF-β in neuronal dysfunction remains an active area of research.<ref>{{cite journal | vauthors = Senatorov VV, Friedman, AR, Milikovsky DZ, Ofer J, Saar-Ashkenazy R, Charbash A, Jahan N, Chin G, Mihaly E, Lin JM, Ramsay HJ, Moghbel A, Preininger MK, Eddings CR, Harrison HV, Patel R, Shen Y, Ghanim H, Sheng H, Veksler R, Sudmant PH, Becker A, Hart B, Rogawski MA, Dillin A, Friedman A, and Kaufer D | title = Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction | journal = Science Translational Medicine | volume = 11 | issue = 521 | pages = eaaw8283 | date = December 2019 | doi = 10.1126/scitranslmed.aaw8283 | pmid = 31801886 |biorxiv=10.1101/537431 | doi-access = free }}</ref><ref>{{cite journal |author1=Daniela Kaufer |author2=Alon Friedman | title = Damage to a Protective Shield around the Brain May Lead to Alzheimer's and Other Diseases | journal = Scientific American | date = May 2021 | url = https://www.scientificamerican.com/article/damage-to-a-protective-shield-around-the-brain-may-lead-to-alzheimers-and-other-diseases/ }}</ref>

=== Other ===
Overactive TGF-β pathway, with an increase of TGF-β2,<ref name="pmid17679942">{{cite journal | vauthors = Maier P, Broszinski A, Heizmann U, Böhringer D, Reinhardau T | title = Active transforming growth factor-beta2 is increased in the aqueous humor of keratoconus patients | journal = Molecular Vision | volume = 13 | pages = 1198–202 | date = July 2007 | pmid = 17679942 | url = http://www.molvis.org/molvis/v13/av13/a130/ }}</ref> was reported in the studies of patients with [[keratoconus]].<ref name="pmid21310385">{{cite journal | vauthors = Engler C, Chakravarti S, Doyle J, Eberhart CG, Meng H, Stark WJ, Kelliher C, Jun AS | display-authors = 6 | title = Transforming growth factor-β signaling pathway activation in Keratoconus | journal = American Journal of Ophthalmology | volume = 151 | issue = 5 | pages = 752–759.e2 | date = May 2011 | pmid = 21310385 | pmc = 3079764 | doi = 10.1016/j.ajo.2010.11.008 }}</ref>

There is substantial evidence in animal and some human studies that TGF-β in breast milk may be a key immunoregulatory factor in the development of infant immune response, moderating the risk of atopic disease or autoimmunity.<ref>{{cite journal | vauthors = Oddy WH, Rosales F | title = A systematic review of the importance of milk TGF-beta on immunological outcomes in the infant and young child | journal = Pediatric Allergy and Immunology | volume = 21 | issue = 1 Pt 1 | pages = 47–59 | date = February 2010 | pmid = 19594862 | doi = 10.1111/j.1399-3038.2009.00913.x | doi-access = free }}</ref>

Skin aging is caused in part by [[TGF-β]], which reduces the subcutaneous fat that gives skin a pleasant appearance and texture. [[TGF-β]] does this by blocking the conversion of [[dermal fibroblasts]] into [[fat cells]]; with fewer fat cells underneath to provide support, the skin becomes saggy and wrinkled. Subcutaneous fat also produces [[cathelicidin]], which is a [[peptide]] that fights bacterial infections.<ref>{{Cite press release |title = UC San Diego Researchers Identify How Skin Ages, Loses Fat and Immunity |url = https://ucsdnews.ucsd.edu/pressrelease/uc_san_diego_researchers_identify_how_skin_ages_loses_fat_and_immunity |date = 2018-12-26 |first = Yadira | last = Galindo | publisher = University of California San Diego}}</ref><ref>{{cite journal | vauthors = Zhang LJ, Chen SX, Guerrero-Juarez CF, Li F, Tong Y, Liang Y, Liggins M, Chen X, Chen H, Li M, Hata T, Zheng Y, Plikus MV, Gallo RL | display-authors = 6 | title = Age-Related Loss of Innate Immune Antimicrobial Function of Dermal Fat Is Mediated by Transforming Growth Factor Beta | journal = Immunity | volume = 50 | issue = 1 | pages = 121–136.e5 | date = January 2019 | pmid = 30594464 | pmc = 7191997 | doi = 10.1016/j.immuni.2018.11.003 | url = | doi-access = free }}</ref>

== See also ==
* [[Anita Roberts]], a molecular biologist who made pioneering observations of TGF-β
* [[Ziad Mallat]], identified a major atheroprotective role of regulatory T cells and associated anti-inflammatory cytokines, IL-10 and TGF-β

== References ==
{{Reflist|33em}}

== Further reading ==
* {{cite journal | vauthors = Moses HL, Roberts AB, Derynck R | title = The Discovery and Early Days of TGF-β: A Historical Perspective | journal = Cold Spring Harbor Perspectives in Biology | volume = 8 | issue = 7 | pages = a021865 | date = July 2016 | pmid = 27328871 | pmc = 4930926 | doi = 10.1101/cshperspect.a021865 }}

== External links ==
* [https://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]
* [https://web.archive.org/web/20071114070732/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]
* [http://www.nature.com/nrm/journal/v1/n3/TGF_system/ The TGF-beta system]—Nature Reviews Molecular Cell Biology
* [[Simple Modular Architecture Research Tool|SMART]]:[http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=TGFB TGFB domain annotation]—[[European Molecular Biology Laboratory]] Heidelberg
* {{MeshName|TGF-beta}}
* [https://www.sciencedaily.com/releases/2008/02/080223122241.htm Biochemists Solve Structure Of TGF-Beta And Its Receptor. 2008] – shows TGF-β3 dimer in TGFB-receptor
* [https://archive.today/20141204114956/https://www.mabtech.com/elisa-analysis-latent-tgf-%CE%B21 Measurement of Human Latent TGF-β1]
* [http://www.novusbio.com/tgfbetapathway.html TGF beta pathway diagram]
* [http://www.ebi.ac.uk/interpro/entry/IPR016319 IntroPro Entry] - IPR016319

{{TGF beta signaling}}
{{Signaling proteins}}
{{TGFβ receptor superfamily modulators}}
{{Signal transduction}}

{{DEFAULTSORT:Transforming Growth Factor Beta}}
[[Category:TGFβ domain]]