Transforming growth factor beta
[8] 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.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-terminal region that becomes the mature TGF-β molecule following its release from the pro-region by proteolytic cleavage.Eight form disulfide bonds within the protein to create a cysteine knot structure characteristic of the TGF-β superfamily.[21] 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.[23] 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].For example, LTBP-4 is reported to bind only to TGF-β1,[26] thus, mutation in LTBP-4 can lead to TGF-β associated complications which are specific to tissues that predominantly involves TGF-β1.[28][29][30] 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.[23] Plasmin and a number of matrix metalloproteinases (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components.[42] 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.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.[47] 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.[55] 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.[56] This molecule, termed Hp-TGM, shares no sequence homology to TGF-β and is secreted by H. polygyrus in a biologically active form.The exact mechanism is unknown, but there is evidence that TGF-β inhibits B 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.[64] TGF-β also induces apoptosis of immature or resting B cells; the mechanism is unknown, but may overlap with its anti-proliferation pathway.[68] However, TGF-β has also been shown to downregulate inflammatory cytokine production in monocytes and macrophages, likely by the aforementioned inhibition of NF-κB.Studies have shown that ACTA2 is associated with TGF-β pathway that enhances contractile properties of HSCs leading to Liver fibrosis.Normal tissue integrity is preserved by feedback interactions between different cell types that express adhesion molecules and secrete cytokines.[75] Furthermore, forkhead box protein 3 (FOXP3) as a transcription factor is an essential molecular marker of regulatory T (Treg) cells.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 statins, drugs that lower cholesterol levels, may enhance the responsiveness of cardiovascular cells to the protective actions of TGF-β.[85] 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.TGF-β/SMAD3 signaling pathway is important in regulating glucose and energy homeostasis and might play a role in diabetic nephropathy.[71] Induced T regulatory cells (iTreg), stimulated by TGF-β in the presence of IL-2, suppressed the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) via a FOXP3 and IL-10 mediated response.[94] 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.
isoformscytokinetransforming growth factor superfamilysignaling proteinswhite blood cellserine/threonine kinaseTGF-β receptorschemotaxismacrophagespolypeptideslatent TGF-beta binding proteinproteinasesplasminthrombospondin-1regulation of inflammatory processesstem cellinfectious diseaseTGF-β superfamilyTGF beta 1TGF beta 2TGF beta 3protein precursorsamino acidssignal peptideC-terminalproteolyticcysteinedisulfide bondscysteine knotdisulfide bondextracellular matrixactivated complexmatrix metalloproteinasesproteolytic degradationJak-STAT signal transduction pathwayreceptor regulated SMADcell nucleusmitogen-activated protein kinaseapoptosisdeath-associated protein 6apoptosis signal-inducing kinase 1Jun amino-terminal kinaseGalunisertibHeligmosomoides polygyrusFOXP3+Th17 cellscell cycleG1 phaseretinoblastoma proteinimmunosuppressionangiogenesisforkhead box protein 3gastric cancerTGF-βMycobacterium tuberculosischolesterolatherosclerosisheart diseasestatinsMarfan syndromearachnodactylyectopia lentismitral valve prolapseaortic dissectionglycoproteinfibrillinelastic fibersLoeys–Dietz syndromediabetic nephropathyexperimental autoimmune encephalomyelitismultiple sclerosisTh17 cellsoligodendrocytemyelin sheathAlzheimer's diseasekeratoconusdermal fibroblastsfat cellscathelicidinpeptideAnita RobertsZiad MallatBibcodeOnline Mendelian Inheritance in ManUniProtCiteSeerXKirschner, Denise E.Wayback MachinebioRxivEuropean Molecular Biology LaboratoryMedical Subject HeadingsCell signalingTGFβ signaling pathwayTGF beta superfamily of ligandsTGF-β1TGF-β2TGF-β3Activin and inhibinBone morphogenetic proteinsGrowth differentiation factorsMyostatin/GDF8Anti-müllerian hormoneTGF beta receptorsActivinfamilyActivin type 1 receptorsACVR1BACVR1CACVRL1BMPR1ABMPR1BActivin type 2 receptorsACVR2AACVR2BbetaglycanTransducersR-SMADI-SMADCerberusChordinDecorinFollistatinGremlinNogginCoreceptorsCripto