The latent transforming growth factor (TGF) β binding proteins (LTBP) are crucial mediators of TGFβ function, as they control growth factor secretion, matrix deposition, presentation and activation. ...Deficiencies in specific LTBP isoforms yield discrete phenotypes representing defects in bone, lung and cardiovascular development mediated by loss of TGFβ signaling. Additional phenotypes represent loss of unique TGFβ-independent features of LTBP effects on elastogenesis and microfibril assembly. Thus, the LTBPs act as sensors for the regulation of both growth factor activity and matrix function.
•The latent TGF beta binding proteins (LTBPs) are important matrix mediators of biological functions.•These molecules are crucial components of the regulation of both TGF beta action and elastin organization.•This review describes the biology of the LTBPs and outlines the physiological and pathological consequences of LTBP activity/loss.•Special attention is paid to in vivo analysis.
The bioavailability of members of the transforming growth factor β (TGF-β) family is controlled by a number of mechanisms. Bona fide TGF-β is sequestered into the matrix in a latent state and must be ...activated before it can bind to its receptors. Here, we review the molecules and mechanisms that regulate the bioavailability of TGF-β and compare these mechanisms with those used to regulate other TGF-β family members. We also assess the physiological significance of various latent TGF-β activators, as well as other extracellular modulators of TGF-β family signaling, by examining the available in vivo data from knockout mouse models and other biological systems.
Mechanisms of tendon injury and repair Thomopoulos, Stavros; Parks, William C.; Rifkin, Daniel B. ...
Journal of orthopaedic research,
June 2015, Letnik:
33, Številka:
6
Journal Article
The cytokine transforming growth factor-beta (TGF-β) has multiple effects in both physiological and pathological conditions. TGF-β is secreted as part of a tripartite complex from which it must be ...released in order to bind to its receptor. Sequestration of latent TGF-β in the extracellular matrix (ECM) is crucial for proper mobilization of the latent cytokine and its activation. However, contrary to expectation, loss-of-function mutations in genes encoding certain matrix proteins that bind TGF-β yield elevated, rather than decreased, TGF-β levels, posing a 'TGF-β paradox.' In this review, we discuss recent findings concerning the relationship of TGF-β, ECM molecules, and latent TGF-β activation and propose a model to resolve the 'TGF-β paradox.'
The LTBPs (or latent transforming growth factor β binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils and have a number of different ...roles in microfibril biology. There are four LTBPs isoforms in the human genome (LTBP-1, −2, −3, and −4), all of which appear to associate with fibrillin and the biology of each isoform is reviewed here.
The LTBPs were first identified as forming latent complexes with TGFβ by covalently binding the TGFβ propeptide (LAP) via disulfide bonds in the endoplasmic reticulum. LAP in turn is cleaved from the mature TGFβ precursor in the trans-golgi network but LAP and TGFβ remain strongly bound through non-covalent interactions. LAP, TGFβ, and LTBP together form the large latent complex (LLC). LTBPs were originally thought to primarily play a role in maintaining TGFβ latency and targeting the latent growth factor to the extracellular matrix (ECM), but it has also been shown that LTBP-1 participates in TGFβ activation by integrins and may also regulate activation by proteases and other factors. LTBP-3 appears to have a role in skeletal formation including tooth development. As well as having important functions in TGFβ regulation, TGFβ-independent activities have recently been identified for LTBP-2 and LTBP-4 in stabilizing microfibril bundles and regulating elastic fiber assembly.
•We describe structures and interactions of the four latent transforming growth factor beta binding proteins (LTBP) proteins.•The biological functions of the four LTBPs
LTBPs, more than just an escort service Todorovic, Vesna; Rifkin, Daniel B.
Journal of cellular biochemistry,
February 2012, Letnik:
113, Številka:
2
Journal Article
The conjunctive presence of mechanical stress and active transforming growth factor β1 (TGF-β1) is essential to convert fibroblasts into contractile myofibroblasts, which cause tissue contractures in ...fibrotic diseases. Using cultured myofibroblasts and conditions that permit tension modulation on the extracellular matrix (ECM), we establish that myofibroblast contraction functions as a mechanism to directly activate TGF-β1 from self-generated stores in the ECM. Contraction of myofibroblasts and myofibroblast cytoskeletons prepared with Triton X-100 releases active TGF-β1 from the ECM. This process is inhibited either by antagonizing integrins or reducing ECM compliance and is independent from protease activity. Stretching myofibroblast-derived ECM in the presence of mechanically apposing stress fibers immediately activates latent TGF-β1. In myofibroblast-populated wounds, activation of the downstream targets of TGF-β1 signaling Smad2/3 is higher in stressed compared to relaxed tissues despite similar levels of total TGF-β1 and its receptor. We propose activation of TGF-β1 via integrin-mediated myofibroblast contraction as a potential checkpoint in the progression of fibrosis, restricting autocrine generation of myofibroblasts to a stiffened ECM.
Lymphocyte homing, which contributes to inflammation, has been studied extensively in the small intestine, but there is little known about homing to the large intestine, the site most commonly ...affected in inflammatory bowel disease. GPR15, an orphan heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, controlled the specific homing of T cells, particularly FOXP3⁺ regulatory T cells (T regs ), to the large intestine lamina propria (LILP). GPR15 expression was modulated by gut microbiota and transforming growth factor-ß1, but not by retinoic acid. GPR15-deficient mice were prone to develop more severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient T regs . Our findings thus describe a T cell-homing receptor for LILP and indicate that GPR15 plays a role in mucosal immune tolerance largely by regulating the influx of T regs .
Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive ...signaling by the transforming growth factor-{szligbeta} (TGF-{szligbeta}) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-{szligbeta} signaling and can be prevented by TGF-{szligbeta} antagonists such as TGF-{szligbeta}-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.
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