Latent TGF-β-binding proteins

Robertson, I. M.; Horiguchi, Masahito; Zilberberg, Lior; Dabovic, Branka; Hadjiolova, Krassimira V.; Rifkin, Daniel B.

doi:10.1016/j.matbio.2015.05.005

Cited by 369 publications

(327 citation statements)

References 85 publications

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“…Under physiological circumstances, extracellular microfibrils serve complex and somewhat divergent functions in regulating TGF-b signaling. They serve both as "positive" regulators of TGF-b signaling, by concentrating latent TGF-b at sites of intended function, and as "negative" regulators of TGF-b signaling, by sequestering latent TGF-b and preventing its conversion to the active form (Ramirez et al 2004;Robertson et al 2015).…”

Section: Marfan Syndromementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Marfan Syndromementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…TGFβ and BMP signaling are regulated at multiple levels, including extracellularly through ligand’s storage in and release from the ECM. By binding to both small latent TGFβ complexes and fibrillins, LTBPs tether TGFβ molecules to the ECM from where they are released and activated through non-proteolytic and proteolytic mechanisms [16]. Direct binding of bioactive pro-BMPs to fibrillins similarly results in growth factor latency [17].…”

Section: Structure and Function Of Fibrillin Proteinsmentioning

confidence: 99%

Fibrillin microfibrils in bone physiology

Smaldone

Ramirez

2016

Matrix Biology

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The severe skeletal abnormalities associated with Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA) underscore the notion that fibrillin assemblies (microfibrils and elastic fibers) play a critical role in bone formation and function in spite of representing a low abundance component of skeletal matrices. Studies of MFS and CCA mice have correlated the skeletal phenotypes of these mutant animals with distinct pathophysiological mechanisms that reflect the contextual contribution of fibrillin-1 and -2 scaffolds to TGFβ and BMP signaling during bone patterning, growth and metabolism. Illustrative examples include the unique role of fibrillin-2 in regulating BMP-dependent limb patterning and the distinct impact of the two fibrillin proteins on the commitment and differentiation of marrow mesenchymal stem cells. Collectively, these findings have important implication for our understanding of the pathophysiological mechanisms that drive age- and injury-related processes of bone degeneration.

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“…Active TGF-β is also required for myofibroblast differentiation and is derived from a latent TGF-β precursor that is associated with the ECM (Robertson et al, 2015). A principal mechanism through which active TGF-β is generated involves integrin-mediated mechanical 'tugging' on latent TGF-β to release the active form (Klingberg et al, 2014;Wipff et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-β on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-β. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of α smooth muscle actin (α-SMA) and Hic-5 in response to TGF-β. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of α-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with α-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-β.

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Latent TGF-β-binding proteins

Cited by 369 publications

References 85 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Fibrillin microfibrils in bone physiology

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

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