Activin signaling as an emerging target for therapeutic interventions

Tsuchida, Kunihiro; Nakatani, Masashi; Hitachi, Keisuke; Uezumi, Akiyoshi; Sunada, Yoshihide; Ageta, Hiroshi; Inokuchi, Kaoru

doi:10.1186/1478-811x-7-15

Cited by 164 publications

(146 citation statements)

References 117 publications

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“…Activins, members of the TGFβ superfamily, elicit numerous context-dependent effects on growth and differentiation [18]. Activins control embryonic patterning of foregut-derived organs [19], have important roles in pancreatic development [20] and have been implicated in the control of insulin secretion [21,22].…”

Section: Introductionmentioning

confidence: 99%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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Aims/hypothesis The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function. Methods MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.Results Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin. Conclusions/interpretation These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.

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Section: Introductionmentioning

confidence: 99%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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“…Activin A, another member of the TGF-b family of ligands, is also expressed in bone and cartilage, and activates the Smad2-and Smad3-dependent pathway with potential overlap with TGF-b functions (Ogawa et al 1992;Massagué and Gomis 2006;Eijken et al 2007;Tsuchida et al 2009;Pauklin and Vallier 2015;Salazar et al 2016). …”

Section: Roles Of Tgf-b and Bmp Signaling In Bone Formation Skeletalmentioning

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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“…Activins bind to their serine-threonine kinase receptor to trigger SMAD signaling pathway and non-SMAD pathways including MAPK, PI3K/AKT and Wnt/β-catenin signaling (Tsuchida et al, 2009). Activin A induced human GBM cells U87 proliferation via SMAD2/3 activation; this effect is negatively regulated by Follistatin that is an Activinbinding protein (Zhang et al, 2010).…”

Section: Activinsmentioning

confidence: 99%

“…Activins are ubiquitous growth factors that regulate DOI:http://dx.doi.org/10.7314/APJCP.2015.16.16.6813 Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression functions as diverse as gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, brain functions, proliferation and differentiation of embryonic stem cells and also cancer growth and metastasis (Tsuchida et al, 2009). Activins bind to their serine-threonine kinase receptor to trigger SMAD signaling pathway and non-SMAD pathways including MAPK, PI3K/AKT and Wnt/β-catenin signaling (Tsuchida et al, 2009).…”

Section: Activinsmentioning

confidence: 99%

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

Nana¹,

Yang²,

Lin³

2015

Asian Pacific Journal of Cancer Prevention

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Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor β (TGFβ) superfamily is a large group of structurally related proteins including TGFβ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The TGFβ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (αvβ3, α5β1) and GBM initiating cells (GICs) as well as inducing a GBMmesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the TGFβ subfamily yields advantageous results, enhancing BMPs production is also beneficial.

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Activin signaling as an emerging target for therapeutic interventions

Cited by 164 publications

References 117 publications

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

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