Properties of inhibin binding to betaglycan, InhBP/p120 and the activin type II receptors

Chapman, Stacey C.; Bernard, Daniel J.; Jelen, S.; Woodruff, Teresa K.

doi:10.1016/s0303-7207(02)00227-7

Cited by 82 publications

(71 citation statements)

References 56 publications

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“…The ligand-driven assembly of heteromeric receptor complex formation can occur in two steps, as seen with TGF␤ ligands, or in a single step, exemplified by BMP-receptor interactions (3). Activin A has high affinity for its type II receptors, ActRII and ActRIIB, but not for its type I receptor, ALK4 (ActRIB), despite the presence of a ligand-binding domain within ALK4 (5)(6)(7)(8). Following a two-step receptor complex formation, ALK4 contacts activin A that is already bound to ActRII/IIB (3,4) (Fig.…”

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“…By binding the type II receptor and preventing the recruitment of the type I receptor, inhibins antagonize the actions of activins, BMPs, and other TGF␤ superfamily members (6,11,12). Additional inhibin-binding proteins that increase the affinity of inhibin for the type II receptors are thought to be involved in mediating the antagonistic actions of inhibin.…”

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confidence: 99%

“…Additional inhibin-binding proteins that increase the affinity of inhibin for the type II receptors are thought to be involved in mediating the antagonistic actions of inhibin. Although several candidate inhibin-binding proteins have been identified to date, only the type III TGF␤ receptor (commonly known as betaglycan) has been shown to increase the binding affinity of inhibin to the type II activin and BMP receptors (6,13,14) (Fig. 1A).…”

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confidence: 99%

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Inhibin α-Subunit N Terminus Interacts with Activin Type IB Receptor to Disrupt Activin Signaling

Zhu

Lin

Zou

et al. 2012

Journal of Biological Chemistry

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Background:The inhibin ␤-subunit interacts with activin type II receptor to antagonize activin signaling. Results: The inhibin ␣-subunit N terminus binds ALK4 to antagonize activin signaling. Conclusion: Inhibin ␣-subunit binding to ALK4 supports potent antagonism of constitutive activin-stimulated FSH production in pituitary cells. Significance: Understanding the mechanisms underlying control of pituitary FSH synthesis may provide treatment approaches to reproductive endocrine disorders.

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Inhibin α-Subunit N Terminus Interacts with Activin Type IB Receptor to Disrupt Activin Signaling

Zhu

Lin

Zou

et al. 2012

Journal of Biological Chemistry

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“…As a consequence, activin type I receptors (ALK4 and ALK2) are excluded from the receptor complex, leading to the inhibition of SMADmediated signaling. 3,[11][12][13][14] Despite the fact that inhibins have been classically considered as activin antagonists, there is evidence showing that they do not always antagonize activin-mediated functions in several cell types, suggesting the existence of an independent inhibinmediated signaling pathway. 3 Compelling evidence has shown that activins also regulate various non-reproductive processes, such as mesoderm induction, liver proliferation, skin morphogenesis, erythropoiesis, bone formation, neuron survival and immune function.…”

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When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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Activins and inhibins are members of the transforming growth factor-b superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses. Keywords: activin; inhibin; inflammation; immune cells; immunity; tolerance Activins and inhibins are members of the transforming growth factor-b (TGF-b) superfamily that were initially described as regulators of reproductive processes in mammals, and were first named after their positive and negative effect in the release of follicle-stimulating hormone from the pituitary gland, respectively. 1 These dimeric ligands have been shown to modulate a variety of cellular functions such as apoptosis, proliferation, differentiation, cellular migration, among others. 2,3 Activin A (bA/bA) is the best-characterized ligand of this subfamily, although there are other bioactive forms, activin B (bB/bB) and activin AB (bA/bB), which differ in their potency and cellular function. 4 Activin A is a molecule with pleiotropic functions, which shares with TGF-b the SMAD2/3 canonical signaling pathway (reviewed by Shi and Massague 5 ) but uses distinct type II (ActRIIs) and type I (ALK2, ALK4 and ALK7) receptors. [6][7][8][9] The biological function of activins can be blocked by follistatin (FS), a glycoprotein that binds activin A with high affinity, functioning as a ligand trap. 10 On the other hand, inhibins are heterodimers formed by uncommon a-and b-subunits and exist in two isoforms, inhibin A (a/bA) and B (a/bB). Inhibins have been shown to antagonize activinmediated functions by a mechanism that involves binding to b-glycan (TGFbRIII) and formation of a ternary complex with ActRIIs. As a consequence, activin type I receptors (ALK4 and ALK2) are excluded from the receptor complex, leading to the inhibition of SMADmediated signaling. 3,[11][12][13][14] Despite the fact that inhibins have been classically considered as activin antagonists, there is evidence showing that they do not always antagonize activin-mediated functions in several cell types, suggesting the existence of an independent inhibinmediated signaling pathway. 3 Compelling evidence has shown that activins also regulate various non-reproductive processes, such as mesoderm induction, liver proliferation, skin morphogenesis, erythropoiesis, bone formation, neu...

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“…On the other hand, those formed with inhibin A and the corresponding type II receptors antagonize the effects of activin or BMP. As a matter of fact, up to date, betaglycan stands as the only identified inhibin A receptor capable of mediating its characteristic activin antagonism (15,16). Although the glycosaminoglycan chains are not required for all of these functions (10,17), they may modulate them.…”

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The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

Velasco-Loyden

Arribas

López‐Casillas

2004

Journal of Biological Chemistry

126

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Betaglycan is a membrane-anchored proteoglycan that binds transforming growth factor-␤ (TGF-␤) via its core protein. A soluble form of betaglycan can be released by proteolytic cleavage (also known as shedding) of the membrane-bound form, yielding soluble betaglycan. The mechanism leading to the generation of soluble betaglycan is poorly understood. Because the membrane and soluble forms of betaglycan have opposite effects regulating the availability of TGF-␤, it is important to characterize the shedding of betaglycan further. Here we present evidence showing that in certain cell types, pervanadate, a general tyrosine phosphatase inhibitor, induces the release of the previously described fragment that encompasses almost the entire extracellular domain of betaglycan (sBG-120). In addition, treatment with pervanadate unveils the existence of a novel 90-kDa fragment (sBG-90). Noticeably, the cleavage that generates sBG-90 is mediated by a tissue inhibitor of metalloprotease-2-sensitive protease. Overexpression of all membrane type matrix metalloproteases (MT-MMPs) described to date indicates that MT1-MMP and MT3-MMP are endowed with ability to generate sBG-90. Furthermore, the patterns of expression of different MTMMPs in the cell lines used in this study suggest that MT1-MMP is the protease involved in the shedding of sBG-90. Overexpression of MT1-MMP in COS-1 cells, which do not express detectable levels of this metalloprotease, confirms the feasibility of this hypothesis. Unexpectedly, during the course of these experiments, we observed that MT2-MMP decreases the levels of MT1-MMP and betaglycan. Finally, binding competition experiments indicate that, similar to the wild type membrane betaglycan, sBG-90 binds the TGF-␤2 isoform with greater affinity than TGF-␤1, suggesting that once released, it could affect the cellular availability of TGF-␤.

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Properties of inhibin binding to betaglycan, InhBP/p120 and the activin type II receptors

Cited by 82 publications

References 56 publications

Inhibin α-Subunit N Terminus Interacts with Activin Type IB Receptor to Disrupt Activin Signaling

Inhibin α-Subunit N Terminus Interacts with Activin Type IB Receptor to Disrupt Activin Signaling

When versatility matters: activins/inhibins as key regulators of immunity

The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

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