Activin isoforms signal through type I receptor serine/threonine kinase ALK7

Tsuchida, Kunihiro; Nakatani, Masashi; Yamakawa, Noriko; Hashimoto, Osamu; Hasegawa, Yoshihisa; Sugino, Hiromu

doi:10.1016/j.mce.2004.03.009

Cited by 130 publications

(95 citation statements)

References 23 publications

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“…Upon ligand binding, one of the activin type II receptors (ActRII or ActRIIB) dimerizes with a type I receptor (ActRIA, ActRIB or activin receptorlike kinase 7), resulting in phosphorylation of the type I receptor by the type II receptor. 2,3 Although we and others have firmly established a neuroprotective role of activin in acute brain injury, [4][5][6] it remained unclear whether activin also influences the operation of neuronal circuits under physiological conditions. To explore the functions of activin in normal adult brain, we recently generated transgenic (tg) mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB) under the control of the CaMKIIa promoter.…”

Section: Introductionmentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Section: Introductionmentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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“…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).…”

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confidence: 99%

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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“…Activin activities are mediated by heteromeric receptor complexes, consisting of type I (ActRIA/Alk2, ActRIB/Alk4, and Alk7) and type II (ActRII and ActRIIB) receptors, which are all serine/threonine kinases (Mathews and Vale, 1993;Tsuchida et al, 2004). In addition, activins bind to the soluble glycoprotein follistatin that inhibits activin action (Nakamura et al, 1990).…”

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confidence: 99%

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

et al. 2005

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Activin is a member of the transforming growth factor b (TGF-b) family, which plays a crucial role in skin morphogenesis and wound healing. To gain insight into the underlying mechanisms of action, we searched for activin-regulated genes in cultured keratinocytes. One of the identified target genes encodes Id1, a negative regulator of helix-loop-helix transcription factors. We show that Id1, Id2, and Id3 are strongly downregulated by activin in keratinocytes in vitro and in vivo. To determine the role of Id1 in keratinocyte biology, we generated stable HaCaT keratinocyte cell lines overexpressing this protein. Our results revealed that enhanced levels of Id1 do not affect proliferation of keratinocytes in monoculture under exponential culture conditions or in response to activin or TGF-b1. However, in three-dimensional organotypic cultures, Id1-overexpressing HaCaT cells formed a hyperthickened and disorganized epithelium that was characterized by enhanced keratinocyte proliferation, abnormal differentiation, and an increased rate of apoptosis. These results identify an important function of Id1 in the regulation of epidermal homeostasis.

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Activin isoforms signal through type I receptor serine/threonine kinase ALK7

Cited by 130 publications

References 23 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

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

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

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