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Activin signaling as an emerging target for therapeutic interventions.

Tsuchida K, Nakatani M, Hitachi K, Uezumi A, Sunada Y, Ageta H, Inokuchi K - Cell Commun. Signal (2009)

Bottom Line: Non-Smad signaling also plays an important role in activin signaling.Extracellularly, follistatin and related proteins bind to activins and related TGF-beta ligands, and control the signaling and availability of ligands.The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases.Accordingly, activin signaling may be a target for therapeutic interventions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan. tsuchida@fujita-hu.ac.jp.

ABSTRACT
After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-beta (TGF-beta) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-beta, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-beta ligands, and control the signaling and availability of ligands.The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.

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Related in: MedlinePlus

Signal transduction through activin receptors. Activin, myostatin and GDF11 signal through type II and type I serine/threonine kinase receptors. Type IIR is the principal ligand binding receptors, and ligand/typeIIR complexes recruit and associate with type IR. Type IR is phosphorylated and activated by type IIR kinase. Smad2 and 3, activin/TGF-β specific Smads, are phosphorylated by activated type IR. In the nucleus, Smad2/3/4 complexes regulate gene expression with additional transcriptional cofactors. Smad-independent pathway such as MAPK is also activated downstream of activin receptors. Inhibin acts antagonistic to activin by forming high affinity complexes with ActRII and betaglycan. Follistatin, myostatin propeptide and receptor ectodomain inhibit the activities of activin and related factors in the extracellular space to prevent ligand/receptor interaction. Chemical type IR kinase inhibitors act in the cell to disrupt receptor/intracellular signaling.
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Figure 1: Signal transduction through activin receptors. Activin, myostatin and GDF11 signal through type II and type I serine/threonine kinase receptors. Type IIR is the principal ligand binding receptors, and ligand/typeIIR complexes recruit and associate with type IR. Type IR is phosphorylated and activated by type IIR kinase. Smad2 and 3, activin/TGF-β specific Smads, are phosphorylated by activated type IR. In the nucleus, Smad2/3/4 complexes regulate gene expression with additional transcriptional cofactors. Smad-independent pathway such as MAPK is also activated downstream of activin receptors. Inhibin acts antagonistic to activin by forming high affinity complexes with ActRII and betaglycan. Follistatin, myostatin propeptide and receptor ectodomain inhibit the activities of activin and related factors in the extracellular space to prevent ligand/receptor interaction. Chemical type IR kinase inhibitors act in the cell to disrupt receptor/intracellular signaling.

Mentions: Activin type II receptor, ACVR2 or ActRIIA, has been identified and characterized as a transmembrane serine/threonine kinase for activin A [10]. A second activin type II receptor, ACVR2B or ActRIIB, has also been identified [4]. In addition, TGF-β type II receptor, BMP type II receptor and Müllerian duct inhibiting substance type II receptor specific to each ligand have been characterized [2]. To date, seven type I receptors, activin receptor-like kinases 1 to 7 (ALK1-7), have been characterized for the TGF-β family [11]. Like type II receptors, type I receptors possess a serine/threonine kinase domain. However, different from type II receptors, type I receptors have a unique GS domain near the intracellular juxtamembrane regions preceding the kinase domain. The amino acid sequences of L45 loops of type I receptors located between the kinase subdomains IV and V are responsible for the preference of Smad proteins and determine the specificity between the activin/TGF-β subgroup (ALK4, 5, 7) and BMP subgroup (ALK1, 2, 3, 6) [2,11]. ALK4 is known as activin type IB receptor, ACVR1B or ActRIB, whereas ALK7 is known as activin type IC receptor, ACVR1C. ALK4 and ALK7 are type I receptors for activins and nodal, and ALK4 and ALK5 are receptors for myostatin and GDF11 (Table S1; additional file 1) [1,2]. Once activins bind to ActRIIA or ActRIIB, type I receptors are recruited to the ligand/ActRII complex, and the GS domains of type I receptors become phosphorylated by ActRII kinases. Activin/TGF-β-specific Smad, Smad2 and Smad 3, are phosphorylated by activated type I receptors (Figure 1). In the case of nodal, the co-receptor Cripto and related factors are required for the complete activation [9]. Cripto facilitates nodal signaling by binding to both nodal and activin receptors. Interestingly, Cripto may also act as an inhibitory factor for activin signaling when overexpressed [12](Table S1; additional file 1).


Activin signaling as an emerging target for therapeutic interventions.

Tsuchida K, Nakatani M, Hitachi K, Uezumi A, Sunada Y, Ageta H, Inokuchi K - Cell Commun. Signal (2009)

Signal transduction through activin receptors. Activin, myostatin and GDF11 signal through type II and type I serine/threonine kinase receptors. Type IIR is the principal ligand binding receptors, and ligand/typeIIR complexes recruit and associate with type IR. Type IR is phosphorylated and activated by type IIR kinase. Smad2 and 3, activin/TGF-β specific Smads, are phosphorylated by activated type IR. In the nucleus, Smad2/3/4 complexes regulate gene expression with additional transcriptional cofactors. Smad-independent pathway such as MAPK is also activated downstream of activin receptors. Inhibin acts antagonistic to activin by forming high affinity complexes with ActRII and betaglycan. Follistatin, myostatin propeptide and receptor ectodomain inhibit the activities of activin and related factors in the extracellular space to prevent ligand/receptor interaction. Chemical type IR kinase inhibitors act in the cell to disrupt receptor/intracellular signaling.
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Related In: Results  -  Collection

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Figure 1: Signal transduction through activin receptors. Activin, myostatin and GDF11 signal through type II and type I serine/threonine kinase receptors. Type IIR is the principal ligand binding receptors, and ligand/typeIIR complexes recruit and associate with type IR. Type IR is phosphorylated and activated by type IIR kinase. Smad2 and 3, activin/TGF-β specific Smads, are phosphorylated by activated type IR. In the nucleus, Smad2/3/4 complexes regulate gene expression with additional transcriptional cofactors. Smad-independent pathway such as MAPK is also activated downstream of activin receptors. Inhibin acts antagonistic to activin by forming high affinity complexes with ActRII and betaglycan. Follistatin, myostatin propeptide and receptor ectodomain inhibit the activities of activin and related factors in the extracellular space to prevent ligand/receptor interaction. Chemical type IR kinase inhibitors act in the cell to disrupt receptor/intracellular signaling.
Mentions: Activin type II receptor, ACVR2 or ActRIIA, has been identified and characterized as a transmembrane serine/threonine kinase for activin A [10]. A second activin type II receptor, ACVR2B or ActRIIB, has also been identified [4]. In addition, TGF-β type II receptor, BMP type II receptor and Müllerian duct inhibiting substance type II receptor specific to each ligand have been characterized [2]. To date, seven type I receptors, activin receptor-like kinases 1 to 7 (ALK1-7), have been characterized for the TGF-β family [11]. Like type II receptors, type I receptors possess a serine/threonine kinase domain. However, different from type II receptors, type I receptors have a unique GS domain near the intracellular juxtamembrane regions preceding the kinase domain. The amino acid sequences of L45 loops of type I receptors located between the kinase subdomains IV and V are responsible for the preference of Smad proteins and determine the specificity between the activin/TGF-β subgroup (ALK4, 5, 7) and BMP subgroup (ALK1, 2, 3, 6) [2,11]. ALK4 is known as activin type IB receptor, ACVR1B or ActRIB, whereas ALK7 is known as activin type IC receptor, ACVR1C. ALK4 and ALK7 are type I receptors for activins and nodal, and ALK4 and ALK5 are receptors for myostatin and GDF11 (Table S1; additional file 1) [1,2]. Once activins bind to ActRIIA or ActRIIB, type I receptors are recruited to the ligand/ActRII complex, and the GS domains of type I receptors become phosphorylated by ActRII kinases. Activin/TGF-β-specific Smad, Smad2 and Smad 3, are phosphorylated by activated type I receptors (Figure 1). In the case of nodal, the co-receptor Cripto and related factors are required for the complete activation [9]. Cripto facilitates nodal signaling by binding to both nodal and activin receptors. Interestingly, Cripto may also act as an inhibitory factor for activin signaling when overexpressed [12](Table S1; additional file 1).

Bottom Line: Non-Smad signaling also plays an important role in activin signaling.Extracellularly, follistatin and related proteins bind to activins and related TGF-beta ligands, and control the signaling and availability of ligands.The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases.Accordingly, activin signaling may be a target for therapeutic interventions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan. tsuchida@fujita-hu.ac.jp.

ABSTRACT
After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-beta (TGF-beta) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-beta, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-beta ligands, and control the signaling and availability of ligands.The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.

No MeSH data available.


Related in: MedlinePlus