Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

Abstract

Abstract. Activin, myostatin and other members of the TGF-β superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-β, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and four type I receptors, ALK1, 2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. The signal transduction pathway through activin type II receptors, ActRIIA and ActRIIB, with type I receptors is involved in various human diseases. In this review, we discuss the role of signaling through activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers.

The bright and the dark sides of activin in wound healing and cancer

“…The major type I activin receptor is ActRIB, also known as Alk4, but ActRIC (Alk7) can also mediate activin signalling. ActRIA (Alk2) had been shown to bind activin, but it is predominantly a receptor for bonemorphogenetic proteins (reviewed by Tsuchida et al, 2008). Once phosphorylated by the type II receptor, and thereby activated, the type I receptor kinase phosphorylates the receptor-Smad proteins (R-Smads), SMAD2 and SMAD3.…”

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

“…1,2 Recently, a growing number of transcription factors, membrane and cytoskeletal proteins, and cytokines have been found to participate in the molecular mechanisms leading to muscle atrophy, including caveolin 3 and myostatin. [3][4][5][6][7][8] Caveolin 3, a muscle-specific integral membrane protein, forms flask-shaped invaginations of the plasma membrane known as caveolae, and regulates signal transduction pathways by binding specific lipid-modified signal molecules, including Ha-Ras, G protein-coupled receptors, Srk-family kinases, and nitric oxide synthases.…”

“…Each member of the TGF-b family binds to a membrane serine/ threonine kinase receptor, termed as a type II receptor, which then recruits a type I kinase receptor. 1,14 Seven different type I receptors, the activin receptor-like kinases 1-7 (ALK1-7), thus determine the intracellular signal specificity of the 33 members of the TGF-b family. 1,14 Small-molecule inhibitors of TGF-b type I receptor (TbRI) kinase were originally developed to compete with the binding of adenosine triphosphate to the kinase domain of ALK5, the type I receptor for TGF-b1-3.…”

“…1,14 Seven different type I receptors, the activin receptor-like kinases 1-7 (ALK1-7), thus determine the intracellular signal specificity of the 33 members of the TGF-b family. 1,14 Small-molecule inhibitors of TGF-b type I receptor (TbRI) kinase were originally developed to compete with the binding of adenosine triphosphate to the kinase domain of ALK5, the type I receptor for TGF-b1-3. 12 TbRI kinase inhibitors have been found to suppress tumor enlargement and metastasis in the advanced stages of cancer in animals.…”

“…[15][16][17][18] Notably, these inhibitors also suppress a similar kinase domain of ALK4, the type I receptor for activin, and potentially block ALK4/5, the type I receptor for myostatin. 1,12,19,20 However, the impact and clinical significance of TbRI kinase inhibitors on the skeletal muscle signaling of activin, myostatin, and TGF-b1-3 is unknown.…”