Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer.
Activin, myostatin and other members of the TGF-beta 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-beta, 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.
Tsuchida
Kunihiro
K
Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi, Japan.
Nakatani
Masashi
M
Uezumi
Akiyoshi
A
Murakami
Tatsuya
T
Cui
Xueling
X
D029404:Activin Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D028341:Activins / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000502:physiology; D058851:GPI-Linked Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009140:Musculoskeletal Diseases / Q000188:drug therapy*; D055435:Myostatin; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D000970:Antineoplastic Agents; D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C525911:MSTN protein, human; D008562:Membrane Glycoproteins; D055435:Myostatin; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C070636:TDGF1 protein, human; D016212:Transforming Growth Factor beta; D028341:Activins; D004815:Epidermal Growth Factor; D029404:Activin Receptors