title: The transforming growth factor-beta type III receptor mediates distinct subcellular trafficking and downstream signaling of activin-like kinase (ALK)3 and ALK6 receptors.
abstract: Bone morphogenetic proteins (BMPs) signal through the BMP type I and type II receptors to regulate cellular processes, including embryonic development. The type I BMP receptors activin-like kinase (ALK)3 and ALK6 share a high degree of homology, yet possess distinct signaling roles. Here, we report that although the transforming growth factor (TGF)-beta type III receptor (TbetaRIII) enhanced both ALK3 and ALK6 signaling, TbetaRIII more potently enhanced ALK6-mediated stimulation of the BMP-responsive promoters XVent2 and 3GC2, and up-regulation of the early response gene Smad6. In contrast, TbetaRIII specifically enhanced ALK3-mediated up-regulation of the early response gene ID-1. TbetaRIII associated with ALK3 primarily through their extracellular domains, whereas its interaction with ALK6 required both the extracellular and cytoplasmic domains. TbetaRIII, along with its interacting scaffolding protein beta-arrestin2, induced the internalization of ALK6. In contrast, TbetaRIII colocalized with and resulted in the cell surface retention of ALK3, independently of beta-arrestin2. Although complex formation between TbetaRIII, ALK6, and beta-arrestin2 and TbetaRIII/ALK6 internalization resulted in maximal BMP signaling, the TbetaRIII mutant unable to interact with beta-arrestin2, TbetaRIII-T841A, was unable to do so. These studies support a novel role for TbetaRIII in mediating differential ALK3 and ALK6 subcellular trafficking resulting in distinct signaling downstream of ALK3 and ALK6.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: Nam Y
authors.initials: NY
authors.lastname: Lee
authors.forename: Kellye C
authors.initials: KC
authors.lastname: Kirkbride
authors.forename: Richard D
authors.initials: RD
authors.lastname: Sheu
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
mesh_terms: D000818:Animals; D019390:Arrestins / Q000502:physiology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D019556:COS Cells; D002460:Cell Line / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007668:Kidney; D051379:Mice; D046912:Multiprotein Complexes / Q000502:physiology; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology*; D011509:Proteoglycans / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D018243:Teratocarcinoma / Q000473:pathology; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D019485:Bone Morphogenetic Proteins; D046912:Multiprotein Complexes; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D000071557:beta-Arrestins; C071736:betaglycan; C498212:Bmpr1a protein, mouse; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I