title: TGF-β-activated kinase 1 (Tak1) mediates agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells.
abstract: BACKGROUND
  The role of Smad-independent TGF-β signaling in craniofacial development is poorly elucidated.
  
  
  RESULTS
  In craniofacial mesenchymal cells, Tak1 regulates both R-Smad C-terminal and linker region phosphorylation in TGF-β signaling.
  
  
  CONCLUSIONS
  Tak1 plays an irreplaceable role in craniofacial ecto-mesenchyme during embryogenesis.
  
  
  CONCLUSIONS
  Understanding the mechanisms of TGF-β signaling contributes to knowledge of pathogenetic mechanisms underlying common craniofacial birth defects. Although the importance of TGF-β superfamily signaling in craniofacial growth and patterning is well established, the precise details of its signaling mechanisms are still poorly understood. This is in part because of the concentration of studies on the role of the Smad-dependent (so-called "canonical") signaling pathways relative to the Smad-independent ones in many biological processes. Here, we have addressed the role of TGF-β-activated kinase 1 (Tak1, Map3k7), one of the key mediators of Smad-independent (noncanonical) TGF-β superfamily signaling in craniofacial development, by deleting Tak1 specifically in the neural crest lineage. Tak1-deficient mutants display a round skull, hypoplastic maxilla and mandible, and cleft palate resulting from a failure of palatal shelves to appropriately elevate and fuse. Our studies show that in neural crest-derived craniofacial ecto-mesenchymal cells, Tak1 is not only required for TGF-β- and bone morphogenetic protein-induced p38 Mapk activation but also plays a role in agonist-induced C-terminal and linker region phosphorylation of the receptor-mediated R-Smads. Specifically, we demonstrate that the agonist-induced linker region phosphorylation of Smad2 at Thr-220, which has been shown to be critical for full transcriptional activity of Smad2, is dependent on Tak1 activity and that in palatal mesenchymal cells TGFβRI and Tak1 kinases mediate both overlapping and distinct TGF-β2-induced transcriptional responses. To summarize, our results suggest that in neural crest-derived ecto-mesenchymal cells, Tak1 provides a critical point of intersection in a complex dialogue between the canonical and noncanonical arms of TGF-β superfamily signaling required for normal craniofacial development.
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Ann Arbor, MI 48109, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yumoto
authors.forename: Penny S
authors.initials: PS
authors.lastname: Thomas
authors.forename: Jamie
authors.initials: J
authors.lastname: Lane
authors.forename: Kouichi
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Maiko
authors.initials: M
authors.lastname: Inagaki
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Scott
authors.forename: Manas K
authors.initials: MK
authors.lastname: Ray
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ishii
authors.forename: Robert
authors.initials: R
authors.lastname: Maxson
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002478:Cells, Cultured; D002972:Cleft Palate / Q000201:enzymology / Q000235:genetics; D004475:Ectoderm / Q000166:cytology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006257:Head / Q000196:embryology; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D008334:Mandible / Q000002:abnormalities; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D055411:TGF-beta Superfamily Proteins / Q000502:physiology; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D051896:Smad Proteins, Receptor-Regulated; D055411:TGF-beta Superfamily Proteins; D051155:Wnt1 Protein; D000099151:MAP Kinase Kinase Kinase 7; C495246:Wnt1 protein, mouse
keywords: Bone Morphogenetic Protein (BMP); Craniofacial Birth Defects; Craniofacial Development; Embryo; Linker Region Phosphorylation; SMAD Transcription Factor; Transforming Growth Factor beta (TGFbeta)
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