TAK1 mediates BMP signaling in cartilage.
Although many signals are capable of activating MAPK signaling cascades in chondrocytes in vitro, the function of these pathways remains unclear in vivo. Here we report the phenotype of mice with a conditional deletion of TGF-beta-activated kinase 1 (TAK1), a MAP3K family member, in cartilage using the collagen 2alpha promoter. These mice display chondrodysplasia characterized by neonatal-onset runting, delayed formation of secondary ossification centers, and defects in formation of the elbow and tarsal joints. This constellation of defects resembles the phenotype of mice deficient for receptors or ligands involved in signaling by BMP family members. Chondrocytes from these mice show evidence of defective BMP signaling in vivo and in vitro. Surprisingly, deletion of TAK1 seems to affect not only activation of the p38 MAPK signaling cascade, but also activation of the BMP-responsive Smad1/5/8. Biochemical analysis suggests that TAK1 can interact with Smad proteins and promote their activation through phosphorylation, revealing a previously unrecognized crosstalk between the MAPK and Smad arms of BMP signaling.
Greenblatt
Matthew B
MB
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
Shim
Jae-Hyuck
JH
Glimcher
Laurie H
LH
D000818:Animals; D001846:Bone Development / Q000235:genetics; D001848:Bone Diseases, Developmental / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002356:Cartilage / Q000378:metabolism* / Q000502:physiology; D005552:Forelimb / Q000196:embryology / Q000378:metabolism; D007596:Joints / Q000196:embryology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D013640:Tarsal Joints / Q000196:embryology / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D019485:Bone Morphogenetic Proteins; D020930:MAP Kinase Kinase Kinases; D051785:Smad Proteins; D000099151:MAP Kinase Kinase Kinase 7
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