Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells.
The bone morphogenic proteins (BMPs) play important roles in vertebrate development. In Xenopus, BMPs act as epidermal inducers and also as negative regulators of neurogenesis. Antagonism of BMP signaling results in neuralization. BMPs signal through the cell-surface receptors and downstream Smad molecules. Upon stimulation with BMP, Smad1, Smad5, and Smad8 are phosphorylated by the activated BMP receptors, form a complex with Smad4, and translocate into the nucleus, where they regulate the expression of BMP target genes. Here, we show that the Ski oncoprotein can block BMP signaling and the expression of BMP-responsive genes in both Xenopus and mammalian cells by directly interacting with and repressing the activity of BMP-specific Smad complexes. This ability to antagonize BMP signaling results in neuralization by Ski in the Xenopus embryo and blocking of osteoblast differentiation of murine W-20-17 cells. Thus, Ski is able to repress the activity of all receptor-associated Smads and may regulate vertebrate development by modulating the signaling activity of transforming growth factor-beta family members.
Wang
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W
Life Sciences Division, Lawrence Berkeley National Laboratory, and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Mariani
F V
FV
Harland
R M
RM
Luo
K
K
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004475:Ectoderm; D005260:Female; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors; D010750:Phosphoproteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta; D014407:Tumor Cells, Cultured; D029867:Xenopus Proteins; D014982:Xenopus laevis
C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C497402:MXD1 protein, Xenopus; D009414:Nerve Growth Factors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C497399:SMAD1 protein, human; C497796:SMAD4 protein, human; C512653:Ski protein, mouse; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051902:Smad5 Protein; C497800:Smad5 protein, Xenopus; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525812:bmp4 protein, Xenopus; C490808:smad4.1 protein, Xenopus; C117263:smad4.2 protein, Xenopus; C060614:SKI protein, human