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Chapter 08 Video 2: Bone Morphogenic Protein Mechanism

December 22, 2016

Contributors: Wellington K Hsu, MD

At the cell surface, the ligand binds a complex of transmembrane receptor serine/threonine kinases (types I and II) and induces transphosphorylation of the GS segments (red) in the type I receptor by the type II receptor kinases. The consequently activated type I receptors phosphorylate selected Smads at C-terminal serines, and these receptor-activated Smads (R-Smads) then form a complex with a common Smad4. Activated Smad complexes translocate into the nucleus, where they regulate transcription of target genes, through physical interaction and functional cooperation with DNA-binding transcription factors (X) and CBP or p300 coactivators. Activation of R-Smads by type I receptor kinases is inhibited by Smad6 or Smad7. R-Smads and Smad4 shuttle between nucleus and cytoplasm. The E3 ubiquitin ligases Smurf1 and Smurf2 mediate ubiquitination and consequent degradation of R-Smads, yet can also interact with Smad6/7 and thereby ubiquitinate the type I receptors (not shown).

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