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Signaling by BMP

Signaling by BMP. ELV. Important points to be illustrated. BMP homodimer binds to preformed heterotetramers of BMP Type I Receptor homodimer and BMP Type II Receptor homodimer .

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Signaling by BMP

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  1. Signaling by BMP

  2. ELV

  3. Important points to be illustrated • BMP homodimer binds to preformed heterotetramers of BMP Type I Receptor homodimer and BMP Type II Receptor homodimer. • Ligand traps (BMP antagonists) – peptides secreted into extracellular matrix (Chordin/Noggin family, Tsg family, DAN/Cerberus family) - bind BMP, blocking receptor epitopes on BMP and inhibiting binding of BMP to its receptors. • BMP type II receptor phosphorylates BMP type I receptor on serine and threonine residues in the cytoplasmic domain (four residues on each BMP type I receptor monomer). • SMAD Signaling: • Activation: • The phosphorylated heterotetrametic BMP receptor complex is internalized into early endosomes by clathrin-mediated endocytosis • The endosomal membrane protein endofin associates with BMP receptor complex and facilitates recruitment of SMAD1, SMAD 5 and SMAD8 to BMP receptor complex • SMAD1/5/8 are phosphorylated by BMP type I receptor. • Phosphorylated SMAD1/5/8 undergoes conformational change and dissociates from BMP receptor complex • In the cytosol, two phosphorylated SMAD1/5/8 molecules associate with SMAD4 to form a heterotrimer (similar to TGF beta signaling). • Heterotrimer of SMAD1/5/8 and SMAD4 translocates to the nucleus where it directly binds DNA and, through association with other transcription factors, depending on the cellular context, promotes expression of genes involved in cell differentiation etc. • In the nucleus, SKI can associate with SMAD heterotrimer and recruit transcriptional repressors to repress transcription from SMAD-regulated promoters. • Downregulation: • Ubiquitin ligase SMURF binds and ubiquitinates cytosolic SMAD1/5/8 (before they associate with BMP receptor complex) targeting them for degradation • I-SMAD (inhibitory SMADs) binds phosphorylated BMP type I receptor (transcription of I-SMADs is stimulated by SMAD1/5/8:SMAD4 trimers) • I-SMAD recruits E3 ubiquitin ligase SMURF to BMP type I receptor, leading to ubiqutination of BMP type I receptor and subsequent degradation • Nuclear ubiquitin ligases (use this name instead of “Ubiquitin conjugating enzyme”) ubiquitinate SMAD1/5/8 and SMAD4, leading to trimer dissociation and translocation of Ub-SMAD1/5/8 and SMAD4 to the cytosol, where they are degraded.

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