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Full Abstracts – CELL BIOLOGY AND SIGNAL TRASDUCTION I
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The classic fibrodysplasia ossificans progressiva mutation reveals the latent kinase activity of the
Drosophila
BMP type I receptor Saxophone.
Viet
Le, Kristi Wharton. MCB Dept, Brown University, Providence, RI.
Bone Morphogenetic Protein (BMP) signaling is important for processes such as cell proliferation, apoptosis, patterning and specification during
development. Dysregulation of BMP signaling is implicated in many disease states. In the developing Drosophila wing the BMP type I receptor, Saxophone
(Sax) has been shown to exhibit a dual behavior where it can inhibit as well as facilitate BMP signaling. Here, we demonstrate that Sax is unable to
phosphorylate Mad, the transducer of the pathway, in response to the BMP ligand Gbb. Two mutations downstream of the GS activation domain of Sax
uncover its latent kinase activity in a ligand-dependent fashion. Curiously, both mutations result in ligand-independent type I receptor hyperactivity in the
context of other type I receptors. One mutation, K262H, corresponds to the mutation in ALK2 (R206H), the human Sax ortholog that is responsible for the
classic form of the bone disease fibrodysplasia ossificans progressiva (FOP). The other mutation, Q263D, corresponds to the standard mutation made in all
BMP/TGF-β type I receptors to generate constitutively active receptors. These results suggest that the GS domain is an important region that masks the
kinase activity of Sax. We are investigating the possibility that the activity of the Sax kinase is only stimulated when Sax is in a complex with the other BMP
type I receptor, Tkv. We are also testing the possibility that Sax acts as a silent co-receptor in conjunction with Tkv, acting to facilitate the binding of
heterodimeric ligands (i.e. Dpp:Gbb) in particular. Lastly, we consider how differences in the effect of the classic FOP mutation on Sax and ALK2 kinase
activity impact our understanding of FOP.