Molecular dissection of the dual functioning Drosophila ALK1/2 BMP type I receptor ortholog Saxophone

Le, Viet Quoc

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Year:: 2014
Contributor:: Le, Viet Quoc (creator); Wharton, Kristi (Director); DeLong, Alison (Reader); McKeown, Michael (Reader); Page, Rebecca (Reader); Rosen, Vicki (Reader); Brown University. BIOMED: Molecular Biology, Cell Biology, and Biochemistry (sponsor)
Genre:: theses
Subject:: Sax; BMP signaling; receptor kinase activation; type I receptor; type II receptor; ALK2; ACVR1; FOP; Drosophila
Extent:: 18, 260 p.
DOI: https://doi.org/10.7301/Z05X2785

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Abstract:: The bone morphogenetic protein (BMP) signaling pathway is an essential regulator of developmental and cellular processes. Secreted ligands initiate BMP signaling by binding to a quadripartite receptor complex consisting of two type I and two type II receptor kinases. The type I receptor kinase, which is activated by the type II receptor in the signaling complex, phosphorylates R-Smad transcription factors to elicit cellular responses via target gene regulation. The existence of multiple BMP receptors raises the possibility that different combinations of receptors can affect signaling output of receptor complexes. This concept is supported by studies in cell culture, zebrafish, and Drosophila indicating that type I receptor permutations within a complex can dramatically impact signaling activity. Although it has been suggested that type I receptors influence each other’s activity, the precise mechanism is unknown. In Drosophila, two type I receptors, Tkv and Sax, and two type II receptors, Punt and Wit, transduce signals initiated by the BMP ligands Dpp, Gbb, and Scw. The interplay between these components is essential in a variety of developmental contexts. During wing development, a dual function has been ascribed to Sax where it can facilitate or antagonize signaling. Genetic characterization of this behavior led to a model in which Sax mediates signaling in a complex with Tkv, but inhibits BMP signals when paired with another Sax receptor. From experiments described here, we have identified protein subdomains that determine type I receptor signaling activity. These regions are important in type II receptor-mediated activation of type I receptor kinases and dimerization of type I receptors. In a Drosophila model for the bone disease fibrodysplasia ossificans progressiva (FOP), we have demonstrated that the constitutive activity of the FOP mutant receptor ALK2[R206H] is type II receptor-dependent, further underscoring the importance of the type II receptor. We propose that Sax:Sax dimers inhibit signaling by adopting a configuration that is incompatible for activation by type II receptors. Our work provides a backdrop for understanding how type I receptors can influence signaling activity of a receptor complex by affecting interactions with the type II receptor.
Notes:: Thesis (Ph.D. -- Brown University (2014)

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Le, Viet Quoc, "Molecular dissection of the dual functioning Drosophila ALK1/2 BMP type I receptor ortholog Saxophone" (2014). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z05X2785

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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations

Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department.
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