Abstract
ABSTRACTBMP7 evokes acute chemotropic PI3K-dependent responses, such as growth cone collapse and monocyte chemotaxis, as well as classical Smad-dependent gene transcription. That these divergent responses can be activated in the same cell raises the question of how the BMP-dependent signaling apparatus is manipulated to produce chemotropic and transcriptional signals. RNA interference and site-directed mutagenesis were used to explore functional and structural BMP receptor requirements for BMP7-evoked chemotropic activity. We show that specific type II BMP receptor subunits, ActRIIA and BMPR2, are required for BMP7-induced growth cone collapse in developing spinal neurons and for chemotaxis of monocytes. Reintroduction of wild-type ActRIIA into monocytic cells lacking endogenous ActRIIA restores BMP7-evoked chemotaxis, whereas expression of an ActRIIA K76A receptor variant fails to rescue. BMP7-evoked Smad-dependent signaling is unaffected by either ActRIIA knockdown or expression of the ActRIIA K76A variant. In contrast, BMP7-evoked PI3K-dependent signaling is significantly disturbed in the presence of ActRIIA K76A. These results support a model for selective engagement of chemotropic BMPs with type II BMP receptors, through specific residues, that results in strict regulation of PI3K-dependent signal transduction.This article has an associated First Person interview with the first author of the paper.
Highlights
Bone Morphogenetic Proteins (BMPs) are a large protein family, belonging to the TGFβ superfamily of secreted factors (Miyazono et al, 2010; Heldin and Moustakas, 2016)
We show that specific type II BMP receptor subunits, ActRIIA and BMPR2, are required for BMP7-induced growth cone collapse in developing spinal neurons and for chemotaxis of monocytes
BMP7-evoked PI3K-dependent signaling is significantly disturbed in the presence of ActRIIA K76A. These results support a model for selective engagement of chemotropic BMPs with type II BMP receptors, through specific residues, that results in strict regulation of PI3K-dependent signal transduction
Summary
Bone Morphogenetic Proteins (BMPs) are a large protein family, belonging to the TGFβ superfamily of secreted factors (Miyazono et al, 2010; Heldin and Moustakas, 2016). Dysregulation of BMP signaling is associated with various pathologies involving neurological, cardiovascular and pulmonary systems (Wang et al, 2014; Brazil et al, 2015; Gallo MacFarlane et al, 2016). In light of this diversity, much progress has been made elucidating BMP ligand/receptor interactions and revealing components of signaling cascades downstream of these interactions (Derynck and Zhang, 2003; Miyazono et al, 2010; Heldin and Moustakas, 2016)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have