Chemotropic signaling by BMP7 requires selective interaction at a key residue in ActRIIA

Abstract

BMP7 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 BMPdependent 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 amodel for selective engagement of chemotropic BMPs with type II BMP receptors, through specific residues, that results in strict regulation of PI3K-dependent signal transduction.