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

Jeanette C Perron; Alcina A Rodrigues; Nirupama Surubholta; Jane Dodd

doi:10.1242/bio.042283

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

Biol Open. 2019 Jul 16;8(7):bio042283. doi: 10.1242/bio.042283.

Authors

Jeanette C Perron¹, Alcina A Rodrigues², Nirupama Surubholta², Jane Dodd³

Affiliations

¹ Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA perronj@stjohns.edu.
² Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA.
³ Departments of Physiology & Cellular Biophysics and Neuroscience, Columbia University, New York, NY 10032, USA.

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 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.

Keywords: ActRIIA; BMP7; Chemotaxis; Growth cone collapse; PI3K.