A tale of two receptors: Bmp heterodimers recruit two type I receptors but use the kinase activity of only one

Bone morphogenetic proteins (BMPs) are members of the larger transforming growth factor β (TGF-β) family of cytokines that play diverse roles in embryonic development, adult tissue homeostasis, and human disease (1). BMPs are grouped into subfamilies based on sequence similarity, and can signal as either homodimers or heterodimers. It has been known for over 25 y that BMP2 and BMP4, which comprise one subfamily, can heterodimerize with BMP5, BMP6, or BMP7, which belong to a distinct subfamily, and that these heterodimeric ligands have significantly higher per-molecule activity than their respective homodimers (2). For example, homodimers of BMP2, BMP4, BMP5, BMP6, or BMP7 can all induce bone formation, but BMP2/5, BMP2/6, BMP2/7, and BMP4/7 heterodimers can do so at 30- to 50-fold lower concentrations (3⇓–5). Likewise, BMP2/6 heterodimers show enhanced ability to activate downstream signaling in embryonic stem cells (6), and Bmp2/7 and Bmp4/7 heterodimers show heightened ability to induce ventral fate in Xenopus and zebrafish (7, 8). More-recent studies have shown that endogenous BMP2/7, BMP4/7, or BMP2/6 heterodimers are the obligate signaling ligands in a number of in vivo contexts, including during dorsoventral patterning in Drosophila (9) and zebrafish embryos (10), cell fate specification and patterning in early mouse embryos (11), and regulation of iron homeostasis in adult mice (12). Despite growing evidence that BMP heterodimers are required to signal in vivo, the reasons why these heterodimers have higher per-molecule activity than homodimers has remained a mystery. In PNAS, Tajer et al. (13) cast light on this longstanding conundrum by exploring potential roles for BMP antagonists and receptors in enhancing the potency of BMP heterodimers. Previous work from the Mullins laboratory established that Bmp2/7 heterodimers are solely responsible for all Bmp activity in early zebrafish embryos (10). This was somewhat surprising, since endogenous Bmp2 and Bmp7 … [↵][1]1Email: Jan.Christian{at}hsc.utah.edu. [1]: #xref-corresp-1-1