Forming a Complex: Turbocharging BMP Signal Activation by Heterodimeric Ligands and Heteromeric Receptor Complexes

Bone morphogenetic protein (BMP) signaling functions in a vast range of biological contexts. The basic signaling mechanism of this pathway is well-defined, with BMP ligand dimers recruiting tetrameric receptor complexes that phosphorylate Smads to regulate gene expression. Research has found that the mechanism of BMP signal activation may not be as simple as this linear relay, specifically in considering signal activation by ligand homodi-mers versus heterodimers. Focusing largely on in vivo vertebrate contexts, we discuss how BMP heterodimers exhibit enhanced or exclusive signaling over homodimers, demonstrating that not all signal inputs are functionally equivalent. Challenging the notion that ligand-receptor binding affinity is the primary driver of signal activation, we highlight evidence that some receptors do not signal even when high-affinity ligands are present. Further, not all receptors in the signaling complex are equal, with the kinase activity of some being dispensable while others are obligatory. These observations shift the focus of BMP signal activation to mechanisms by which heterodimeric ligands with specific receptor combinations facilitate signal outcomes in different contexts.