SMAD versus Non-SMAD Signaling Is Determined by Lateral Mobility of Bone Morphogenetic Protein (BMP) Receptors*

Background: BMP-2 signals via heteromeric complexes of transmembrane receptors (BMPRI and BMPRII) to induce SMAD and non-SMAD signaling. Results: BMPRI and BMPRII show distinct lateral mobility behaviors, essential for signaling specificity. Conclusion: SMAD and non-SMAD signaling is differentially affected by alterations in BMP receptor mobility. Significance: This demonstrates a regulatory mechanism for fine-tuning BMP signaling through localization and biophysical properties of BMP receptors on the plasma membrane. Bone (or body) morphogenetic proteins (BMPs) belong to the TGFβ superfamily and are crucial for embryonic patterning and organogenesis as well as for adult tissue homeostasis and repair. Activation of BMP receptors by their ligands leads to induction of several signaling cascades. Using fluorescence recovery after photobleaching, FRET, and single particle tracking microscopy, we demonstrate that BMP receptor type I and II (BMPRI and BMPRII) have distinct lateral mobility properties within the plasma membrane, which is mandatory for their involvement in different signaling pathways. Before ligand binding, BMPRI and a subpopulation of BMPRII exhibit confined motion, reflecting preassembled heteromeric receptor complexes. A second free diffusing BMPRII population only becomes restricted after ligand addition. This paper visualizes time-resolved BMP receptor complex formation and demonstrates that the lateral mobility of BMPRI has a major impact in stabilizing heteromeric BMPRI-BMPRII receptor complexes to differentially stimulate SMAD versus non-SMAD signaling.