Abstract
BMP signaling plays key roles in development, stem cells, adult tissue homeostasis, and disease. How BMP receptors are extracellularly modulated and in which physiological context, is therefore of prime importance. R-spondins (RSPOs) are a small family of secreted proteins that co-activate WNT signaling and function as potent stem cell effectors and oncogenes. Evidence is mounting that RSPOs act WNT-independently but how and in which physiological processes remains enigmatic. Here we show that RSPO2 and RSPO3 also act as BMP antagonists. RSPO2 is a high affinity ligand for the type I BMP receptor BMPR1A/ALK3, and it engages ZNRF3 to trigger internalization and degradation of BMPR1A. In early Xenopus embryos, Rspo2 is a negative feedback inhibitor in the BMP4 synexpression group and regulates dorsoventral axis formation. We conclude that R-spondins are bifunctional ligands, which activate WNT- and inhibit BMP signaling via ZNRF3, with implications for development and cancer.
Highlights
Bone Morphogenetic Proteins (BMPs) signaling plays key roles in development, stem cells, adult tissue homeostasis, and disease
We tested if RSPO2 could suppress BMP signaling in human cells
Inhibition of BMP signaling by RSPO2 and RSPO3 was independent of WNT/β-catenin signaling, since it remained unaffected by siRNA knockdown of βcatenin (Fig. 1b, Supplementary Fig. 1c, d)
Summary
BMP signaling plays key roles in development, stem cells, adult tissue homeostasis, and disease. 1234567890():,; Bone Morphogenetic Proteins (BMPs) are a subfamily of TGFβ growth factors that exert a plethora of crucial functions in embryonic development, adult tissue homeostasis, as well as regeneration, and they underlie human pathology such as skeletal disorders, cancer, and fibrosis in multiple organs[1,2,3,4,5]. Due to their accessibility, extracellular components of the BMP pathway are of particular interest as therapeutic targets[6] and mechanistic understanding of receptor modulation should improve the ability to manipulate BMP-dependent processes. These inconsistencies in our current understanding raise the questions: do RSPOs possess WNT-independent functions? Do they engage other receptors? If so, in which physiological processes is this relevant?
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