An LRP1-Dependent Endocytic Mechanism Governs the Signaling Output of the BMP System in Endothelial Cells and in Angiogenesis
- Pi, X., Schmitt, C.E., Xie, L., Portbury, A.L., Wu, Y., Lockyer, P., Dyer, L.A., Moser, M., Bu, G., Flynn, E.J., Jin, S.W., and Patterson, C.
- Circulation research 111(5): 564-574 (Journal)
- Registered Authors
- Flynn, Edward J., Jin, Suk-Won, Schmitt, Chris
- angiogenesis, endothelial cells, bone morphogenetic protein, low density lipoprotein receptor-related protein 1, endocytosis
- MeSH Terms
- Bone Morphogenetic Protein 4/genetics
- Bone Morphogenetic Protein 4/metabolism*
- Bone Morphogenetic Protein Receptors, Type I/genetics
- Bone Morphogenetic Protein Receptors, Type I/metabolism
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- Cell Line
- Cell Movement/physiology
- Endothelial Cells/cytology
- Endothelial Cells/physiology*
- HEK293 Cells
- Neovascularization, Physiologic/physiology*
- RNA, Small Interfering/genetics
- Receptors, LDL/genetics
- Receptors, LDL/metabolism*
- Signal Transduction/physiology
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 22777006 Full text @ Circ. Res.
Rationale: Among the extracellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp endothelial cell precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and-sink mechanism.
Objective: To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper’s differential effects on Bmp4 signaling.
Methods and Results: Using an array of biochemical and cell biology techniques, we report that LRP1 (Low density lipoprotein receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a co-receptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures.
Conclusions: Together, these data reveal a novel role for LRP1 in the regulation of Bmp4 signaling by regulating receptor complex endocytosis. In addition, these data introduce LRP1 as a critical regulator of vascular development. These observations demonstrate Bmper's ability to fine-tune Bmp4 signaling at the single-cell level, unlike the spatial regulatory mechanisms applied by other Bmp modulators.