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
  • Animals
  • 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
  • Endocytosis/physiology*
  • Endothelial Cells/cytology
  • Endothelial Cells/physiology*
  • HEK293 Cells
  • Humans
  • Mice
  • Neovascularization, Physiologic/physiology*
  • Phenotype
  • RNA, Small Interfering/genetics
  • Receptors, LDL/genetics
  • Receptors, LDL/metabolism*
  • Signal Transduction/physiology
  • Tumor Suppressor Proteins/genetics
  • Tumor Suppressor Proteins/metabolism*
  • Zebrafish
  • 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.

Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes