LRP1-dependent endocytic mechanism governs the signaling output of the bmp system in endothelial cells and in angiogenesis

Circ Res. 2012 Aug 17;111(5):564-74. doi: 10.1161/CIRCRESAHA.112.274597. Epub 2012 Jul 9.

Abstract

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 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor 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.

Publication types

  • Research Support, N.I.H., Extramural

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*

Substances

  • Bmp4 protein, mouse
  • Bmper protein, zebrafish
  • Bone Morphogenetic Protein 4
  • Carrier Proteins
  • Lrp1 protein, mouse
  • RNA, Small Interfering
  • Receptors, LDL
  • Tumor Suppressor Proteins
  • Zebrafish Proteins
  • bmp4 protein, zebrafish
  • crossveinless 2 protein, mouse
  • low density lipoprotein receptor-related protein 1, zebrafish
  • Bmpr1b protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I