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

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

Author information

1
Health Care Entrepreneurship, UNC Center for Heart and Vascular Care, Division of Cardiology, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126, USA. pxinchun@med.unc.edu

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.

PMID:
22777006
PMCID:
PMC3495066
DOI:
10.1161/CIRCRESAHA.112.274597
[Indexed for MEDLINE]
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