| First Author | Pi X | Year | 2012 |
| Journal | Circ Res | Volume | 111 |
| Issue | 5 | Pages | 564-74 |
| PubMed ID | 22777006 | Mgi Jnum | J:212647 |
| Mgi Id | MGI:5581916 | Doi | 10.1161/CIRCRESAHA.112.274597 |
| Citation | Pi X, et al. (2012) LRP1-dependent endocytic mechanism governs the signaling output of the bmp system in endothelial cells and in angiogenesis. Circ Res 111(5):564-74 |
| abstractText | 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. |
