Identification of direct negative cross-talk between the SLIT2 and bone morphogenetic protein-Gremlin signaling pathways

The Journal of Biological Chemistry
Kathleen E TumeltyStephen P Berasi

Abstract

Slit guidance ligand 2 (SLIT2) is a large, secreted protein that binds roundabout (ROBO) receptors on multiple cell types, including neurons and kidney podocytes. SLIT2-ROBO-mediated signaling regulates neuronal migration and ureteric bud (UB) outgrowth during kidney development as well as glomerular filtration in adult kidneys. Additionally, SLIT2 binds Gremlin, an antagonist of bone morphogenetic proteins (BMPs), and BMP-Gremlin signaling also regulates UB formation. However, direct cross-talk between the ROBO2-SLIT2 and BMP-Gremlin signaling pathways has not been established. Here, we report the discovery of negative feedback between the SLIT2 and BMP-Gremlin signaling pathways. We found that the SLIT2-Gremlin interaction inhibited both SLIT2-ROBO2 signaling in neurons and Gremlin antagonism of BMP activity in myoblasts and fibroblasts. Furthermore, BMP2 down-regulated SLIT2 expression and promoter activity through canonical BMP signaling. Gremlin treatment, BMP receptor inhibition, and SMAD family member 4 (SMAD4) knockdown rescued BMP-mediated repression of SLIT2. BMP2 treatment of nephron progenitor cells derived from human embryonic stem cells decreased SLIT2 expression, further suggesting an interaction between the BMP2...Continue Reading

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Citations

Mar 7, 2020·Bone Research·Na LiMatthew B Greenblatt
Oct 13, 2019·The Journal of Biological Chemistry·Louise R DuttonDerek P Brazil
Feb 16, 2021·EMBO Molecular Medicine·Natalija PopovicBruno Larrivée
Feb 19, 2021·Bone Research·Na LiMatthew B Greenblatt

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