# Identification of a novel GREMLIN1 uptake pathway in epithelial cells that requires BMP binding

## TL;DR

This study reveals a new pathway by which GREM1 is taken up by epithelial cells, requiring binding to BMP, which helps explain how GREM1 inhibits BMP signaling.

## Contribution

The discovery that GREM1 uptake requires BMP binding introduces a novel mechanism for GREM1-mediated BMP antagonism.

## Key findings

- GREM1 is endocytosed by epithelial cells via clathrin- and caveolin-mediated pathways.
- Heparin sulfate proteoglycans are necessary for GREM1 binding and uptake.
- BMP binding is essential for GREM1 internalization, as a BMP-resistant mutant failed to be taken up.

## Abstract

GREM1 binding to BMP targets in the extracellular matrix prevents their engagement with cognate BMP receptors, attenuating BMP-dependent signaling and gene expression. Some evidence suggests that GREM1 can directly bind to receptor tyrosine kinases on the plasma membrane, further complicating our understanding of GREM1 biology. To attempt to clarify the complexities of GREM1 signaling, we show that GREM1 protein is produced and secreted by intestinal fibroblasts and endocytosed by neighboring epithelial cells. GREM1 uptake occurs by both clathrin- and caveolin-mediated endocytosis. Cell membrane heparin sulfate proteoglycans are required for GREM1 binding and uptake, and once internalized, GREM1 appears to localize to the early endosomes and can be resecreted. The addition of BMP2 enhanced GREM1 uptake into cells. Remarkably, the generation of a BMP-resistant GREM1 mutant abolished GREM1 uptake both in the presence and in the absence of BMP2. These data suggest that GREM1 binding and uptake into cells requires BMP binding, a process that may contribute to the antagonism of BMP signaling by GREM1.