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.