Cutting Edge: Bone Morphogenetic Protein Antagonists Drm/Gremlin and Dan Interact with Slits and Act as Negative Regulators of Monocyte Chemotaxis

Abstract

Drm/Gremlin and Dan, two homologous secreted antagonists of bone morphogenic proteins, have been shown to regulate early development, tumorigenesis, and renal pathophysiology. In this study, we report that Drm and Dan physically and functionally interact with Slit1 and Slit2 proteins. Drm binding to Slits depends on its glycosylation and is not interfered with by bone morphogenic proteins. Importantly, Drm and Dan function as inhibitors for monocyte migration induced by stromal cell-derived factor 1α (SDF-1α) or fMLP. The inhibition of SDF-1α-induced monocyte chemotaxis by Dan is not due to blocking the binding of SDF-1α to its receptor. Thus, the results identify that Drm and Dan can interact with Slit proteins and act as inhibitors of monocyte chemotaxis, demonstrating a previously unidentified biological role for these proteins.

NBL1 and anillin (ANLN) genes over-expression in pancreatic carcinoma.

“…In pituitary gonadotrope cells, NBL1 is stimulated by GnRH [27]; it inhibits monocyte chemotaxis in vitro (28). In dorsal root ganglia of rat, it may act as neurotransmitter [29].…”

Evidence for protein 4.1B acting as a metastasis suppressor

“…A dynamic actin cytoskeleton is essential for cell motility and metastasis and, therefore, the increased availability of a regulator of actin turnover such as RIL would be an advantage to a metastasising cell. Grem1, encoding gremlin, a negative regulator of monocyte chemotaxis (Chen et al, 2004), is downregulated with metastasis. This could explain the strong chemotaxis to PDGF-IGF and enhanced motility in our metastasising cells.…”

Bone Morphogenetic Protein-4 Inhibitor Gremlin Is Overexpressed in Idiopathic Pulmonary Fibrosis

“…15 In addition, BMP-independent functions for gremlin have been described. 16 The role of BMP-4 signaling in IPF has not been clarified so far. Using established cell lines isolated from patients with IPF, we find here consistent overexpression of gremlin mRNA.…”