Gremlin Products

Gremlin, also known as Increased in High Glucose protein 2 (IHG-2) and Down-regulated in Mos-transformed cells protein (Drm), is a 28 kDa member of the Dan family of secreted glycoproteins. Human Gremlin is synthesized as a 184 amino acid (aa) precursor that contains a 24 aa signal sequence and a 160 aa mature region. The mature region contains one potential site for N-linked glycosylation (Asn 42), a cysteine-rich region, and a cysteine knot motif (aa 94 - 184) whose structure is shared by members of the TGF-beta superfamily.

Post-translational modifications include glycosylation and phosphorylation. Gremlin exists in both secreted and membrane-associated forms. There are two isoforms for human Gremlin. Isoform 1 is the standard protein, and in isoform 2, there is a deletion of aa 39 - 79. Human Gremlin shares 99% and 86% aa sequence identity with mouse and chick Gremlin, respectively. Northern blot analysis shows that Gremlin mRNA is highly expressed in the small intestine, fetal brain and colon, and weakly expressed in adult brain, ovary, prostate, pancreas and skeletal muscle.

Gremlin functions as a bone morphogenetic protein (BMP) antagonist. It acts by binding to, and forming heterodimers with, BMP-2, BMP-4, and BMP-7, thus preventing them from interacting with their cell surface receptors. This mechanism is thought to be responsible for the pattern-inducing activity of Gremlin during embryonic development and to play a role in human diseases, such as diabetic nephropathy. However, intracellular BMP-independent mechanisms of action may mediate the ability of Gremlin to suppress transformation and tumorigenesis under certain experimental conditions. Gremlin also interacts with Slit proteins and acts as an inhibitor of monocyte chemotaxis. In addition, Gremlin has been found to be a proangiogenic factor expressed by endothelium.