Gremlin (protein)

Gremlin is an inhibitor in the TGF beta signaling pathway.

Gremlin, also known as Drm, is a highly conserved 20.7-kDa, 184 amino acid glycoprotein part of the DAN family and is a cysteine knot-secreted protein. Gremlin was first identified in differential screening as a transcriptional down-regulated gene in v-mos-transformed rat embryonic fibrolasts.

Gremlin 1 (grem 1) is known for its antagonistic reaction with bone morphogenetic proteins (BMPs) in the TGF beta signaling pathway. Grem 1 inhibits BMP-2, -4, and -7. Inhibition by grem 1 of BMPs in mice allow the expression of fibroblast growth factors (FGFs) 4 and 8 and Sonic hedgehog (SHH) which are necessary for proper limb development. Grem 1 regulation of BMP-4 in mice embryos is essential in kidney and lung branching morphogenesis.

Data from microarrays of cancer and non-cancer tissues suggest that grem1 and other BMP antagonists are important in the survival of cancer stroma survival and proliferation in some cancers. Grem 1 expression is found in many cancers and is thought to play important roles in uterine cervix, lung, ovary, kidney, breast, colon, pancreas, and sarcoma carcinomas. More specifically, the grem 1 binding site (between residues 1 to 67) interacts with the binding protein, YWHAH (whose binding site for grem1 is between residues 61-80) and is seen as a potential therapeutic and diagnostic target against human cancers. Grem 1 also plays a BMP-dependent role in angiogenesis on endothelium of human lung tissue, which implies an important role for grem 1 in the development of cancer.

Deletion of grem 1 in mice causes increased bone formation and increased trabecular bone volume where overexpression causes inhibition of bone formation and osteopenia. Deletion of one copy of grem1 does not produce an abnormal phenotype and deletion of both copies causes only a small difference in phenotype in one-month-old male mice, but this difference cannot be observed after 3 months of age. Grem1 plays an important role in bone development and a lesser known function later in adulthood. Overexpression of gremlin 1 decreases osteoblast differentiation or the inhibition of bone formation and the ability for bone remodeling. Overexpression of grem1 in stromal and osteoblastic cells in addition to the inhibition of BMP, grem 1 inhibits activation Wnt/β-catenin signaling activity. The interaction between grem 1 and the Wnt signaling pathway is not fully understood.