The DAN family: Modulators of TGF‐β signaling and beyond

Abstract

Extracellular binding proteins or antagonists are important factors that modulate ligands in the transforming growth factor (TGF-b) family. While the interplay between antagonists and ligands are essential for developmental and normal cellular processes, their imbalance can lead to the pathology of several disease states. In particular, recent studies have implicated members of the differential screening-selected gene in neuroblastoma (DAN) family in disease such as renal fibrosis, pulmonary arterial hypertension, and reactivation of metastatic cancer stem cells. DAN family members are known to inhibit the bone morphogenetic proteins (BMP) of the TGF-b family. However, unlike other TGF-b antagonist families, DAN family members have roles beyond ligand inhibition and can modulate Wnt and vascular endothelial growth factor (VEGF) signaling pathways. This review describes recent structural and functional advances that have expanded our understanding of DAN family proteins with regards to BMP inhibition and also highlights their emerging roles in the modulation of Wnt and VEGF signaling pathways.

Structure of Neuroblastoma Suppressor of Tumorigenicity 1 (NBL1)

“…The spatial and temporal interplay of BMP ligands with their secreted extracellular antagonists is critical to focus and fine-tune signaling for normal development and homeostasis, where misregulation of this balance causes or perpetuates innumerable different disease states, including osteoarthritis, several cancer phenotypes, diabetic kidney nephropathy, and pulmonary arterial hypertension (3,(5)(6)(7)(8)(9)(10)(11). Although BMP ligands are structurally similar, their extracellular antagonists are highly diverse, spanning large multidomain proteins, as seen for the Follistatin and Chordin families of antagonists, to small, single domain proteins, such as Noggin and members of the DAN family (1,3,4,12).…”

“…However, our understanding of DAN family-mediated antagonism remains underdeveloped, despite being the largest known family of BMP antagonists in vertebrates (12). Furthermore, based upon their characterized importance in numerous disease states, where different DAN proteins have been directly linked to the diseases mentioned above, there is a strong need to evaluate these proteins structurally and functionally to aid in future therapeutic design processes to restore the proper balance of BMP signaling (12).…”

“…However, it is not known how these results translate to the remainder of the DAN family. To complicate matters, the DAN family consists of 7 different members that all show unique differences in BMP affinity and specificity, in addition to identified non-canonical roles (such as in Wnt and VEGF signaling) (12). For example, several antagonists have been implicated with very high affinity toward specific, canonical BMP ligands (BMP2, BMP4, and BMP7), including PRDC, Gremlin, and Coco (3,12).…”

“…To complicate matters, the DAN family consists of 7 different members that all show unique differences in BMP affinity and specificity, in addition to identified non-canonical roles (such as in Wnt and VEGF signaling) (12). For example, several antagonists have been implicated with very high affinity toward specific, canonical BMP ligands (BMP2, BMP4, and BMP7), including PRDC, Gremlin, and Coco (3,12). On the other hand, SOST and USAG-1 have been somewhat enigmatic in the literature in terms of BMP inhibition (3,12).…”

“…For example, several antagonists have been implicated with very high affinity toward specific, canonical BMP ligands (BMP2, BMP4, and BMP7), including PRDC, Gremlin, and Coco (3,12). On the other hand, SOST and USAG-1 have been somewhat enigmatic in the literature in terms of BMP inhibition (3,12). For these two members, although not conclusive, it is likely that they function as moderate to weak inhibitors of BMP signaling, where they maintain the unique ability to directly antagonize Wnt signaling (21)(22)(23)(24).…”