Promiscuity and specificity in BMP receptor activation

Abstract

a b s t r a c tBone Morphogenetic Proteins (BMPs), together with Transforming Growth Factor (TGF)-b and Activins/Inhibins constitute the TGF-b superfamily of ligands. This superfamily is formed by more than 30 structurally related secreted proteins. Since TGF-b members act as morphogens, either a strict relation between a particular ligand to a distinct cellular receptor and/or temporospatial expression patterns of ligands and receptors is expected. Instead, only a limited number of receptors exist implicating promiscuous interactions of ligands and receptors. Furthermore, in complex tissues a multitude of different ligands can be found, which signal via overlapping subsets of receptors. This raises the intriguing question how concerted interactions of different ligands and receptors generate highly specific cellular signals, which are required during development and tissue homeostasis.

Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

“…Here we show that FOP-ACVR1 transduced BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling (10,(32)(33)(34) and contributes to inflammatory responses (35,36). Our in vitro and in vivo data indicate that activation of TGF-β and aberrant BMP signaling by Activin-A in FOP-cells is one cause of HO in FOP.…”

“…Because Activin-A normally transduces TGF-β-SMAD2/3 signaling (10,(32)(33)(34), the phosphorylation of SMAD2/3 and activation of a TGF-β-responsive luciferase reporter construct (CAGALuc) were analyzed. The levels of phosphorylation and activation in FOP-iMSCs were similar to those in resFOP-iMSCs (SI Appendix, Fig.…”

“…FOP is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification (1)(2)(3)(4)(5)(6). The responsive mutation for classic FOP is 617G > A (R206H) in the intracellular glycineand serine-rich (GS) domain (7) of ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP) (8)(9)(10). ACVR1 mutations in atypical FOP patients have been found also in other amino acids of the GS domain or protein kinase domain (11,12).…”

In Vivo Host Response and Degradation of Copolymer Scaffolds Functionalized with Nanodiamonds and Bone Morphogenetic Protein 2

“…[ 44 ] The bioactivity of physisorped BMP-2 was also demonstrated by upregulation of BMPR1A and RUNX2 by week 1, indicating activation of the BMP signaling pathway and a subsequent increase of osteogenicity. [ 45 ] This led to increased mRNA expression for ALP and BMP-2 in the nDP+BMP-2 scaffolds. The signifi cantly elevated levels of COL1a2 and COL2a1 at week 1 in nDP+BMP-2 scaffold group demonstrate the presence of early osteogenic potential before mineralization.…”

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

“…They mediate their function by binding to two molecules of type 1 (BMPR1 a , BMPR1 b , or ACVR1) and two molecules of type 2 (BMPR2, ACVRL1, ActRII, or ActRII B ) serine/threonine kinase receptors (2). Depending on the presence or absence of preformed BMPR complexes, the signaling is mediated via the SMAD family of transcription factors following a defined canonical pathway or by less defined noncanonical intracellular effectors (3,4). Translocation to the nucleus of these transcription factors initiates transcription of BMP target genes (5,6).…”