A Bone Morphogenetic Protein (BMP)-derived Peptide Based on the Type I Receptor-binding Site Modifies Cell-type Dependent BMP Signalling

Sci Rep. 2019 Sep 17;9(1):13446. doi: 10.1038/s41598-019-49758-x.

Abstract

Bone morphogenetic proteins (BMPs) are multifunctional cytokines of the transforming growth factor β (TGFβ) superfamily with potential therapeutic applications due to their broad biological functionality. Designing BMP mimetics with specific activity will contribute to the translational potential of BMP-based therapies. Here, we report a BMP9 peptide mimetic, P3, designed from the type I receptor binding site, which showed millimolar binding affinities for the type I receptor activin receptor like kinase 1 (ALK1), ALK2 and ALK3. Although showing no baseline activity, P3 significantly enhanced BMP9-induced Smad1/5 phosphorylation as well as ID1, BMPR2, HEY1 and HEY2 gene expression in pulmonary artery endothelial cells (hPAECs), and this activity is dependent on its alpha helix propensity. However, in human dermal microvascular endothelial cells, P3 did not affect BMP9-induced Smad1/5 phosphorylation, but potently inhibited ALK3-dependent BMP4-induced Smad1/5 phosphorylation and gene expression. In C2C12 mouse myoblast cells, P3 had no effect on BMP9-induced osteogenic signalling, which is primarily mediated by ALK2. Interestingly, a previously published peptide from the knuckle region of BMP9 was found to inhibit BMP4-induced Smad1/5 phosphorylation. Together, our data identify a BMP9-derived peptide that can selectively enhance ALK1-mediated BMP9 signalling in hPAECs and modulate BMP9 and BMP4 signalling in a cell type-specific manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / chemistry
  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism*
  • Animals
  • Binding Sites
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Line
  • Endothelial Cells
  • Growth Differentiation Factor 2 / chemistry
  • Growth Differentiation Factor 2 / metabolism
  • Humans
  • Mice
  • Molecular Mimicry
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Phosphorylation
  • Signal Transduction
  • Smad1 Protein / metabolism
  • Smad8 Protein / metabolism
  • Structure-Activity Relationship

Substances

  • Bone Morphogenetic Proteins
  • GDF2 protein, human
  • Growth Differentiation Factor 2
  • Peptides
  • SMAD1 protein, human
  • SMAD9 protein, human
  • Smad1 Protein
  • Smad8 Protein
  • ACVRL1 protein, human
  • Activin Receptors, Type II