Introduction to Fibrodysplasia ossificans progressiva (FOP)

  • In 2006, a landmark study showed that a point mutation in the ALK2 receptor is linked to FOP (Shore et al., 2006)
  • ACVR1/ALK2 is part of the family of type I BMP receptors (BMPRs)
  • BMPRs play a crucial role in bone formation during development
  • The study suggests that the identified ALK2 R206H mutation leads to receptor hyperactivation

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The GS- domain of ALK2

  • Structurally defined element within the intracellular part of ALK2
  • Located between the transmembrane segment and the kinase domain of ALK2
  • The GS domain interacts with various intracellular proteins, which form part of the signaling cascade
  • GS domain interactors include Smad proteins and FKBP12

ALK2 hyperactivation hypothesis

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Unanswered questions around the activation of the ALK2 R206H mutant

  • Does the R206H mutation change the interaction pattern of ALK2?
  • Which components of the signal cascade are affected?
  • Can these interactions be identified using a proteomics approach?
  • Do these changed interaction patterns shed any light on the disease mechanism of FOP?

Aim of the study

  • Identification of ALK2 interacting proteins using two proteomics approaches
  • Use of two different cellular model systems, Hek293 cells and U2OS cells
  • Investigation of differences in the interaction patterns of ALK2 wild type and ALK2 R206H
  • Visualization using the network software Cytoscape
  • Identification of possible novel targets for treatment of FOP