INVESTIGATING THE ROLE OF MAGP2 IN THE REGULATION OF THE TGFß SIGNALING PATHWAY AND HERITABLE TAAD

Aortic abnormalities exist in several human genetic disorders, including thoracic aortic aneurysms and dissections (TAAD), Loeys-Dietz syndrome, and Marfan syndrome. In many of these cases, mutations in genes related to the transforming growth factor beta (TGFβ) signaling pathway have been identified. Such mutations may result in mis-regulation of TGFβ signaling pathway activity, which is implicated as the causal factor for many diseases featuring TAAD. In some cases of heritable TAAD, mutations have been found in microfibril associated glycoprotein 2 (MAGP2). MAGP2 has been shown to interact with the TGFβ1 ligand, but the potential regulatory effect of MAGP2 on TGFβ1 is still unknown. To investigate this idea, I first showed that recombinant MAGP2 and recombinant TGFβ1 directly interacted using co-immunoprecipitation. However, recombinant MAGP2 did not have any regulatory effect on TGFβ activity in vitro. Wild-type MAGP2 and a TAAD-associated MAGP2 mutant harvested from the conditioned media of transfected cells also had no effect on TGFβ signaling in vitro. Unfortunately, conditioned media MAGP2 did not show detectable binding with TGFβ, unlike recombinant MAGP2. This was likely due to technical limitations with conditioned media. This study showed that direct binding of MAGP2 to TGFβ does not prevent TGFβ signaling activity in vitro. Additional studies will be required to elicit the mechanisms for MAGP2 associated TAAD and the connection between MAGP2 and TGFβ1.