Stephenson JR, Paavola KJ, Schaefer SA, Kaur B, Van Meir EG, Hall RA

Brain-specific angiogenesis inhibitor-1 (BAI1) is an adhesion G protein-coupled receptor (GPCR) that has been studied primarily for its anti-angiogenic and anti-tumorigenic properties. We found that over-expression of BAI1 results in activation of the Rho pathway via a Galpha12/13-dependent mechanism, with truncation of the BAI1 N-terminus (NT) resulting in a dramatic ...

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enhancement in receptor signaling. This constitutive activity of the truncated BAI1 mutant also resulted in enhanced downstream phosphorylation of ERK as well as increased receptor association with beta-arrestin2 and increased ubiquitination of the receptor. To gain insights into the regulation of BAI1 signaling, we screened the C-terminus (CT) of BAI1 against a proteomic array of PDZ domains to identify novel interacting partners. These screens revealed that the BAI1-CT interacts with a variety of PDZ domains from synaptic proteins, including MAGI-3. Removal of the BAI1 PDZ-binding motif resulted in attenuation of the receptor's signaling to Rho, but had no effect on ERK activation. Conversely, co-expression with MAGI-3 was found to potentiate signaling to ERK by constitutively-active BAI1 in a manner that was dependent on the receptor's PDZ-binding motif. Biochemical fractionation studies revealed that BAI1 is highly enriched in post-synaptic density (PSD) fractions, a finding consistent with our observations that BAI1 can interact with PDZ proteins known to be concentrated in the PSD. These findings demonstrate that BAI1 is a synaptic receptor that can activate both the Rho and ERK pathways, with the receptor's NT and CT regions playing key roles in the regulation of BAI1 signaling activity.

Date: Jun. 19, 2013

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