Brain-specific Angiogenesis Inhibitor-1 Signaling,Regulation, and Enrichment in the Postsynaptic Density |
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Authors: | Jason R Stephenson Kevin J Paavola Stacy A Schaefer Balveen Kaur Erwin G Van Meir Randy A Hall |
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Institution: | From the ‡Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322.;the §Laboratory of Molecular Neuro-oncology and ;¶Departments of Neurosurgery and Hematology & Medical Oncology, School of Medicine, and ;‖Winship Cancer Institute, Emory University, Atlanta, Georgia 30322 |
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Abstract: | Brain-specific angiogenesis inhibitor-1 (BAI1) is an adhesion G protein-coupled receptor that has been studied primarily for its anti-angiogenic and anti-tumorigenic properties. We found that overexpression of BAI1 results in activation of the Rho pathway via a Gα12/13-dependent mechanism, with truncation of the BAI1 N terminus resulting in a dramatic 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 β-arrestin2 and increased ubiquitination of the receptor. To gain insights into the regulation of BAI1 signaling, we screened the C terminus of BAI1 against a proteomic array of PDZ domains to identify novel interacting partners. These screens revealed that the BAI1 C terminus interacts with a variety of PDZ domains from synaptic proteins, including MAGI-3. Removal of the BAI1 PDZ-binding motif resulted in attenuation of receptor 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 PDZ-binding motif of the receptor. Biochemical fractionation studies revealed that BAI1 is highly enriched in post-synaptic density fractions, a finding consistent with our observations that BAI1 can interact with PDZ proteins known to be concentrated in the post-synaptic density. These findings demonstrate that BAI1 is a synaptic receptor that can activate both the Rho and ERK pathways, with the N-terminal and C-terminal regions of the receptor playing key roles in the regulation of BAI1 signaling activity. |
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Keywords: | 7-Helix Receptor Adhesion Arrestin Brain G Protein-coupled Receptors (GPCR) G Proteins Rho GTPases Scaffold Proteins Signaling Synapses |
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