title: Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density.
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 Gα(12/13)-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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Stephenson
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Paavola
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Schaefer
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: Randy A
authors.initials: RA
authors.lastname: Hall
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D054731:PDZ Domains; D057907:Post-Synaptic Density / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction
chemical_list: C468226:ADGRB1 protein, human; D042501:Angiogenic Proteins; D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins
keywords: 7-Helix Receptor; Adhesion; Arrestin; Brain; G Protein-coupled Receptors (GPCR); G Proteins; Rho GTPases; Scaffold Proteins; Signaling; Synapses