An activity-based probe reveals dynamic protein-protein interactions mediating IGF-1R transactivation by GABAB receptor.
Summary of "An activity-based probe reveals dynamic protein-protein interactions mediating IGF-1R transactivation by GABAB receptor."
Many G-Protein-coupled receptors (GPCRs) can activate receptor tyrosine kinases (RTKs) in the absence of RTK ligands, a phenomenon called transactivation. However, the underlying molecular mechanisms remain undefined. Here we investigate the molecular basis of GABAB receptor-mediated transactivation of IGF-1R in primary neurons. We take a chemical biology approach by developing an activity-based probe targeting the GABAB receptor. This probe enables us first to lock GABAB receptor in an inactive state and then activate it with a positive allosteric modulator, thereby permitting monitoring of the dynamic of the protein complex associated with IGF-1R transactivation. We find that activation of GABAB receptor induces a dynamic assembly and disassembly of a protein complex, including both receptors and their downstream effectors. FAK, a non-receptor tyrosine kinase, plays a key role in coordinating this dynamic process. Importantly, this dynamic of the GABAB receptor associated complex is critical for transactivation and transactivation-dependent neuronal survival. Our work has identified an important mechanism underlying GPCR transactivation of RTKs, which was enabled by a new chemical biology tool generally applicable for dissecting GPCR signaling.
This article was published in the following journal.
Name: The Biochemical journal
Medical and Biotech [MESH] Definitions
Two-hybrid System Techniques
Screening techniques first developed in yeast to identify genes encoding interacting proteins. Variations are used to evaluate interplay between proteins and other molecules. Two-hybrid techniques refer to analysis for protein-protein interactions, one-hybrid for DNA-protein interactions, three-hybrid interactions for RNA-protein interactions or ligand-based interactions. Reverse n-hybrid techniques refer to analysis for mutations or other small molecules that dissociate known interactions.
Myelin P0 Protein
A protein that accounts for more than half of the peripheral nervous system myelin protein. The extracellular domain of this protein is believed to engage in adhesive interactions and thus hold the myelin membrane compact. It can behave as a homophilic adhesion molecule through interactions with its extracellular domains. (From J Cell Biol 1994;126(4):1089-97)
Bcl-associated Death Protein
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Protein Array Analysis
Ligand-binding assays that measure protein-protein, protein-small molecule, or protein-nucleic acid interactions using a very large set of capturing molecules, i.e., those attached separately on a solid support, to measure the presence or interaction of target molecules in the sample.
Receptor Activity-modifying Protein 1
A receptor activity-modifying protein that is a subunit of specific G-PROTEIN COUPLED RECEPTORS. The CALCITONIN GENE-RELATED PEPTIDE RECEPTOR is formed from a dimer of this protein and CALCITONIN RECEPTOR-LIKE PROTEIN, while an isoform of the ISLET AMYLOID POLYPEPTIDE RECEPTOR is formed from this protein dimerizing with the CALCITONIN RECEPTOR.
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