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.
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Journal Details
This article was published in the following journal.
Name: The Biochemical journal
ISSN: 1470-8728
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22394253
- DOI: http://dx.doi.org/10.1042/BJ20120188
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