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An activity-based probe reveals dynamic protein–protein interactions mediating IGF-1R transactivation by the GABA B receptor

An activity-based probe reveals dynamic protein–protein interactions mediating IGF-1R... Many GPCRs (G-protein-coupled receptors) can activate RTKs (receptor tyrosine kinases) in the absence of RTK ligands, a phenomenon called transactivation. However, the underlying molecular mechanisms remain undefined. In the present study we investigate the molecular basis of GABA B (γ-aminobutyric acid B) receptor-mediated transactivation of IGF-1R (insulin-like growth factor type I receptor) in primary neurons. We take a chemical biology approach by developing an activity-based probe targeting the GABA B receptor. This probe enables us first to lock the GABA B 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 the GABA B receptor induces a dynamic assembly and disassembly of a protein complex, including both receptors and their downstream effectors. FAK (focal adhesion kinase), a non-RTK, plays a key role in co-ordinating this dynamic process. Importantly, this dynamic of the GABA B receptor-associated complex is critical for transactivation and transactivation-dependent neuronal survival. The present study has identified an important mechanism underlying GPCR transactivation of RTKs, which was enabled by a new chemical biology tool generally applicable for dissecting GPCR signalling. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biochemical Journal Portland Press

An activity-based probe reveals dynamic protein–protein interactions mediating IGF-1R transactivation by the GABA B receptor

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Publisher
Portland Press
Copyright
Copyright by Portland Press
ISSN
0264-6021
DOI
10.1042/BJ20120188
pmid
22394253
Publisher site
See Article on Publisher Site

Abstract

Many GPCRs (G-protein-coupled receptors) can activate RTKs (receptor tyrosine kinases) in the absence of RTK ligands, a phenomenon called transactivation. However, the underlying molecular mechanisms remain undefined. In the present study we investigate the molecular basis of GABA B (γ-aminobutyric acid B) receptor-mediated transactivation of IGF-1R (insulin-like growth factor type I receptor) in primary neurons. We take a chemical biology approach by developing an activity-based probe targeting the GABA B receptor. This probe enables us first to lock the GABA B 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 the GABA B receptor induces a dynamic assembly and disassembly of a protein complex, including both receptors and their downstream effectors. FAK (focal adhesion kinase), a non-RTK, plays a key role in co-ordinating this dynamic process. Importantly, this dynamic of the GABA B receptor-associated complex is critical for transactivation and transactivation-dependent neuronal survival. The present study has identified an important mechanism underlying GPCR transactivation of RTKs, which was enabled by a new chemical biology tool generally applicable for dissecting GPCR signalling.

Journal

Biochemical JournalPortland Press

Published: May 1, 2012

Keywords: activity-based probe, gamma-aminobutyric acid B receptor (GABAB receptor), dynamic protein-protein interaction, insulinlike growth factor type I receptor (IGF-1R), transactivation

References