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.

Links

Publisher Full Text

Authors

Lin X, Li X, Jiang M, Chen L, Xu C, Zhang W, Zhao H, Sun B, Xu X, Nan F, Liu J

Institution

Sino-France Laboratory for Drug Screening, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Source

The Biochemical journal 443:3 2012 May 1 pg 627-34

MeSH

Blotting, Western
Cell Line
Focal Adhesion Protein-Tyrosine Kinases
Humans
Molecular Probes
Photoaffinity Labels
Protein Binding
Proto-Oncogene Proteins c-akt
Receptor, IGF Type 1
Receptors, GABA-B
Signal Transduction
Transcriptional Activation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Validation Studies

Language

eng

PubMed ID

22394253