title: An activity-based probe reveals dynamic protein-protein interactions mediating IGF-1R transactivation by the GABA(B) receptor.
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.
authors.affiliation: Sino-France Laboratory for Drug Screening, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Linhai
authors.initials: L
authors.lastname: Chen
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Xu
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhang
authors.forename: Han
authors.initials: H
authors.lastname: Zhao
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Xu
authors.forename: Fajun
authors.initials: F
authors.lastname: Nan
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D015335:Molecular Probes; D019920:Photoaffinity Labels; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D018080:Receptors, GABA-B / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D015335:Molecular Probes; D019920:Photoaffinity Labels; D018080:Receptors, GABA-B; D017526:Receptor, IGF Type 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt