Specific activation of mGlu2 induced IGF-1R transactivation in vitro through FAK phosphorylation

Yong-jian Hu1, Qian Sun1, Wen-hua Zhang1, Yu-jia Huo1, Chan-juan Xu1, Jian-feng Liu1
1 Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
Correspondence to: Chan-juan Xu:, Jian-feng Liu:,
DOI: 10.1038/s41401-018-0033-7
Received: 26 January 2018
Accepted: 20 April 2018
Advance online: 26 June 2018


Metabotropic glutamate receptor 2 (mGlu2) belongs to the group-II metabotropic glutamate (mGlu) receptors and is a neurotransmitter G protein-coupled receptor. The group-II mGlu receptors are promising antipsychotic targets, but the specific role of mGlu2 signaling remains unclear. Receptor tyrosine kinases (RTKs) are also believed to participate in brain pathogenesis. To investigate whether there is any communication between mGlu2 and RTKs, we generated a CHO-mGlu2 cell line that stably expresses mGlu2 and showed that activation of mGlu2 by LY379268, a group II mGlu agonist, was able to transactivate insulin-like growth factor 1 receptor (IGF-1R). We further determined that the Gi/o protein, Gβγ subunits, phospholipase C, and focal adhesion kinase (FAK) were involved in the IGF-1R transactivation signaling axis, which further induced the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and cAMP response element-binding protein. In primary mouse cortical neurons, similar signaling pathways were observed when mGlu2 were stimulated by LY487379, an mGlu2 positive allosteric modulator. Transactivation of IGF-1R through FAK in response to mGlu2 should provide a better understanding of the association of mGlu2 with brain disease.
Keywords: metabotropic glutamate receptor 2; insulin-like growth factor 1 receptor; transactivation; FAK; ERK1/2; LY379268; LY487379; mouse cortical neurons

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