Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression

Cell Communication and Signaling

Research

Matthew P Keasey¹  Seong Su Kang¹  Chiharu Lovins¹  Theo Hagg² 

[1] Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, 40292, Louisville, KY, USA;Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, 40292, Louisville, KY, USA;Pharmacology and Toxicology, University of Louisville, 40292, Louisville, KY, USA;

关键词: Astrocyte;    Ciliary neurotrophic factor;    Focal adhesion kinase;    Integrin;    Intercellular communication;    Mice;    Neurogenesis;    Neuron;    Pharmacological;    Transcriptional gene regulation;   

DOI  :  10.1186/1478-811X-11-35

 received in 2013-02-07, accepted in 2013-05-13,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundCiliary neurotrophic factor (CNTF) expression is repressed in astrocytes by neuronal contact in the CNS and is rapidly induced by injury. Here, we defined an inhibitory integrin signaling pathway.ResultsThe integrin substrates laminin, fibronectin and vitronectin, but not collagen, thrombospondin or fibrinogen, reduced CNTF expression in C6 astroglioma cells. Antibodies against αv and β5, but not α6 or β1, integrin induced CNTF. Together, the ligand and antibody specificity suggests that CNTF is repressed by αvβ5 integrin. Antibodies against Thy1, an abundant neuronal surface protein whose function is unclear, induced CNTF in neuron-astrocyte co-cultures indicating that it is a neuroglial CNTF repressor. Inhibition of the integrin signaling molecule Focal Adhesion Kinase (FAK) or the downstream c-Jun N-terminal kinase (JNK), but not extracellular regulated kinase (ERK) or p38 MAPK, greatly induced CNTF mRNA and protein expression within 4 hours. This selective inhibitory pathway phosphorylated STAT3 on its inhibitory ser-727 residue interfering with activity of the pro-transcription Tyr-705 residue. STAT3 can activate CNTF transcription because it bound to its promoter and FAK antagonist-induced CNTF was reduced by blocking STAT3. Microinjection of FAK inhibitor directly into the brain or spinal cord in adult mice rapidly induced CNTF mRNA and protein expression. Importantly, systemic treatment with FAK inhibitors over 3 days induced CNTF in the subventricular zone and increased neurogenesis.ConclusionsNeuron-astroglia contact mediated by integrins serves as a sensor to enable rapid neurotrophic responses and provides a new pharmacological avenue to exploit the neuroprotective properties of endogenous CNTF.

【 授权许可】

Unknown   
© Keasey et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.