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Early growth response‐1 induction by fibroblast growth factor‐1 via increase of mitogen‐activated protein kinase and inhibition of protein kinase B in hippocampal neurons
Author(s) -
Benz Alexander H,
Shajari Mehdi,
Peruzki Natalie,
Dehghani Faramarz,
Maronde Erik
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00812.x
Subject(s) - protein kinase b , protein kinase a , mapk/erk pathway , microbiology and biotechnology , mitogen activated protein kinase kinase , pi3k/akt/mtor pathway , map kinase kinase kinase , biology , kinase , ask1 , chemistry , phosphorylation , signal transduction
Background and purpose: The transcription factor early growth response‐1 (Egr‐1) and the acidic fibroblast growth factor (FGF‐1) are involved in many regulatory processes, including hippocampus‐associated learning and memory. However, the intracellular signalling mechanisms regulating Egr‐1 in hippocampal cells are not entirely understood. Experimental approach: We used primary mouse hippocampal neurons and the mouse hippocampal neuronal cell line HT22 to investigate how FGF‐1 transiently induces Egr‐1 protein. This was accomplished by a range of techniques including Western blotting, immunofluorescence, specific protein kinase inhibitors and transfectable constitutively active protein kinase constructs. Key results: Protein kinase B (PKB) and mitogen‐activated protein kinase (MAPK) were both initially phosphorylated and activated by FGF‐1 treatment, but when phosphorylated MAPK reached maximal activation, phosphorylated PKB was at its lowest levels, suggesting an interaction between MAPK kinase (MEK‐1/2) and phosphatidyl inositol‐3‐kinase (PI3K) during Egr‐1 induction. Interestingly, pharmacological inhibition of MEK‐1/2 resulted in a robust increase in the phosphorylation of PKB, which was repressed in the presence of increasing doses of a PI3K inhibitor. FGF‐1‐mediated Egr‐1 induction was impaired by inhibition of MEK‐1/2, but not of PI3K. However, elevated levels of PKB, induced by transfection of constitutively active PKB (myrAkt) into hippocampal neuronal HT22 cells, led to reduced levels of Egr‐1 after FGF‐1 application. Conclusions and implications: Our data indicate a contribution of inactive (dephosphorylated) PKB to FGF‐1‐mediated induction of Egr‐1, and strongly suggest a functionally and pharmacologically interesting cross‐talk between MEK‐1/2 and PI3K signalling in hippocampal neurons after FGF‐1 stimulation that may play a role in hippocampal synaptic plasticity.