Interaction of estrogen receptors with insulin-like growth factor-I and Wnt signaling in the nervous system.
Estradiol signaling through estrogen receptors in the nervous system involves a variety of rapid membrane/cytoplasm-initiated events that are integrated with different mechanisms of transcriptional regulation. Here we review the role of glycogen synthase kinase 3 (GSK3) and beta-catenin in the coordination of membrane/cytoplasm-initiated and nuclear-initiated estrogen receptor signaling. Estradiol activates in vitro and in vivo the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in neural cells. By activating this pathway through estrogen receptors, estradiol increases the levels of inactive GSK3beta (phosphorylated in serine 9). In turn, the inhibition of GSK3beta increases the stability of beta-catenin and its nuclear translocation. Then, beta-catenin exerts two different transcriptional effects: (i) regulates beta-catenin/T cell factor (TCF) mediated transcription in a similar but not identical way as Wnt ligands and (ii) regulates estrogen receptor mediated transcription after its association with estrogen receptor alpha. In addition, by the regulation of PI3K/Akt/GSK3/beta-catenin pathway, other factors such as insulin-like growth factor-I (IGF-I) regulate estrogen receptor mediated transcription. Therefore, GSK3 and beta-catenin allow the interaction of membrane/cytoplasm-initiated estrogen receptor signaling, IGF-I signaling, Wnt signaling and nuclear-initiated estrogen receptor signaling in the nervous system.
Varea
Olga
O
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Centro de Biología Molecular Severo Ochoa, CSIC-UAM, E-28049 Madrid, Spain.
Arevalo
Maria-Angeles
MA
Garrido
Juan Jose
JJ
Garcia-Segura
Luis M
LM
Wandosell
Francisco
F
Mendez
Pablo
P
D000818:Animals; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009420:Nervous System / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
D011960:Receptors, Estrogen; D051153:Wnt Proteins; D007334:Insulin-Like Growth Factor I