FIG. 9.

Model of intra- and intercellular signaling induced by GDNF in RMG. RET transmembrane tyrosine kinase is phosphorylated in response to GDNF, NRTN, and ARTN. All ligands are able to induce three intracellular signaling cascades: MEK/ERK, SAPK, and PKB/AKT pathways. Inhibitor experiments demonstrate that MEK acts upstream of PI 3-kinase (PI3-K) to an unidentified target and upstream of SAPK. Both, PI 3-kinase and MEK are able to activate SAPK. Phosphorylated ERK is shuttled into the RMG nucleus, where it induces increased transcription of FGF-2 mRNA. This leads to increased expression and secretion of FGF-2 protein, which then supports survival of PR, which are in close proximity to RMG in intact retina.