Fig. 4.

ASD-derived PTEN mutants fail to inhibit TH in vitro. a Left panel, loss of inhibitory effect of ASD-derived PTEN mutants on TH; PC12 cells stably expressed different PTENs were cultured in media with (Tet+) or without tetracycline (Tet−) [19]. TH was then measured by Western blot; right panel, tumor-associated PTEN mutants cannot inhibit TH. PC12 cells were transiently transfected with either vector or C124S and G129E mutant PTEN, and TH was measured by Western blot. b Cycloheximide chase reveals decreased protein stability of the ASD-derived PTEN mutants. c PTEN-induced molecular mechanism mediating the dopamine synthesis in the brain. PTEN suppresses NGF-induced activation of PI3K and ERK-MAPK pathways. PI3K phosphorylates CREB at Ser133 and further increases the transcription and translation of the TH gene. ERK-MAPK phosphorylates TH at Ser31 and increases the stability of the TH protein. Hyperactivity of both pathways caused by PTEN mutations leads to upregulated TH/dopamine synthesis and triggers the expression of the D2R receptors in neural tissue