These data, viewed together, suggest that ApoE stimulates APP transcription via a non-canonical MAP-kinase pathway that involves ERKs but not JNKs. Consistent with this hypothesis, ApoE3 is taken up into the cell by a receptor-dependent pathway (Fig. S6A). The exclusion of JNKs in ApoE-dependent signaling is surprising because JNKs are canonical substrates for MKK7 (Morrison, 2012), JNKs have been identified as downstream targets for DLK in neurodegeneration (Chen et al., 2012), and APP directly binds to JNK scaffolding proteins (Scheinfeld et al., 2002). To further examine the role of JNK signaling in ApoE signaling, we tested the role of JIP3, the predominant JNK scaffold in neurons. JIP3 knockdown had no effect on the ApoE3-mediated increase in APP and DKL levels or MKK7 and ERK1/2 phosphorylation, but inhibited the MG132-mediated stimulation of MKK7 and JNK phosphorylation as expected (Fig. 4F, S4C). Thus, the JNK-pathway is not required for ApoE signaling.
