Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels; DLK then phosphorylates MKK7, which in turn phosphorylates ERK1/2 but not JNKs (Fig. 3A). Activated phospho-ERK1/2 may then increase Aβ production by enhancing the levels of amyloid-β precursor protein (APP; see below). Although attractive, this hypothesis differs from current concepts of MAP-kinase signaling pathways which suggest that MKK7 primarily phosphorylates JNKs instead of ERKs (Morrison, 2012). Thus, we directly tested whether MKK7 mediates ApoE3-induced ERK1/2 phosphorylation.
