In Caenorhabditis elegans, lin-2, lin-7, and lin-10 genetically interact to control the trafficking of the Let-23 growth factor receptor to the basolateral surface of body epithelia. The human homologue of the lin-10 gene has recently been identified as a member of the X11 gene family. The X11 proteins contain one phosphotyrosine binding (PTB) and two PSD-95⅐Dlg⅐ZO-1 (PDZ) domains as well as an extended amino terminus. We have previously shown that the PTB domain of X11␣ (also known as Mint1)

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... n bind to the amyloid precursor protein (APP) in a phosphotyrosine-independent fashion and can markedly inhibit the processing of APP to the amyloid ␤ (A␤) peptide. Here, we report that X11␣ directly binds to the mammalian homologue of Lin-2 (mLin-2), also known as CASK. This binding is mediated by direct interaction between the Calmodulin Kinase II (CKII)like domain of mLin-2 and the amino terminus of X11␣. Furthermore, we can detect direct interactions between mLin-2 and mammalian Lin-7 (mLin-7). In mouse brain, we have identified a heterotrimeric complex that contains mLin-2, mLin-7, and X11␣ and that is likely important for the localization of proteins in polarized cells. This complex may play an important role in the trafficking and processing of APP in neurons. Protein-protein interactions are crucial for many cellular processes and are mediated by protein domains that are highly conserved in evolution (1). The PTB 1 domain was first identi- Communication