The double-edged sword of Notch signaling in cancer

Abstract

Recent deep sequencing of cancer genomes has produced an explosion of new data implicating Notch signaling in several human cancers. Unlike most other pathways, these data indicate that Notch signaling can be either oncogenic or tumor suppressive, depending on the cellular context. In some instances, these relationships were predicted from mouse models or presaged by developmental roles for Notch, but in other cases were unanticipated. This review discusses the pathogenic and translational significance of these new findings.

Figure 1

Structure of mammalian Notch receptors and ligands. Mammals express 5 Notch ligands, four of which activate Notch receptors (JAG1, JAG2, DLL1, and DLL4), and one of which (DLL3) may function as a decoy. Ligands have an N-terminal DSL domain, variable numbers of EGF repeats, and in the case of Serrate-like ligands (JAG1 and JAG2) a juxtamembrane cysteine-rich domain (CR). Mammals have four Notch receptors, Notch1–4, comprised of non-covalently associated extracellular (N^EC) and transmembrane (N^TM) subunits. N^EC is comprised of 29–34 EGF repeats, 3 Lin12/Notch repeats (LNRs), and the N-terminal portion of the juxtamembrane heterodimerization domain (HD), while N^TM is comprised of a RAM domain, 7 iterated ankyrin repeats (ANK) repeats, an structurally divergent unfolded region with variable transcriptional activation domain function (greatest in Notch1, least in Notch4), and a C-terminal PEST degron domain.

Figure 2

Distribution of Notch1 PEST domain mutations in lymphoid cancers. Positions of nonsense and frameshift mutations in human chronic lymphocytic leukemia (CLL) [–13], human mantle cell lymphoma (MCL)[18], and human [–46] and murine T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) [47, 48] are superimposed on the human C-terminal Notch1 amino acids 2414 and 2555, which includes a Fbxw7 E3-ligase target sequence and the sequence WSSSSP, both implicated in degradation of activated Notch1. Murine Notch1 mutations are aligned according to the homologous amino acid sequences of human Notch1. Disruptive mutations N-terminal of amino acid 2414 of human Notch1 are collected together and thus appear as a single peak. The inset box shows the murine and human genomic sequences around mutational hotspots in human lymphoid tumors (codon 2514) and in murine T-ALL (codon 2361).

Figure 3

Distribution of cancer-associated missense (open circle) and nonsense (closed circle) mutations in NOTCH1, organized by exon and protein domain. Selected activating mutations in T-ALL (blue) and CLL (green) are compared with putative loss-of-function mutations for head and neck SCC (orange), cutaneous SCC (red) and lung SCC (yellow).