Notch Signaling in Neuroendocrine Tumors

Abstract

Carcinoids and neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the neuroendocrine cells of the GI tract, endocrine pancreas, and the respiratory system. NETs remain significantly understudied with respect to molecular mechanisms of pathogenesis, particularly the role of cell fate signaling systems such as Notch. The abundance of literature on the Notch pathway is a testament to its complexity in different cellular environments. Notch receptors can function as oncogenes in some contexts and tumor suppressors in others. The genetic heterogeneity of NETs suggests that to fully understand the roles and the potential therapeutic implications of Notch signaling in NETs, a comprehensive analysis of Notch expression patterns and potential roles across all NET subtypes is required.

Keywords: Notch; SCLC; carcinoid; neuroendocrine tumors; pNET; small-cell lung cancer.

Figure 1

Notch canonical and non-canonical signaling. Notch signaling via the canonical pathway is on the left portion of the figure. Membrane-bound Notch receptor is activated by binding with ligand on a neighboring cell, which results in cleavage by ADAM metalloproteases, followed by cleavage with γ-secretase. These cleavage events release the NICD, which then enters the nucleus to affect the gene transcription. The non-canonical signaling pathway is on the right portion of the figure and illustrates that non-canonical signaling may occur either in the presence or absence of ligand. Further, the signaling may occur via the membrane-bound, uncleaved Notch receptor or via the NICD. Non-canonical Notch signaling is independent of CSL and allows for interaction with PI3K/AKT/mTORC2, Wnt/β-catenin, IKKα/β, NFκB, YY1, and HIF1α pathways at the cytoplasmic and/or nuclear level. Abbreviations: ADAM, a disintegrin and metalloprotease; NEXT, Notch extracellular truncation; NICD, Notch intracellular domain; Co-R, corepressor; Co-A, coactivator.

Figure 2

Notch receptors and ligands. Abbreviations: SP, signal peptide; EGF-LR, epidermal growth factor-like repeats; LNR, Lin-Notch repeat; TMD, transmembrane domain; RAM, RBP-Jκ association module 23; NLS, nuclear localization signal; ANK, ankyrin/CDC10 repeat; TAD, transactivation domain; PEST, proline/glutamic acid/serine/threonine-rich motif; PDZ, PSD-95/Dlg/ZO-1 domain; CR, cysteine-rich domain; DSL, Delta/Serrate/Lag2 domain; NT, N-terminal domain. Posttranslational modifications are indicated by symbols: yellow diamonds, phosphorylation; red diamonds, acetylation/deacetylation sites; green square, prolyl isomerization site; blue circle, O-linked glucosylation; red triangle, O-linked fucosylation; orange star, xylosylation; and inverted orange triangle, ubiquitylation.