Non-canonical notch signaling in cancer and immunity

Abstract

Canonical Notch signaling is initiated by γ-secretase-mediated cleavage of the Notch receptor, leading to the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-Jκ, resulting in the activation of downstream target genes. While canonical Notch signaling is well known to play an active role in several steps during development as well in multiple cell fate decisions, recent evidence from both invertebrate and vertebrate systems indicates that non-canonical, RBP-Jκ-independent signaling is important in several cellular processes including oncogenesis and activation of T lymphocytes. These observations raise the possibility that, through an understanding of non-canonical Notch signaling, novel strategies for inhibiting Notch signaling may prove useful in the design of therapies targeted to block aberrant Notch activity. In this mini-review, we will examine the current data demonstrating a non-canonical role for Notch signaling in both cancer and the immune system and suggest a better understanding of non-canonical signaling may reveal novel strategies to block Notch signaling in disease.

Keywords: Notch; T lymphocytes; cancer; non-canonical; signal transduction.

Figure 1

Non-canonical Notch signaling pathways. Non-canonical Notch signaling may occur either dependent or independent of ligand interaction. Additionally, non-canonical Notch signaling may be γ-secretase dependent or independent with the latter exerting its function as membrane bound Notch. Non-canonical Notch signaling is independent of CSL/RBPJκ and, instead, interacts with PI3K, mTORC2, AKT, Wnt, NFκB, YY1, or HIF-1α pathways at either the cytoplasmic and/or nuclear levels. Non-canonical Notch signaling regulates cell survival, metabolism, and differentiation through interaction with these pathways in many important biological processes including immunity and cancer.