Early genetics in flies revealed that Notch is a complex pleiotropic locus. We now know that Notch is a receptor that plays prominent roles during development and functions locally in many tissues to instruct cell fate decisions. Drosophila has been an excellent model to identify genetically the elements that contribute to the canonical Notch signaling transduction machinery defined as DSL-Notch-CSL-MAML axis. This core pathway is required in many biological events in all animals. Though the canonical Notch pathway is relatively simple, and as the steps of the events are now more deeply understood, an increasing number of reports in the last decade show that many other molecules can influence Notch signaling, some by competing with a given element of the cascade. This may occur at any step bringing more diversity and plasticity to the Notch pathway. Most of these regulatory molecules act in a context-specific manner and/or are themselves key regulators in other pathways, providing increasing examples of how connections among distinct pathway modulate each other ("cross talk"). The noncanonical signals discussed in this chapter are broadly defined and correspond to the following: DSL-independent activations, interactions with non-DSL ligands, CSL-independent signaling, signal transduction without cleavage, differential posttranslational modifications, competition/protection for a cofactor, and cross talk with other signaling pathways [Wnt, bone morphogenic protein (BMP), NF-kappaB, etc.]. Though some deemed controversial, these events may impact human diseases. Understanding the molecular nature of these events will allow avoidance of adverse effects during possible clinical treatments. In this review, we will focus on some noncanonical Notch activities and their in vivo significance during developmental and pathological processes.
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