Drosophila Jak/STAT Signaling: Regulation and Relevance in Human Cancer and Metastasis

Abstract

Over the past three-decades, Janus kinase (Jak) and signal transducer and activator of transcription (STAT) signaling has emerged as a paradigm to understand the involvement of signal transduction in development and disease pathology. At the molecular level, cytokines and interleukins steer Jak/STAT signaling to transcriptional regulation of target genes, which are involved in cell differentiation, migration, and proliferation. Jak/STAT signaling is involved in various types of blood cell disorders and cancers in humans, and its activation is associated with carcinomas that are more invasive or likely to become metastatic. Despite immense information regarding Jak/STAT regulation, the signaling network has numerous missing links, which is slowing the progress towards developing drug therapies. In mammals, many components act in this cascade, with substantial cross-talk with other signaling pathways. In Drosophila, there are fewer pathway components, which has enabled significant discoveries regarding well-conserved regulatory mechanisms. Work across species illustrates the relevance of these regulators in humans. In this review, we showcase fundamental Jak/STAT regulation mechanisms in blood cells, stem cells, and cell motility. We examine the functional relevance of key conserved regulators from Drosophila to human cancer stem cells and metastasis. Finally, we spotlight less characterized regulators of Drosophila Jak/STAT signaling, which stand as promising candidates to be investigated in cancer biology. These comparisons illustrate the value of using Drosophila as a model for uncovering the roles of Jak/STAT signaling and the molecular means by which the pathway is controlled.

Keywords: Drosophila 3; Janus kinase (Jak) 1; cancer metastasis 4; signal transducer and activator of transcription (STAT) 2.

Figure 1

The Drosophila Jak/STAT signaling components and the corresponding human homologs and their protein families. Interleukin or cytokine (the Upd family in flies) binds to its signaling receptor (Dome in flies), which activates the associated Jak (fly Hop) and triggers a chain of events. Activated Jak phosphorylates other Jaks and the receptor, creating a binding site for STAT proteins. Recruited STAT proteins (fly STAT92E), are then phosphorylated. The phospho-STATs dimerize and translocate to the nucleus. The STAT DNA binding domain recognizes promoter and enhancer regions of target genes, resulting in their transcriptional activation. The table above the figure lists the core components of the canonical pathway. The table to the right delineates key regulators of the fly Jak/STAT pathway, their respective human homologs, and their protein families. Positive regulators are listed in green font, negative regulators are in red. See text for details.