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.

IL‐7–Mediated IL‐7R‐JAK3/STAT5 signalling pathway contributes to chemotherapeutic sensitivity in non–small‐cell lung cancer

“…[25][26][27]41 The JAK/STAT signalling pathway is a crucial pathway that involves in tumour cell To compare whether there is a significant difference, same letters marked were considered to have no significant difference between the two groups and different letters marked were considered to have significant difference between the two groups differentiation, migration and proliferation and promotes cell motility by regulating actin dynamics and activating key metastasis-promoting genes. 42,43 In particular, STAT3 activation induced by interleukin family of cytokines can promote migration and invasion via the regulation of downstream target molecules such as Vimentin, Twist, MMP-9 and MMP-7. 44 Chang Q et al found that the autocrine/paracrine IL-6/JAK/STAT3 feed-forward loop has been implicated as a key player of tumour progression and metastasis and an increased level of IL-6 was found in the invasive breast tumours, with its level positively correlated with advanced stage, confirming a pivotal role of IL-6 signalling in breast tumour metastasis in vivo.…”

JAK/STAT signaling in insect innate immunity

“…The key negative regulators include the protein inhibitors of activated STATs (PIASs), SOCS, and protein tyrosine phosphatases (PTPs). In addition to these, other notable negative regulators of JAK/STAT signaling in Drosophila include the Eye transformer (ET), Ken and barbie (Ken), Enhancer of Bithorax (E (Bx)), and Eyes absent (Eya) that have been implicated in the insect developmental processes (Trivedi & Starz‐Gaiano ). The human homologs for Et, Ken, E (Bx), and Eya are glycoprotein 130 (GP130), B cell CLL/Lymphoma 6 (BCL6), Bromodomain PHD finger transcription factor (BPTF), and Eyes absent 2 (Eya2) that lead to melanoma/prostate cancer (Shariat et al .…”

Molecular cloning and characterization of SOCS2 from the mealworm beetle Tenebrio molitor

“…). Many parallels have been identified between human and Drosophila JAK/STAT signaling, including neoplastic growth in JAK‐mutated flies (Trivedi & Starz‐Gaiano ). The core components of the JAK/STAT signaling pathway in Drosophila appear to be restricted and less redundant in comparison to human JAK/STAT components.…”

“…Owing to the direct control of cytokines, such as interleukins, interferons, and growth factors, the JAK/STAT pathway is central to cancer and inflammatory diseases (Banerjee et al 2017;Groner & von Manstein 2017;Yan et al 2016). Many parallels have been identified between human and Drosophila JAK/STAT signaling, including neoplastic growth in JAK-mutated flies (Trivedi & Starz-Gaiano 2018). The core components of the JAK/STAT signaling pathway in Drosophila appear to be restricted and less redundant in comparison to human JAK/STAT components.…”

“…Only SOCS36E (most similar to human SOCS5) and SOCS44A (most similar to human SOCS1) are known to negatively regulate the JAK/STAT pathway (Rawlings et al 2004). With significantly less cross-talk, the Drosophila JAK/STAT signaling regulators have been considered promising candidates for the discovery of therapeutics against metastatic tumors and inflammation (Trivedi & Starz-Gaiano 2018;Yoshimura & Yasukawa 2012). The parallels discussed are also consequential for screening novel regulators of JAK/STAT signaling in flies and other insects.…”