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Hipk is required for JAK/STAT activity during development and tumorigenesis.

ABSTRACT: Drosophila has been instrumental as a model system in studying signal transduction and revealing molecular functions in development and human diseases. A point mutation in the Drosophila Janus kinase JAK (called hop) causes constitutive activation of the JAK/STAT pathway. We provide robust genetic evidence that the Homeodomain interacting protein kinase (Hipk) is required for endogenous JAK/STAT activity. Overexpression of Hipk can phenocopy the effects of overactive JAK/STAT mutations and lead to melanized tumors, and loss of Hipk can suppress the effects of hyperactive JAK/STAT. Further, the loss of the pathway effector Stat92E can suppress Hipk induced overgrowth. Interaction studies show that Hipk can physically interact with Stat92E and regulate Stat92E subcellular localization. Together our results show that Hipk is a novel factor required for effective JAK/STAT signaling.

SUBMITTER: Tettweiler G

PROVIDER: S-EPMC6938406 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Hipk is required for JAK/STAT activity during development and tumorigenesis.

Tettweiler Gritta G Blaquiere Jessica A JA Wray Nathan B NB Verheyen Esther M EM

PloS one 20191231 12

Drosophila has been instrumental as a model system in studying signal transduction and revealing molecular functions in development and human diseases. A point mutation in the Drosophila Janus kinase JAK (called hop) causes constitutive activation of the JAK/STAT pathway. We provide robust genetic evidence that the Homeodomain interacting protein kinase (Hipk) is required for endogenous JAK/STAT activity. Overexpression of Hipk can phenocopy the effects of overactive JAK/STAT mutations and lead ...[more]

PMID: 31891940

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Project description:BackgroundWithin the nucleus of eukaryotic cells, chromatin is organized into compact, silent regions called heterochromatin and more loosely packaged regions of euchromatin where transcription is more active. Although the existence of heterochromatin has been known for many years, the cellular factors responsible for its formation have only recently been identified. Two key factors involved in heterochromatin formation in Drosophila are the H3 lysine 9 methyltransferase Su(var)3-9 and heterochromatin protein 1 (HP1). The linker histone H1 also plays a major role in heterochromatin formation in Drosophila by interacting with Su(var)3-9 and helping to recruit it to heterochromatin. Drosophila STAT (Signal transducer and activator of transcription) (STAT92E) has also been shown to be involved in the maintenance of heterochromatin, but its relationship to the H1-Su(var)3-9 heterochromatin pathway is unknown. STAT92E is also involved in tumor formation in flies. Hyperactive Janus kinase (JAK)-STAT signaling due to a mutation in Drosophila JAK (Hopscotch) causes hematopoietic tumors.ResultsWe show here that STAT92E is a second partner of H1 in the regulation of heterochromatin structure. H1 physically interacts with STAT92E and regulates its ectopic localization in the chromatin. Mis-localization of STAT92E due to its hyperphosphorylation or H1 depletion disrupts heterochromatin integrity. The contribution of the H1-STAT pathway to heterochromatin formation is mechanistically distinct from that of H1 and Su(var)3-9. The recruitment of STAT92E to chromatin by H1 also plays an important regulatory role in JAK-STAT induced tumors in flies. Depleting the linker histone H1 in flies carrying the oncogenic hopscotch (Tum-l) allele enhances tumorigenesis, and H1 overexpression suppresses tumorigenesis.ConclusionsOur results suggest the existence of two independent pathways for heterochromatin formation in Drosophila, one involving Su(var)3-9 and HP1 and the other involving STAT92E and HP1. The H1 linker histone directs both pathways through physical interactions with Su(var)3-9 and STAT92E, as well with HP1. The physical interaction of H1 and STAT92E confers a regulatory role on H1 in JAK-STAT signaling. H1 serves as a molecular reservoir for STAT92E in chromatin, enabling H1 to act as a tumor suppressor and oppose an oncogenic mutation in the JAK-STAT signaling pathway.

Dataset Information

Hipk is required for JAK/STAT activity during development and tumorigenesis.

Publications

Hipk is required for JAK/STAT activity during development and tumorigenesis.

Similar Datasets

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