Dynamics and non-canonical aspects of JAK/STAT signalling

Mohr, Anne; Chatain, Nicolas; Domoszlai, Tamas; Rinis, Natalie; Sommerauer, Michael; Vogt, Michael; Müller‐Newen, Gerhard

doi:10.1016/j.ejcb.2011.09.005

Cited by 83 publications

(67 citation statements)

References 98 publications

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“…In Drosophila, the pathway elements comprise only three ligands (Upd, Upd2 and Upd3), one homodimeric receptor (Dome), one JAK kinase (Hop) and one STAT transcription factor (STAT92E) (Arbouzova and Zeidler, 2006). This contrasts with the complexity found in mammals where multiple ligands and heterodimeric receptors, four JAK kinases and seven STAT proteins exist (Mohr et al, 2012). Despite millions of years of independent evolution, all studies show that the canonical signal transduction pathway is very similar in insects and mammals.…”

Section: Introductionmentioning

confidence: 64%

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Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells

et al. 2013

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SUMMARYIntercellular communication depends on the correct organization of the signal transduction complexes. In many signalling pathways, the mechanisms controlling the overall cell polarity also localize components of these pathways to different domains of the plasma membrane. In the Drosophila ectoderm, the JAK/STAT pathway components are highly polarized with apical localization of the receptor, the associated kinase and the STAT92E protein itself. The apical localization of STAT92E is independent of the receptor complex and is due to its direct association with the apical determining protein Bazooka (Baz). Here, we find that Baz-STAT92E interaction depends on the presence of the Drosophila Src kinases. In the absence of Src, STAT92E cannot bind to Baz in cells or in whole embryos, and this correlates with an impairment of JAK/STAT signalling function. We believe that the requirement of Src proteins for STAT92E apical localization is mediated through Baz, as we can co-precipitate Src with Baz but not with STAT92E. This is the first time that a functional link between cell polarity, the JAK/STAT signalling pathway and the Src kinases has been established in a whole organism.

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Section: Introductionmentioning

confidence: 64%

“…STAT binding to the active receptor leads to its phosphorylation by JAK. Phospho-STAT proteins can homo-or heterodimerize through a conserved SH2 domain, allowing their stable translocation to the nucleus where they activate the transcription of target downstream genes (Mohr et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells

et al. 2013

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“…Moreover, biological functions of STATs independent of tyrosine phosphorylation have been described. These non-canonical functions have been demonstrated to be involved in controlling heterochromatin and microtubule stability or regulating metabolic functions in mitochondria (Mohr et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Consequences of the disease-related L78R mutation for dimerization and activity of STAT3

Domoszlai

Martincuks

Fahrenkamp

et al. 2014

Journal of Cell Science

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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is centrally involved in diverse processes including haematopoiesis, immunity and cancer progression. In response to cytokine stimulation, STAT3 is activated through phosphorylation of a single tyrosine residue. The phosphorylated STAT3 dimers are stabilized by intermolecular interactions between SH2 domains and phosphotyrosine. These activated dimers accumulate in the nucleus and bind to specific DNA sequences, resulting in target gene expression. We analysed and compared the structural organizations of the unphosphorylated latent and phosphorylated activated STAT3 dimers using Fö rster resonance energy transfer (FRET) in fixed and living cells. The latent dimers are stabilized by homotypic interactions between the N-terminal domains. A somatic mutation (L78R) found in inflammatory hepatocellular adenoma (IHCA), which is located in the N-terminal domain of STAT3 disturbs latent dimer formation. Applying intramolecular FRET, we verify a functional role of the SH2 domain in latent dimer formation suggesting that the protomers in the latent STAT3 dimer are in a parallel orientation, similar to activated STAT3 dimers but different from the antiparallel orientation of the latent dimers of STAT1 and STAT5. Our findings reveal unique structural characteristics of STAT3 within the STAT family and contribute to the understanding of the L78R mutation found in IHCA.

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“…For example, several roles were identified for STAT proteins that are independent of CytoRs and JAKs. These include the control of cell growth, differentiation, chemotaxis and immune responses in slime mold downstream of G-protein-coupled receptors (29), and the regulation of metabolic functions in vertebrates by unphosphorylated STATs (40,41). Similarly, several SOCS members are principally involved in the regulation of growth factor receptors and other pathways (39).…”

Section: Emergence Of the Pathwaymentioning

confidence: 99%

Evolution of Cytokine Receptor Signaling

Liongue

Sertori

Ward

2016

The Journal of Immunology

103

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Cytokines represent essential mediators of cell–cell communication with particularly important roles within the immune system. These secreted factors are produced in response to developmental and/or environmental cues and act via cognate cytokine receptors on target cells, stimulating specific intracellular signaling pathways to facilitate appropriate cellular responses. This review describes the evolution of cytokine receptor signaling, focusing on the class I and class II receptor families and the downstream JAK–STAT pathway along with its key negative regulators. Individual components generated over a long evolutionary time frame coalesced to form an archetypal signaling pathway in bilateria that was expanded extensively during early vertebrate evolution to establish a substantial “core” signaling network, which has subsequently undergone limited diversification within discrete lineages. The evolution of cytokine receptor signaling parallels that of the immune system, particularly the emergence of adaptive immunity, which has likely been a major evolutionary driver.

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Dynamics and non-canonical aspects of JAK/STAT signalling

Cited by 83 publications

References 98 publications

Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells

Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells

Consequences of the disease-related L78R mutation for dimerization and activity of STAT3

Evolution of Cytokine Receptor Signaling

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