Opposing roles for Drosophila JAK/STAT signalling during cellular proliferation

Abstract

The JAK/STAT signalling pathway mediates both antiproliferative responses following interferon stimulation and cellular proliferation in response to cytokines such as interleukins and growth factors. Central to these responses are the seven vertebrate STAT molecules, misregulation of which is implicated in a variety of malignancies. We have investigated the proliferative role of the single Drosophila STAT92E, part of the evolutionarily conserved JAK/STAT cascade. During second instar larval wing disc development pathway activity is both necessary and sufficient to promote proliferation of this epithelial cell type. However by later stages, endogenous STAT92E is stimulated by a noncannonical mechanism to exert pronounced antiproliferative effects. Ectopic canonical activation is sufficient to further decrease proliferation and leads to the premature arrest of cells in the G2 phase of the cell cycle. The single STAT92E present in Drosophila therefore mediates both proproliferative functions analogous to vertebrate interleukin-stimulated STAT3 and antiproliferative functions analogous to interferon-stimulated STAT1. Pro-and antiproliferative roles therefore represent ancestral activities conserved through evolution and subsequently assigned to distinct molecules.

STAT92E is a positive regulator ofDrosophilainhibitor of apoptosis 1 (DIAP/1) and protects against radiation-induced apoptosis

“…In younger wing discs (second to third instar), WTSTDpZ expression in the pouch appeared somewhat more dependent on STAT92E than in the third-instar tissue (Fig. S2), possibly reflecting the underlying shift in the STAT92E activation pattern based on the gradually shifting distribution of the ligand upd during development (7,18). A control in which stat92E Ϫ/Ϫ clones were induced in the MTSTDpZ background had no effect on reporter expression (data not shown).…”

“…This remaining expression of DIAP1 in stat92E Ϫ/Ϫ clones is consistent with the likelihood that a small amount of DIAP1 is controlled by some other transcription factor. This small amount of DIAP1 might still allow the survival of stat92E Ϫ/Ϫ clones under unstressed conditions; stat92E Ϫ/Ϫ clones are known to survive to adulthood and contribute to WT structures (7). In contrast, diap1-null clones are quickly eliminated through apoptosis (12,13).…”

“…The simpler Jak-STAT pathway in Drosophila consists of the ligands unpaired 1, 2, and 3 and the receptor domeless, with which one Jak family kinase, hopscotch, is associated. Mutations in the pathway affect a wide variety of processes including a positive effect on the cell cycle (6)(7)(8).…”

JAK/STAT signalling inDrosophila: insights into conserved regulatory and cellular functions

“…Recent forward and reverse genetic screens (Box 1) Baeg et al, 2005;Mukherjee et al, 2005;Müller et al, 2005) have identified multiple novel loci, the knockdown of which is sufficient to modulate the strength of JAK/STAT pathway activity. Strikingly, a comparison of the genes identified in these different screens reveals a relatively small overlap in the candidates identified.…”

Lines is required for normal operation of Wingless, Hedgehog and Notch pathways during wing development

“…N in turn activates the expression of Wg in cells along the DV boundary Rulifson et al, 1996), and further refinement involves a series of positive-and negativefeedback loops between both pathways. In addition to these primary signaling events, several other pathways are also important for coordination of cell proliferation in developing tissues, including the JAK/STAT pathway (Mukherjee et al, 2005).…”