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First published online June 22, 2006
doi: 10.1242/10.1242/dev.02411

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

Natalia I. Arbouzova^* and Martin P. Zeidler^,

Department of Molecular Developmental Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.

View larger version (26K): [in a new window]   Fig. 1. The canonical model of JAK/STAT signalling. Pre-dimerised complexes of a pathway receptor (grey) and JAKs (blue) are activated following ligand (red) binding. Phosphorylation (purple circles) of the JAKs and the receptors generate docking sites for the normally cytosolic STATs that are recruited to the active complex. Following phosphorylation of the STATs, STAT dimers form, which translocate to the nucleus and bind to a palindromic DNA sequence in the promoters of target genes to activate their transcription. The names of the pathway components in Drosophila are provided in brackets in the key.

View larger version (14K): [in a new window]   Fig. 2. Positive regulators of Drosophila JAK/STAT signalling. (A) Three UPD-related ligands, each of which contain N-terminal signal sequences (S) and have predicted N-linked glycosylation sites (dots). (B) DOME contains fibronectin type III-like repeats (FN3) (characteristic of cytokine receptors), a transmembrane region (blue box) and a coiled-coil domain (cc). (C) Hopscotch contains an N-terminal FERM (4.1, ezrin, radixin, moesin) domain found in all JAKs that is required for association with the receptor (Usacheva et al., 2002), an SH2 domain, a regulatory pseudo-kinase domain and a Tyr kinase (Y-kinase) domain. (D) STAT92E contains a N-terminal domain found in all STATs that mediates tetramerisation (Johnson et al., 1999; Vinkemeier et al., 1998), a coiled-coil region and a DNA-binding domain (DBD). An SH2 domain is also present, and is required for receptor binding and dimerisation. In mammalian STATs, the C terminus also contains a transcriptional activation domain. In NSTAT92E, the absence of the N-terminal region produces a protein that acts as a dominant negative (Henriksen et al., 2002). (E) BRWD3 contains eight WD40 motifs and two BROMO domains, which are frequently present in chromatin-associated proteins. Proteins and domains are shown to scale.

View larger version (15K): [in a new window]   Fig. 3. Negative regulators of Drosophila JAK/STAT signalling. (A) The SOCS genes are named for their chromosomal locations, and each contains an SH2 domain and a SOCS box (SB). (B) ZIMP [also called PIAS or Su(var)2-10] contains a putative chromatin binding SAP (SAF, Acinus and PIAS) domain and a zinc-containing ring finger (RF) implicated in SUMOlation. (C) A truncated STAT92E splice variant lacking an N-terminal protein:protein interaction domain results in a dominant-negative protein (Henriksen et al., 2002). Compare to Fig. 2D. (D) PTP61FC is a spliceform of ptp61F that contains a C-terminal nuclear localisation signal (N) and an Y-phosphatase domain. (E) KEN contains an N-terminal BTB/POZ (BTB) domain and three C-terminal C2H2 zinc-finger motifs. Proteins and domains shown to scale.

View larger version (21K): [in a new window]   Fig. 4. KEN selectively regulates STAT92E targets depending on the binding sites present. (A) In vitro selection experiments have defined the optimal DNA-binding sites of KEN and STAT92E. The `core' positions essential for binding are shown in red (for KEN) or green (for STAT92E). There is overlap in the sequences recognised. (B) Reporters differing only in their STAT92E-binding sites respond differently to the activity of STAT92E and KEN. In reporters to which only STAT92E can bind (green; top row), activation by STAT92E cannot be modulated by KEN. When both STAT92E and KEN are able to bind to a reporter (green and red; lower row), activation by STAT92E can be countered by the co-expression of KEN. Neither reporter is active in the absence of STAT92E. Green tick represents activation of reporter transcription, red cross implies repression.

View larger version (76K): [in a new window]   Fig. 5. JAK/STAT pathway activation leads to cellular overproliferation. (A,B) Late third instar Drosophila larvae: (A) wild type or (B) carrying a gain-of-function hop allele. Constitutively activated JAK/STAT signalling leads to the proliferation of lamellocytes, which aggregate to form prominent and, ultimately lethal, melanised tumours (dark cells). (C) Wild-type and (D) upd-overexpressing Drosophila eye imaginal discs, at the same magnification, are stained to show the structure of the disc (red) and mitotic cells (green). The morphogenetic furrow (MF) is marked, with the first and second mitotic waves visible ahead and behind it. The increased density of mitotic cells in the first mitotic wave is visible in the dorsal region of the upd-overexpressing disc. (E,F) Scanning electron micrographs of the adult eyes derived from (E) wild-type and (F) upd-overexpressing Drosophila showing the dorsal overgrowth of the adult eye that results from pathway mis-activation. (E) Reproduced, with permission, from Bach et al. (Bach et al., 2003).

View larger version (51K): [in a new window]   Fig. 6. The stem cell niche at the tip of the Drosophila testis. (A) A small group of somatic hub cells (blue) are located at the tip of the Drosophila testis and express the UPD ligand and so maintain the fate of adjacent stem cells (yellow). As the germline stem cells divide (top), daughter cells are born (middle), with one remaining adjacent to the hub and maintaining stem cell fate, and the other beginning to differentiate towards the gonialblast and spermatogonial fate (dark yellow). Somatic stem cells (light green) are also present that give rise to the cyst cells (dark green), which encase the differentiating spermatogonia. (B) An enhancer trap in the upd locus mirrors the hub cell-specific expression of upd at the testis tip. Scale bar: 10 µm. Reproduced, with permission, from Tulina and Matunis (Tulina and Matunis, 2001).