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The Roles of the Drosophila JAK/STAT Pathway

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The Roles of the Drosophila JAK/STAT Pathway Oncogene (2000) 19, 2598 ± 2606 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc The roles of the Drosophila JAK/STAT pathway Martin P Zeidler1, Erika A Bach1 and Norbert Perrimon*,1 1Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, MA 02115, USA The JAK/STAT signal transduction pathway has been to nuclear translocation. Once in the nucleus activated conserved throughout evolution such that true structural STAT dimers bind to consensus DNA target sites and functional homologues of components originally where they act as activators of transcription (Figure 1a identi®ed in vertebrate systems are also present in the and other reviews in this issues). model genetic system Drosophila melanogaster.In Interestingly the JAK/STAT pathway and STAT- addition to roles during larval hematopoiesis reminis- like molecules in particular are present throughout cent of the requirement for this pathway in mammalian evolution. To date one (or possibly two) STATs have systems, the JAK/STAT pathway in Drosophila is also been found in the nematode C. elegans (Lui et al., involved in a number of other developmental events. 1999), and three STAT-like molecules have been Recent data has demonstrated further roles for the identi®ed in the slime mould Dictyostelium (M JAK/STAT pathway in the establishment of sexual Fukazawa and JG Williams, unpublished data reported identity via the early embryonic expression of Sex in Williams, 1999). However, neither organism appears lethal, the segmentation of the embryo via the control to have JAK-like protein kinases. of pair rule genes including even skipped and the In the Drosophila system a `complete' JAK/STAT establishment of polarity within the adult compound pathway that consists of one JAK (called hopscotch) eye via a mechanism that includes the four jointed and one STAT (called stat92E) has been identi®ed, in gene. Use of the powerful genetics in the model stark contrast to the multitude of JAK and STAT organism Drosophila may identify new components of homologues present in mammals. The presence of a the JAK/STAT pathway, de®ne new roles for this relatively simple JAK/STAT pathway, together with pathway, and provide insights into the function of this the wealth of sequence data and genetic techniques signal transduction system. Here we review the roles of available, make Drosophila a very powerful system with STAT and its associated signaling pathway during both which to study this pathway. These advantages, embryonic and adult stages of Drosophila development especially with respect to developmental requirements and discuss future prospects for the identi®cation and for JAK/STAT signaling, are particularly relevant for characterization of novel pathway components and the ¯y model system and hold much promise for the targets. Oncogene (2000) 19, 2598 ± 2606. future elucidation of interactions between the JAK/ STAT pathway and other signal transduction cascades Keywords: hopscotch; unpaired; stat92E; ommatidia; involved in developmental decisions. segmentation; polarity In this review we discuss recent developments into our understanding of the components and roles of the JAK/STAT pathway during Drosophila development Introduction and address potential future directions in the ®eld. The JAK/STAT signal transduction cascade was ®rst Characterization of Drosophila JAK/STAT pathway identi®ed in mammalian systems because of its role in components the transduction of a variety of cytokines and growth factor signals (reviewed in Darnell, 1997). Extensive With the recent cloning of unpaired (upd) and its studies in mammalian systems have led to the identi®cation as a potential ligand for the Drosophila development of a canonical model in which the non- JAK/STAT pathway (Harrison et al., 1998), three receptor tyrosine kinase JAK is associated with the pathway components have been identi®ed on the intracellular portion of transmembrane cytokine recep- basis of their biochemical, genetic and mutant tors (Figure 1a). Following ligand binding, receptors phenotypes. dimerize bringing two JAK molecules into juxtaposi- The hopscotch (hop) locus encodes a 1177 amino acid tion where they trans-phosphorylate one another. protein that shares all the characteristics of mammalian JAKs activated in this manner then tyrosine phosphor- JAK family non-receptor tyrosine kinases. Hop is most ylate their associated receptors causing normally similar to human JAK2 (27% identity), with higher cytosolic STAT molecules to bind to the receptor levels of homology in kinase and kinase-like domains complex via their SRC homology 2 (SH2) domains. (Figure 1b, Binari and Perrimon, 1994). The Drosophila The STAT molecules recruited in this manner are STAT homologue Stat92E is also highly homologous themselves activated by JAK-mediated phosphoryla- to human STAT5 (37% identity). Stat92E includes a tion of an invariant tyrosine residue in their C-terminal SH2 domain, DNA binding domain and the single region and then either homo- or hetero-dimerize prior tyrosine residue around position 700 found in all STAT-like genes (Figure 1b, Hou et al., 1996; Yan et al., 1996a). Indeed this residue in Stat92E (Y711) has *Correspondence: N Perrimon been shown to be phosphorylated in response to Roles of the Drosophila JAK/STAT pathway MP Zeidler et al 2599 pathway activation in tissue culture systems (Yan et al., examples of canonical JAK- and STAT-like proteins 1996a). present in ¯ies. It has previously been reported that a second, non- While mutations in the unpaired locus have been Stat92E derived STAT-like activity is detectable in known for over 75 years, only recently has the Drosophila cell extracts (Yan et al., 1996a; Sweitzer et associated gene been identi®ed as a ligand for the al., 1995). A series of searches of the Drosophila Drosophila JAK/STAT pathway (Venderosa and genome sequencing project data were therefore con- Muller, 1954; Harrison et al., 1998). The unpaired ducted on a complete 106 coverage database to locus encodes a predicted 47 kDa secreted protein with address this question. Using Stat92E protein sequences an N-terminal signal sequence and several potential N- as `probes' for tblastn search programs no candidate linked glycosylation sites (Figure 1b). While a protein STAT-like molecules, other than stat92E itself, were similar to Upd called Om1E has been identi®ed in the identi®ed (E Spana, personal communication). While, closely related fruit ¯y Drosophila ananassae, no known it remains possible that a STAT-like protein, which has vertebrate homologues have been found in publicly diverged suciently far from Stat92E to be undetect- available databases to date (Harrison et al., 1998; Juni able with sequence based searches, is in fact present, it et al., 1996). Biochemical analysis of Upd revealed that seems that the complex situation in vertebrate model the protein has an apparent molecular weight of systems is not mirrored in Drosophila. Therefore both 65 kDa, is indeed glycosylated and is localized in the Hopscotch and Stat92E probably represent the sole extracellular matrix. Furthermore, tissue culture experi- s s Figure 1 (a) The JAK/STAT pathway in which receptor/JAK (red) complexes dimerize on binding of ligand (blue) (1). Following receptor and JAK phosphorylation (2) cytosolic STATs (green) are recruited to the complex (3). Phosphorylated STAT molecules dimerize (4) and translocate to the nucleus where they bind DNA and activate transcription (5). (b) Schematic representation of the Drosophila Unpaired (blue), Hopscotch (red) and Stat92E (green) proteins. Gray bars in Unpaired represent potential amino-linked glycosylation sites. The activating mutations in Hopscotch are indicated (see text for details) as is the invariant tyrosine residue in Stat92E. SS=signal sequence, DB=DNA binding domain and SH2=Src Homology 2 domain. Each protein is drawn to scale (scale bar is 100 amino acids) and numbers represent amino acid position Oncogene Roles of the Drosophila JAK/STAT pathway MP Zeidler et al 2600 ments have shown that Upd is capable of inducing Sex determination Hop phosphorylation and activation in Clone 8 tissue culture cells. Furthermore, activation of the JAK/ The sisterless C (sisC) gene has been known for some STAT pathway by Upd does not require co-expression time as a component of the Drosophila sex determina- of Upd in the signaling cell as Upd supplied by either a tion system (Cline, 1993) and the recent identi®cation physically separate, but co-cultured, (S2) cell type, or of sisC as an allele of Upd has implicated the JAK/ even from previously conditioned media, is sucient to STAT pathway in one of the earliest processes of activate Hop (Harrison et al., 1998). Taken together embryonic development. with in vivo evidence showing that Upd functions as an The process of sexual identity determination in activator of JAK/STAT signaling in the eye (Zeidler et Drosophila is based on very early mechanisms which al., 1999b), it is clear that Unpaired represents a bona detect the X chromosome to autosome ratio of the ®de JAK/STAT pathway ligand. newly fertilized embryo (with XY individuals becoming Although the identity of Drosophila JAK and STAT males and XX developing into females). The cellular homologues and a pathway ligand are now known, mechanism which determines the number of X the identity of a pathway receptor(s) remains unclear. chromosomes establishes the expression state of the Vertebrate studies have shown that the JAK/STAT Sex lethal gene which acts as a `master switch' to pathway is downstream of cytokine receptors and determine sexual identity and X chromosome dosage receptor tyrosine kinases such as EGFR and PDGFR compensation. The dose of X chromosomes present in (Darnell, 1997). While a similar situation may also be a newly fertilized embryo is relayed into this sexual the case in Drosophila no evidence had emerged to determination machinery via the activity of a number date regarding the nature of a potential pathway of X-linked signal element (XSE) genes which are receptor.
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