STAT activation by Drosophila Torso RTK

Overactivation of receptor tyrosine kinases (RTKs), caused by either oversupply of ligands or mutations that result in ligandindependent constitutive activation, has been linked to many cancers and other human diseases (reviewed by Robertson et al., 2000). An important question is why such overactivation, which has been generally presumed to be quantitative in nature, could lead to qualitative changes of cellular properties. It has been proposed that a constitutively activated RTK hyperactivates a canonical downstream signal transduction pathway, such as the Ras-MAPK signaling cassette, and that the qualitative changes in gene expression are determined by the variation in signaling duration and/or intensity (Ghiglione et al., 1999; Greenwood and Struhl, 1997; Marshall, 1995; Sewing et al., 1997; Woods et al., 1997). Alternatively, however, overactivated RTK could signal via alternative pathways that are not essential for or engaged by wild-type RTK under physiological conditions, thus augmenting the signaling capacity of this overactivated RTK. To investigate how overactivation of an RTK results in aberrant gene expression, we chose to study the Torso (Tor) pathway in the early Drosophila embryo. Tor is a fly RTK most homologous to the mammalian PDGF receptor. During Drosophila development, Tor specifies cell fates in the terminal regions of the embryo (Duffy and Perrimon, 1994). Tor mRNA is synthesized during oogenesis, deposited into the unfertilized egg, and translated following fertilization. Tor proteins are uniformly distributed on the cell membrane of the early embryo, but are activated at the terminal regions by a ligand that diffuses from the egg poles (Casanova and Struhl, 1993; Sprenger and Nusslein-Volhard, 1992). Previous studies have documented that Tor activates the evolutionarily conserved Ras1/Draf/MEK/MAPK signaling cassette (Duffy and Perrimon, 1994) to induce the expression of target genes such as tailless (tll) (Pignoni et al., 1990; Pignoni et al., 1992), which is essential for specifying cell fates in the terminal regions (Steingrimsson et al., 1991). The current model is that the tll promoter is repressed in the early embryo. The MAPK pathway abrogates tll repression, thereby enabling tll activation by an unknown ubiquitous transcription factor(s) (Liaw et al., 1995; Paroush et al., 1997). tll expression at the posterior end is precisely restricted in a domain from 0 to 15% of the egg length (EL) in wild-type embryos (Fig. 1A). The extent of this domain is a sensitive readout of the strength of Tor activation (Hou et al., 1995; Li et al., 1998; Li et al., 1997). Thus, a decrease in Tor signaling, such as caused by tor or Draf loss-of-function mutations, results in reduction or elimination of tll expression in the posterior domain in a manner reflecting the severity of the mutation 4241 Development 129, 4241-4248 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV5506