Functions and mechanisms of receptor tyrosine kinase Torso signaling: lessons from Drosophila embryonic terminal development

Abstract

The Torso receptor tyrosine kinase (RTK) is required for cell fate specification in the terminal regions (head and tail) of the early Drosophila embryo. Torso contains a split tyrosine kinase domain and belongs to the type III subgroup of the RTK superfamily that also includes the platelet-derived growth factor receptors, stem cell or steel factor receptor c-Kit proto-oncoprotein, colony-stimulating factor-1 receptor, and vascular endothelial growth factor receptor. The Torso pathway has been a model system for studying RTK signal transduction. Genetic and biochemical studies of Torso signaling have provided valuable insights into the biological functions and mechanisms of RTK signaling during early Drosophila embryogenesis.

Fig. 1

Expression patterns of the Torso target gene tailless and cuticle phenotypes of two classes of torso mutants. Loss-of-function (lof) mutations in torso eliminate posterior tailless (tll) expression and posterior structures; gain-of-function (gof) mutations result in expansion of tll expression and ectopic and enlargement of posterior structures at the expense of central elements. Note the loss of Filzkörper (arrow in wild-type [WT] embryo) and A8 in the torso lof mutant embryo and deletion of central denticle belts and enlargement and ectopic Filzkörper in torso^GOF embryo. Embryos are shown anterior to the left, posterior right. Dark blue stain in the left panels indicates tll mRNA, as detected by in situ hybridization. Darkfield photographs of embryonic cuticular preparations are shown in the central panels, and schematic representations of these cuticular patterns are shown on the right. Red color indicates tissues derived from the acron (left) and telson (right). These tissues include the head skeletons (open arrows), the eighth abdominal denticle belt (A8), and the Filzkörper (closed arrows). A1 to A8, abdominal denticle belts; T1 to T3, thoracic segments.

Fig. 2

Structure of receptor tyrosine kinases. Schematic outline of Torso and other receptor tyrosine kinases (RTKs). The type III RTK subfamily also includes c-Kit, CSF-1R (also known as c-FMS), and FMS-like tyrosine kinase-3 (FLT-3, not shown). These RTKs contain a kinase insert region with phosphotyrosine residues that serve as docking sites for downstream signaling molecules. This feature is not shared by other subfamily of RTKs, such as fibroblast growth factor receptor (FGF-R) and RET (REarranged during Transfection). The extracellular domain of Torso is not similar to the type III RTKs. PDGF-R, platelet-derived growth factor receptor; VEGF-R, vascular endothelial growth factor receptor; Ig, immunoglobulin.

Fig. 3

Activation of Torso. Nasrat and Polehole are present uniformly on the outer plasma membrane of the embryo. Torso-like is associated to the inner surface of the vitelline membrane in the anterior and posterior pole. Trunk is processed and activated only at the poles by collective actions of Torso-like, Nasrat/Polehole, and an unidentified factor(s). Processed C-terminal fragment of Trunk activates Torso. Torso in turn impedes the further diffusion of active Trunk molecules.

Fig. 4

Mechanism of Torso signal transduction. Ligand (Trunk) binding triggers dimerization and autophosphorylation of Torso on multiple tyrosine residues. Phosphotyrosines located in the activation loop of the tyrosine kinase domain are essential for Torso enzymatic activity. Phosphotyrosines located outside of the kinase domain serve to recruit Csw and possibly DSHC and other adaptors or SH2-containing signaling molecules, which may include STAT92E. The adaptor molecules redundantly or synergistically recruit Son of Sevenless (Sos) to the membrane. Sos converts GDP-Ras1 to GTP-Ras1, linking Torso activation to the Ras1/Draf/Dsor1/Rolled signaling cassette. In addition, Torso is able to activate Draf by means of a Ras1-independent pathway (dashed line 1), and Ras1 plays a role in activating an unknown Draf activator (dashed line 2) in addition to binding to Draf. Thus, multiple signaling routes originating from Torso can converge on the Draf kinase, leading to expression of downstream target genes. In the posterior terminal region, Torso signaling induces target gene tailless (tll) and huckebein (hkb) mainly by derepression, counteracting repressor complexes, including Capicua (Cic) and Groucho (Gro) and possibly other proteins that bind to the regulatory regions of tll and hkb. Gro is a conserved transcription repressor that is recruited to specific genes by its DNA-binding partner Cic. After relief of repression, the expression of tll and hkb depends on participation of transcription activators that may or may not require input from Torso signaling. Gene regulation by Torso in the anterior terminal region is more complex (see text for detail) and is not depicted in this schematic drawing.