The insect membrane-protein, Torso, is a member of the receptor-tyrosine-kinase family, and is activated by its ligand, prothoracicotropic hormone (PTTH). Although PTTH is one of the most important regulators of insect development, the mechanism of Torso activation by the hormone has remained elusive. In this study, using heterologous expression in cultured Drosophila S2 cells, we detected ligand-independent dimerization of silkworm Torso, and found that the receptor molecules in the dimer were linked by intermolecular disulfide bridges. By examining the oligomerization states of several truncation and substitution mutants of Torso, atypical cysteine residues in the transmembrane region were identified as being responsible for the intermolecular linkage in the dimer. The replacement of all of the cysteines in the region with phenylalanines abolished the disulfide-bond-mediated dimerization; however, non-covalent dimerization of the mutant was detected using a cross-linking reagent, both with and without ligand stimulation. This non-covalent dimerization caused apparent receptor autophosphorylation independently of the ligand stimulation, but did not promote the ERK phosphorylation in the downstream signaling pathway. The unique Torso structure with the intermolecular disulfide bridges in the transmembrane region is necessary to maintain the liganddependent receptor functions of autophosphorylation and downstream activation.Cellular-membrane receptors play important roles as mediators, in the signal transduction of extracellular stimuli to the activation of intracellular biochemical pathways. The receptors are composed of several types of membrane proteins, such as G-protein-coupled receptors (GPCRs), enzyme-linked receptors, ion-channel-linked receptors, and others 1 . To perform their transduction activities, GPCRs usually require other protein partners such as G-proteins, while the enzyme-linked receptors can activate the intracellular pathways by themselves, using the catalytic domains in their own intracellular regions. For example, receptor tyrosine kinases (RTKs) commonly have intracellular tyrosine kinase domains, which phosphorylate the tyrosine residues of the receptors themselves and those within other intracellular protein molecules.Insects also utilize cellular-membrane RTKs to receive extracellular hormonal signals. Among the insect hormonal receptors, Torso, a member of the RTK family, was recently reported to contribute to the activation of prothoracic gland cells in response to stimulation by prothoracicotropic hormone (PTTH) 2 , although Torso was originally discovered as an anteroposterior axis determinant in Drosophila embryos [3][4][5] . In Drosophila larvae, Torso is expressed specifically in the prothoracic glands, and the torso knock-down caused delayed larval development 2 . This phenotype of the knocked-down larvae may be derived from the lack of the molting hormone,
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