Rhomboid and Star facilitate presentation and processing of the DrosophilaTGF-alpha homolog Spitz

Activation of the Drosophila epidermal growth factor receptor (DER) by the transmembrane ligand, Spitz (Spi), requires two additional transmembrane pr oteins, Rhomboid and Star. Genetic evidence suggests that Rhomboid and Star facilitate DER signaling by processing membrane-bound Spi (mSpi) to an act ive, soluble form. To test this model, we use an assay based on Xenopus ani mal cap explants in which Spi activation of DER is Rhomboid and Star depend ent. We show that Spi is on the cell surface but is kept in an inactive sta te by its cytoplasmic and transmembrane domains; Rhomboid and Star relieve this inhibition, allowing Spi to signal. We show further that Spi is likely to be cleaved within its transmembrane domain. However, a mutant form of m Spi that is not cleaved still signals to DER in a Rhomboid and Star-depende nt manner. These results suggest strongly that Rhomboid and Star act primar ily to present an active form of Spi to DER, leading secondarily to the pro cessing of Spi into a secreted form.