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  • The EMBO Journal (2007) 26, 1211 - 1220
  • doi:10.1038/sj.emboj.7601581

Published online: 15 February 2007

Rhomboid cleaves Star to regulate the levels of secreted Spitz

Rachel Tsruya1, Alexandra Wojtalla2, Shari Carmon1, Shaul Yogev1, Aderet Reich1, Eitan Bibi3, Gunter Merdes2,4, Eyal Schejter1 and Ben-Zion Shilo1

  1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
  2. ZMBH, INF282, Heidelberg, Germany
  3. Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
  4. Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland

Correspondence to:

Ben-Zion Shilo, Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: +972 8 9343169; Fax: +972 8 9344108; E-mail: benny.shilo@weizmann.ac.il

Received 6 December 2006; Accepted 2 January 2007

Intracellular trafficking of the precursor of Spitz (Spi), the major Drosophila EGF receptor (EGFR) ligand, is facilitated by the chaperone Star, a type II transmembrane protein. This study identifies a novel mechanism for modulating the activity of Star, thereby influencing the levels of active Spi ligand produced. We demonstrate that Star can efficiently traffic Spi even when present at sub-stoichiometric levels, and that in Drosophila S2R+ cells, Spi is trafficked from the endoplasmic reticulum to the late endosome compartment, also enriched for Rhomboid, an intramembrane protease. Rhomboid, which cleaves the Spi precursor, is now shown to also cleave Star within its transmembrane domain both in cell culture and in flies, expanding the repertoire of known Rhomboid substrates to include both type I and type II transmembrane proteins. Cleavage of Star restricts the amount of Spi that is trafficked, and may explain the exceptional dosage sensitivity of the Star locus in flies.

  • Keywords:

    • EGFR signaling,
    • intramembrane proteolysis,
    • Rhomboid,
    • Spitz,
    • Star