Intracellular trafficking by Star regulates cleavage of the <i>Drosophila</i> EGF receptor ligand Spitz

Tsruya, Rachel; Schlesinger, Ayelet; Reich, Aderet; Gabay, Limor; Sapir, Amir; Shilo, Ben‐Zion

doi:10.1101/gad.214202

Cited by 115 publications

(143 citation statements)

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“…Rhomboid is concentrated in the Golgi apparatus, while the EGF ligand Spitz is confined to the endoplasmic reticulum (ER). Star is distributed broadly, but its coexpression results in translocation of Spitz from the ER to the Golgi apparatus, where Spitz is cleaved from its transmembrane anchor, and secreted from the cell ready to initiate EGFR signaling in neighboring cells Pascall et al 2002;Tsruya et al 2002). The sequence of events was revealed by pulse-chase experiments , and these observations in cultured cells were corroborated directly in Drosophila Tsruya et al 2002).…”

Section: The Spitz Activation Pathwaysupporting

confidence: 56%

“…Instead, biochemical analysis of Spitz in developing Drosophila embryos ) and heterologous expression in a frog explant assay (Bang and Kintner 2000) revealed that Spitz is cleaved from its transmembrane anchor, and this required both the Rhomboid and Star proteins. Although these systems ultimately proved to be too complicated to reveal the molecular details of the signaling mechanism, Spitz processing could be recapitulated in transfected insect and mammalian cells Pascall et al 2002;Tsruya et al 2002). Careful cell biological analyses by several groups revealed that Spitz is activated through regulated ligand trafficking and proteolytic cleavage (Fig.…”

Section: The Spitz Activation Pathwaymentioning

confidence: 99%

“…Signaling molecules like Rhomboid, Star, and Spitz were assumed to be at the cell surface, but surprisingly all three were found to reside in internal organelles Pascall et al 2002;Tsruya et al 2002). Rhomboid is concentrated in the Golgi apparatus, while the EGF ligand Spitz is confined to the endoplasmic reticulum (ER).…”

Section: The Spitz Activation Pathwaymentioning

confidence: 99%

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Rhomboid proteins: conserved membrane proteases with divergent biological functions

Urban¹

2006

Genes Dev.

114

110

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The rhomboid gene was discovered in Drosophila, where it encodes a seven transmembrane protein that is the signal-generating component of epidermal growth factor (EGF) receptor signaling during development. Although metazoan developmental regulators are rarely conserved outside the animal kingdom, rhomboid proteins are conserved in all kingdoms of life, but the significance of this remains unclear. Recent biochemical reconstitution and high-resolution crystal structures have provided proof that rhomboid proteins function as novel intramembrane proteases, with a serine proteaselike catalytic apparatus embedded within the membrane bilayer, buried in a hydrophilic cavity formed by a protein ring. A thorough consideration of all known examples of rhomboid function suggests that, despite biochemical similarity in mechanism and specificity, rhomboid proteins function in diverse processes including quorum sensing in bacteria, mitochondrial membrane fusion, apoptosis, and stem cell differentiation in eukaryotes; rhomboid proteins are also now starting to be linked to human disease, including early-onset blindness, diabetes, and parasitic diseases. Regulating cell signaling is at the heart of rhomboid protein function in many, but not all, of these processes. Further study of these novel enzymes promises to reveal the evolutionary path of rhomboid protein function, which could provide insights into the forces that drive the molecular evolution of regulatory mechanisms.Developmental biology has progressed from descriptive observation to mechanistic analysis in the latter half of the 20th century (Wolpert 1998). Powerful genetic tools applied to model organisms have led to an intricate and beautiful picture of how genes build complex organisms. Parallel analyses in diverse animals and sequencing of their genomes revealed that a relatively small number of master genes and core regulatory pathways are used repeatedly in different contexts to build complex patterns, and these factors are conserved among animals.In addition to revealing some of the underlying logic of how organisms are constructed, these approaches were powerful in identifying the factors that mediate this intricate level of organization. But little is still known about how these key regulators exert their functions biochemically, which is central to understanding core biological processes that drive development at the molecular level.Most developmental regulators are conserved in the animal kingdom but are not found in other kingdoms, including plants, perhaps because plants and animals evolved multicellular development after splitting from a common ancestor (Meyerowitz 2002). But in recent years a small number of factors have been discovered that are conserved across kingdoms, raising the exciting possibility that they are key regulators that evolved very early. One such class of regulatory proteins are intramembrane proteases.Intramembrane proteolysis, the cleavage of membrane proteins within their membrane spanning segments, has recently been discovered to...

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Section: The Spitz Activation Pathwaysupporting

confidence: 56%

Section: The Spitz Activation Pathwaymentioning

confidence: 99%

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Rhomboid proteins: conserved membrane proteases with divergent biological functions

Urban¹

2006

Genes Dev.

114

110

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“…Rhomboid mutants show increased vesicular Wingless staining in the posterior compartment, suggesting that Rhomboid is required for Wingless degradation posteriorly (Dubois et al 2001). Notably, Rhomboid activates the EGFR ligand Spitz (Schweitzer et al 1995;Urban et al 2001;Tsruya et al 2002), and EGFR mutants also show increased posterior Wingless staining (Dubois et al 2001). Therefore, Hedgehog and EGFR signaling limit the Wingless gradient by upregulating Wingless degradation.…”

Section: Modifying the Gradient: Creating Gradient Asymmetrymentioning

confidence: 98%

When cell biology meets development: endocytic regulation of signaling pathways

2002

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“…Transfection of S2 Cells-UAS-mSpitz-GFP (mSpi-GFP, a gift from Ben-Zion Shilo, Weizmann Institute of Science, Israel) was used as an endoplasmic reticulum marker as described previously (27). UAS-GFP.RN3 (26) was used as a negative control.…”

Section: Generation Of Transgenic Strains and Rescue Crosses-drosophilamentioning

confidence: 99%

CYP306A1, a Cytochrome P450 Enzyme, Is Essential for Ecdysteroid Biosynthesis in the Prothoracic Glands of Bombyx and Drosophila

Niwa¹,

Matsuda

Yoshiyama

et al. 2004

Journal of Biological Chemistry

276

251

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Ecdysteroids mediate a wide variety of developmental and physiological events in insects. In the postembryonic development of insects, ecdysone is synthesized in the prothoracic gland (PG). Although many studies have revealed the biochemical and physiological properties of the enzymes for ecdysteroid biosynthesis, most of the molecular identities of these enzymes have not been elucidated. Here we describe an uncharacterized cytochrome P450 gene, designated Cyp306a1, that is essential for ecdysteroid biosynthesis in the PGs of the silkworm Bombyx mori and fruit fly Drosophila melanogaster. Using the microarray technique for analyzing gene expression profiles in PG cells during Bombyx development, we identified two PG-specific P450 genes whose temporal expression patterns are correlated with changes in ecdysteroid titer during development. Amino acid sequence analysis showed that one of the Bombyx P450 genes belongs to the CYP306A1 subfamily. The temporal and spatial expression pattern of the Drosophila Cyp306a1 homolog is essentially the same as that of Bombyx Cyp306a1. We also found that Drosophila Cyp306a1 is disrupted in the phantom (phm) mutant, known also as the Halloween mutant. The morphological defects and decreased expression of ecdysone-inducible genes in phm suggest that this mutant cannot produce a high titer of ecdysone. Finally we demonstrate that S2 cells transfected with Cyp306a1 convert ketodiol to ketotriol via carbon 25 hydroxylation. These results strongly suggest that CYP306A1 functions as a carbon 25 hydroxylase and has an essential role in ecdysteroid biosynthesis during insect development.

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Intracellular trafficking by Star regulates cleavage of the Drosophila EGF receptor ligand Spitz

Abstract: Spitz (Spi) is a TGF␣ homolog that is a cardinal ligand for the

Cited by 115 publications

References 46 publications

Rhomboid proteins: conserved membrane proteases with divergent biological functions

Rhomboid proteins: conserved membrane proteases with divergent biological functions

When cell biology meets development: endocytic regulation of signaling pathways

CYP306A1, a Cytochrome P450 Enzyme, Is Essential for Ecdysteroid Biosynthesis in the Prothoracic Glands of Bombyx and Drosophila

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