Abstract
Argos, a secreted inhibitor of the Drosophila epidermal growth factor receptor, and the only known secreted receptor tyrosine kinase inhibitor, acts by sequestering the EGFR ligand Spitz. We use computational modeling to show that this biochemically-determined mechanism of Argos action can explain available genetic data for EGFR/Spitz/Argos interactions in vivo. We find that efficient Spitz sequestration by Argos is key for explaining the existing data and for providing a robust feedback loop that modulates the Spitz gradient in embryonic ventral ectoderm patterning. Computational analysis of the EGFR/Spitz/Argos module in the ventral ectoderm shows that Argos need not be long-ranged to account for genetic data, and can actually have very short range. In our models, Argos with long or short length scale functions to limit the range and action of secreted Spitz. Thus, the spatial range of Argos does not have to be tightly regulated or may act at different ranges in distinct developmental contexts.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Body Patterning / genetics
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Computational Biology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drosophila / embryology
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Drosophila / metabolism*
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Drosophila Proteins / biosynthesis
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Ectoderm / cytology
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Ectoderm / metabolism
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Enzyme Induction
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Epidermal Growth Factor / metabolism
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / metabolism
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Eye Proteins / genetics
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Eye Proteins / metabolism*
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Feedback, Physiological
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Gene Dosage
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Genes, Insect
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In Situ Hybridization
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Insect Proteins / genetics
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Insect Proteins / metabolism*
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Kinetics
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Membrane Proteins / biosynthesis
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Membrane Proteins / metabolism
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Models, Biological
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Mutation
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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RNA, Messenger / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Drosophila Proteins
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Eye Proteins
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Insect Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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RNA, Messenger
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Rho protein, Drosophila
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sim protein, Drosophila
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aos protein, Drosophila
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spi protein, Drosophila
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Epidermal Growth Factor
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ErbB Receptors