Computational analysis of EGFR inhibition by Argos.
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.
Department of Chemical Engineering, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Carl Icahn Laboratory, Washington Road, Princeton, NJ 08544, USA.
Gregory T
GT
Reeves
Rachel
R
Kalifa
Daryl E
DE
Klein
Mark A
MA
Lemmon
Stanislav Y
SY
Shvartsman
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D019521:Body Patterning / Q000235:genetics; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000196:embryology / Q000378:metabolism*; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism; D004790:Enzyme Induction; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D018628:Gene Dosage; D017344:Genes, Insect; D017403:In Situ Hybridization; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D005136:Eye Proteins; D019476:Insect Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C081481:Rho protein, Drosophila; C089449:sim protein, Drosophila; C075638:aos protein, Drosophila; C076026:spi protein, Drosophila