Genetic identification of effectors downstream of Neu (ErbB-2) autophosphorylation sites in a Drosophila model.
The ErbB-2/Neu receptor tyrosine kinase plays a causal role in tumorigenesis in mammals. Neu's carboxyl terminus contains five phosphorylated tyrosines that mediate transformation through interaction with cytoplasmic SH2 or PTB containing adaptor proteins. We show that Drosophila adaptors signal from individual phosphotyrosine sites of rat Neu. Activated Neu expression in the midline glia suppressed apoptosis, similar to that seen with activated Drosophila EGF-R expression. Expression in eye and wing tissues generated graded phenotypes suitable for dosage-sensitive modifier genetics. Suppression of ErbB-2/Neu-induced phenotypes in tissues haplosufficient for genes encoding adaptor protein or second messengers suggests that pTyr 1227(YD) signals require Shc, and that pTyr 1253 (YE) signalling does not employ Ras, but does require Raf function. Signalling from pTyr (YB) was affected by a haplosufficiency in drk (Grb-2), and in genes thought to function downstream of Grb-2: dab, sos, csw (Shp-2), and dos (Gab-1). These data demonstrate the power of Drosophila genetics to unmask the molecules that signal from oncogenic ErbB-2/Neu.
Settle
Mark
M
Department of Biology, McMaster University, Hamilton, ON, Canada.
Gordon
Michael D
MD
Nadella
Mythili
M
Dankort
David
D
Muller
William
W
Jacobs
J Roger
JR
D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology; D005123:Eye / Q000254:growth & development; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry*; D011494:Protein Kinases; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D011506:Proteins / Q000235:genetics / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000502:physiology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000502:physiology; D018010:Receptors, Invertebrate Peptide / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020839:Son of Sevenless Protein, Drosophila / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship; D014921:Wings, Animal / Q000254:growth & development
D033942:Adaptor Proteins, Vesicular Transport; D029721:Drosophila Proteins; D066246:ErbB Receptors; D005136:Eye Proteins; D009419:Nerve Tissue Proteins; D019000:Phosphotyrosine; D011494:Protein Kinases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D011506:Proteins; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D018010:Receptors, Invertebrate Peptide; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; D020839:Son of Sevenless Protein, Drosophila; C100319:Dos protein, Drosophila; C095222:Shc protein, Drosophila; C080216:dab protein, Drosophila; C080530:drk protein, Drosophila; C066532:Egfr protein, Drosophila; C098692:Csw protein, Drosophila