A genetic approach to identify the requirements for phosphotyrosine specific outputs of Neu/ErbB2

Abstract

<p> DER, the Drosophila Epidermal Growth Factor Receptor (DEgfr) is the only known fly orthologue of vertebrate Neu/ErbB2 receptor tyrosine kinase family. Receptor Tyrosine Kinases (RTKs) like DER and ErbB2 play an important role in regulating cell differentiation, cell proliferation and cell survival in metazoan animals. Neu/ErbB2 is over-expressed in 20-30% human breast cancers, which correlates with poor clinical prognosis in cancer patients. </p> <p> Our previous studies showed that rat-NeriJErbB2 could successfully signal in vivo using Drosophila adaptor and second messenger molecules. Here we regenerated the transgenic fly lines with various neu add-back alleles. We further re-established mis-expression phenotypes in various adult structures such as wings and eyes, the tissues known to require DEgfr signaling. By using genetic approach, we have demonstrated that the tyrosine residue at the 1028 site (NeuYA), might have an inhibitory role in RTK signaling. In addition we have already generated a number of double add-back neu alleles where tyrosine site at the 1028 site (neuYA) was added back to another Neu allele and made neuYAB, neuYAc neuYAD and neuYAE. Transgenic flies with these alleles will be generated to further study the inhibitory role of Neu^YA. </p> <p> Finally, our on going large-scale genetic screening is likely to reveal the component(s) of NeuYE (Y1253) pathway that does not utilize the function of Ras. </p>