Because C terminal autophosphorylation depends on the catalytic activity of HER2, the lack of phosphorylation heat shock protein 90 inhibitor in Y1248 in the C terminus of HER2 in drug-resistant cells implies that maintenance of Y877 phosphorylation doesn’t defeat lapatinibinduced inhibition of the receptors kinase activity. Still another possible role for Y877 phosphorylation in increasing HER2/HER3 heterodimer development is proposed. Maintenance of HER2/HER3 heterodimers would have been a system for partial preservation of PI3K activity in light of the six p85 binding sites in HER3. This could support a position for prolonged Y877 phosphorylation in getting the HER3 PI3K Akt axis in order to circumvent drug action. We also identified increased phosphorylation of the corresponding initial hook residue of Yes, Y426, in immune cells. Moreover, we found phosphorylation at Y222 Yes entirely in lapatinib Ribonucleic acid (RNA) resistant cells. Phosphorylation at Y216 Src can somewhat boost the kinase activity of Src and can overcome the inhibitory effects of phosphorylation at the regulatory Y527 site. Of note, heregulin, a HER3 ligand that activates HER2/HER3 signaling, has been demonstrated to induce phosphorylation of Y216 in Src in MCF 7 breast cancer cells. Further, higher levels of phosphorylation at Y216 correlates with an increase of HER2 expression in breast tumors. Just like Y877 HER2, the phosphorylation at Y222 in Yes was restricted to lapatinib resistant cells where the catalytic action of HER2 remained inhibited, suggesting that the HER2 kinase isn’t involved in phosphorylation of Y216 Yes. The relationship of increased Yes action indicated by Y222 and Y426 phosphorylation with persistent Y877 HER2 phosphorylation Celecoxib Celebra in resistant cells recommended that Y877 in HER2 is a Src kinase substrate. Yes and Fyn also can mediate Y877 HER2 phosphorylation. In contrast, an early in the day report found that Y877 phosphorylation was lowered by treatment with PD168393, a HER2 TKI, leading to the that Y877 was an autophosphorylation site. These observations contrast with the degree of phosphorylation at this site detected with immunoaffinity enrichment for pTyr just before evaluation by immunoblot, while we observed the same end in immunoblots of whole cell lysates after treatment or by MS. Utilizing the more sensitive and specific MS based method, we discovered that the relative level of phosphorylation of Y877 HER2 is not decreased whatsoever by lapatinib. This means that HER2 isn’t the kinase that phosphorylates Y877 HER2, and further underscores the value of chronic Y877 phosphorylation in resistant cells.