RAF and MEK inhibitors are being created as treatments for cancers with activation of RAF/MEK/ERK signaling. But, with the exception of BRAF mutant melanomas, the efficacy of the drugs as single agents is underwhelming thus far. Feedback activation of similar oncogenic pathways including PI3K/AKT has been invoked, though there hdac3 inhibitor are many possible reasons for this insufficient efficiency. This idea is analogous to findings that mTORC1 inhibitors are limited by feedback activation of PI3K signaling. In this study, we discover that MEK inhibitor induced activation of PI3K/AKT occurs in multiple ERBB influenced cancer designs via loss of an inhibitory threonine phosphorylation within the protected JM domains of HER2 and EGFR. Phosphorylation of the threonine residue is shown to impair EGFR service, likely through disruption of receptor dimerization. Our results suggest that direct ERK mediated phosphorylation of HER2 T677 and EGFR T669 suppresses activation of ERBB3. These findings agree with these by Li and colleagues who observed that MEK Neuroendocrine tumor inhibition did not enhance phosphorylation of EGFR T669A homodimers expressed in CHO KI cells. In this study, we extend previous findings by directly showing the results of EGFR T669A on ERBB3/PI3K/AKT signaling in an EGFRmutant cancer cell line. Moreover, we show that while multiple mechanisms for MAPK feedback regulation of AKT signaling have been suggested, T669A mutation of EGFR is sufficient to stop MEK inhibitor induced feedback activation of PI3K/AKT, suggesting that the feedback we describe herein is among the principal mechanisms controlling AKT activation in EGFR and HER influenced cancers. In addition to increased ERBB3 tyrosine phosphorylation, we also notice increased expression of total ERBB3 protein following MEK inhibition. This increase seems to be post transcriptional as no change in ERBB3 mRNA levels was seen with AG-1478 EGFR inhibitor AZD6244. We were not able to definitively establish the mechanism for increased expression of total ERBB3. But, we observed that increased ERBB3 expression was not entirely a result of increased tyrosine phosphorylation of ERBB3. Curiously, inhibition of ERK mediated phosphorylation of the threonine JM site internet sites were required for both total ERBB3 levels and increased phospho. For instance, expression of T669A EGFR in CHO KI cells and HCC827 cells led to enhanced basal ERBB3 expression and phosphorylation, that was not further augmented by AZD6244. This suggests that the increases in both total and phosho ERBB3 will be the result of increased dimer development between ERBB3 and EGFR, which results from reduction of inhibitory threonine phosphorylation within the JM domain of EGFR. Even though we believe that the information support such a design, it remains possible that phosphorylation of the EGFR JM area affects tyrosine phosphorylated and total ERBB3 levels with a mechanism perhaps not linked to heterodimer formation.