Functional Crosstalk Between EphB6 and EGFR

Abstract

The Eph receptor tyrosine kinases, and their ephrin ligands, are well known for actively affecting cancer development and progression. Among them, the kinase inactive member, EphB6, has gained much attention, as published reports observe that it is both upregulated or downregulated in different cancers, and can both promote or suppress the disease in different malignancies and within different molecular contexts. In an effort to dissect EphB6 functioning in cancer, we previously established an EphB6 interactome, which suggested collaboration between EphB6 and the pro-oncogenic ErbB receptors which are overexpressed in numerous tumor types and are also well known for promoting cancer development and progression. After discovering that EphB6 indeed interacts with two members of the ErbB family, EGFR and ErbB4, my research focused on investigating possible functional crosstalk between EphB6 and EGFR in two different cancer cell line models. I found that the EphB6-EGFR interaction occurs in cancer cells, is driven by the extracellular portions of EphB6, and is strengthened by stimulation with the EGFR ligand, EGF. Additionally, my experiments reveal that this interaction leads to EphB6 tyrosine phosphorylation, while at the same time enhancing EGFR activation, both in an EGF-dependent manner. Remarkably, I also discovered that this crosstalk between EphB6 and EGFR modulates EGFR-controlled signaling by increasing EGF-induced activation of the proliferation-promoting p90 ribosomal S6 kinase. In agreement, I observe that EphB6 enhances proliferation of cancer cells in response to EGF stimulation. Further, I observed that EphB6 increased cancer cells susceptibility to erlotinib, an anti-cancer drugs targeting EGFR. Finally, I found that EphB6 also acts in an EGFR-independent manner to suppress the Akt kinase. Overall, my work uncovers an entirely new mode of functioning for EphB6, in cancer, through EGFR, where EphB6 gives cancer cells a proliferation advantage by enhancing EGFR activation and signaling, while at the same time making these cells relatively more susceptible to anti-cancer drugs targeting EGFR. My findings therefore suggest that EphB6 expression might represent a marker of sensitivity of cancer cells to EGFR targeting therapeutic approaches, and that co-targeting EGFR and EphB6 requires careful assessment of models representing tumors sensitive, or resistant to EGFR inhibition.