Phosphorylation of PLCγ1 by EphA2 Receptor Tyrosine Kinase Promotes Tumor Growth in Lung Cancer

EphA2 receptor tyrosine kinase (RTK) is often expressed at high levels in cancer and has been shown to regulate tumor growth and metastasis across multiple tumor types, including non-small cell lung cancer. A number of signaling pathways downstream of EphA2 RTK have been identified; however, mechanisms of EphA2 proximal downstream signals are less well characterized. In this study, we used a yeast-two-hybrid screen to identify phospholipase C gamma 1 (PLC gamma 1) as a novel EphA2 interactor. EphA2 interacts with PLC gamma 1 and the kinase activity of EphA2 was required for phosphorylation of PLC gamma 1. In human lung cancer cells, genetic or pharmacologic inhibition of EphA2 decreased phosphorylation of PLC gamma 1 and loss of PLC gamma 1 inhibited tumor cell growth in vitro. Knockout of PLC gamma 1 by CRISPR-mediated genome editing also impaired tumor growth in a Kras(G12D)-p53-Lkb1 murine lung tumor model. Collectively, these data show that the EphA2-PLC gamma 1 signaling axis promotes tumor growth of lung cancer and provides rationale for disruption of this signaling axis as a potential therapeutic option.