Fig. 7. Model for EGFR-EphA2 heterodimerization.

When PIP₂ levels are normal, EGFR (blue) and EphA2 (orange) do not interact in the absence of ligand. When EGF is present, active heterodimer forms in which EGFR Y1068 and EphA2 S897 are phosphorylated. The active conformation of the ICDs allows a more open EphA2 kinase domain with the EGFR JM free to move away from the membrane. Under increased PIP₂ conditions, PIP₂ promotes inactive heterodimer formation. The inactive dimer is likely stabilized by the EGFR JM electrostatically interacting with the membrane, and the EGFR ICD is pulled toward the membrane to close the EphA2 kinase domain.