Lack of evidence that CYTH2/ARNO functions as a direct intracellular EGFR activator

EGFR signaling instructs complex cellular programs through its tyrosine kinase activity, which therefore needs to be tightly controlled. A key regulatory step entails the conversion of EGFR from a default inactive conformation to one endowed with catalytic activity. This structural transition is initiated by ligand-dependent dimerization of the receptor extracellular domain, which in turn promotes asymmetric dimerization and attendant allosteric activation of juxtaposed EGFR tyrosine kinase domains (TKD). A study published in Cell (Bill et al., 2010) expanded this model, suggesting that Cytohesins, upon binding to the EGFR TKD, stabilize a catalytically optimal conformation of TKD dimers, thereby enhancing EGFR signaling. Since EGFR activation is suppressed by activity-dependent binding of MIG6 to the TKD, we hypothesized that MIG6 and Cytohesins bind the EGFR TKD competitively. While pursuing this hypothesis, we did not observe significant regulation of EGFR activity by Cytohesins in intact cells as well as cell-free assays.