CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain. Receptor-type tyrosine-protein phosphatase kappa (PTPRK/RPTPk/DEP1) dephosphorylates EGFR, thereby inhibiting receptor ubiquitylation (Ub) by c-CBL, which decelerates the rate of receptor internalization and diminishes MAPK signals generated at the membrane and in endosomes. PTPRK disrupts physical association of ubiquitin ligase complex with EGFR and impairs its internalization (Tarcic et al. 2009, Xu et al. 2005).