The nuclear accumulation of a variant epidermal growth factor receptor (EGFR) lacking the transmembrane domain requires coexpression of a full-length EGFR.

Both the epidermal growth factor (EGF) and its receptor (EGFR) accumulate in the nucleoplasm during liver regeneration. This localization in a nonmembraneous compartment presents a challenge in that the standard form of EGFR is a transmembrane protein and suggests the existence of a variant, soluble form of EGFR. To investigate the localization of such a putative EGFR splice variant, we generated a transmembrane-devoid form of EGFR. We placed this transmembrane-negative [TM(-)] EGFR construct and full-length wild-type (wt) EGFR either in a retroviral transfection vector or in an inducible expression vector. Mouse 3T3 cells, which express endogenous EGFR, were transfected with the TM(-) EGFR construct. The expression of these TM(-) EGFR, detected with a specific antibody against human EGFR using a confocal laser-scanning microscope, was predominantly found in the cytoplasm with no nuclear localization. After an overnight incubation with EGF the TM(-) EGFR accumulated in the nucleus. In mouse NR6 cells, which lack endogenous EGFR, transfected TM(-) EGFR were found in the cytoplasm, but incubation with EGF did not result in a nuclear accumulation of TM(-) EGFR. However, NR6 cells transfected with both TM(-) EGFR and wt EGFR showed nuclear accumulation after EGF treatment. These results suggest that both the wt EGFR and the TM(-) EGFR are required for nuclear accumulation of TM(-) EGFR and may implicate a model of homotypic recognition and translocation of a splice variant of EGFR.