Using the basolateral mutant PS of the normally apical neurotrophin receptor p75 (p75NTR) we have identified two cytoplasmic determinants responsible for this reversed localization in the human intestinal cell line, Caco2. These signals are based on two consecutive leucines (322-323) and a tyrosine (Y308). Truncation of the cytoplasmic tail removing the two leucines or their replacement by alanines led to a nonpolarized expression of the resulting mutants in Caco2 cells. To our surprise, the same mutations had no effect on the basolateral localization of the mutant PS in MDCK cells. In MDCK cells, the basolateral localization was entirely dependent on a cytoplasmic tyrosine Y308, while in Caco-2 cells this tyrosine signal was functional as a basolateral signal only when the cytoplasmic domain of PS was truncated shortly after it. These data indicate for the first time that there is a differential recognition of basolateral signals between MDCK and Caco-2 cells.