Protein tyrosine phosphatases (PTPs) play a fundamental role in regulating diverse cellular processes. PRL-1 is a unique nuclear PTP that is induced in mitogen-stimulated cells and regenerating liver. Database searches using the PRL-1 sequence led to the identification of mouse PRL-2 and PRL-3 which exhibit 87% and 76% identity to mouse PRL-1 in their amino acid sequences. All three mouse PRL proteins contain a C-terminal consensus sequence for prenylation. All PRL proteins bear significant sequence homology to Cdc14p and the recently identified tumor suppressor PTEN/MMAC1, in regions other than the conserved PTP signature motif. The nucleotide sequences of the coding regions of mouse PRL-2 and PRL-3 are, respectively, 71% and 62%, identical to mouse PRL-1, while the 5' un-translated regions of mouse PRL-1, PRL-2, and PRL-3 are much more divergent. Northern blot analysis revealed that PRL-2 is preferentially expressed in skeletal muscle, while PRL-3 is preferentially expressed in both skeletal muscle and heart, although both PRL-2 and PRL-3 are expressed at lower levels in other tissues.