Protein-protein interactions play an important role in the specificity of cellular signaling cascades. By using the yeast two-hybrid system, a specific interaction was identified between the second PDZ domain of the cytosolic protein tyrosine phosphatase hPTP1E and a novel protein, which was termed ZRP-1 to indicate its sequence similarity to the Zyxin protein family. The mRNA encoding this protein is distributed widely in human tissues and contains an open reading frame of 1428 base pairs, predicting a polypeptide of 476 amino acid residues. The deduced protein displays a prolinerich amino-terminal region and three double zinc finger LIM domains at its carboxyl terminus. The specific interaction of this novel protein with the second PDZ domain of hPTP1E was demonstrated both in vitro, using bacterially expressed proteins, and in vivo, by co-immunoprecipitation studies. Deletion analysis indicated that an intact carboxyl terminus is required for its interaction with the second PDZ domain of hPTP1E in the yeast two-hybrid system and suggested that other sequences, including the LIM domains, also participate in the interaction. The genomic organization of the ZRP-1 coding sequence is identical to that of the lipoma preferred partner gene, another Zyxin-related protein, suggesting that the two genes have evolved from a recent gene duplication event.Protein-protein interactions play a crucial role in maintaining the normal function of cells. Such interactions are important in the transmission of signals within the cell. Scaffolding, anchoring, and adaptor proteins, which bring together the various signaling molecules through such interactions, are determinant in fine-tuning these pathways and often contain modular structural domains mediating protein-protein interactions (1-3). A partial list of these domains include Src homology 2 and 3 (SH2 and SH3) domains (4), Tyr(P) binding domains (5), pleckstrin homology domain (6, 7), and PDZ domain (8, 9).PDZ domains consist of a motif of approximately 90 amino acid residues, found in one or multiple copies in a variety of signaling proteins. This domain derives its name from the three proteins originally shown to contain these sequences as follows: post-synaptic density protein, PSD-95 (10), the Drosophila septate junction protein discs-large tumor suppressor, Dlg (11), and the epithelial tight junction protein, ZO-1 (12). Other PDZ domain-containing proteins include nitric oxide synthase (13), the Drosophila dishevelled protein, Dsh (14), the channel-interacting PDZ domain protein (15), etc. (for reviews see Refs. 9 and 16).PDZ domains have also been found in a subfamily of protein tyrosine phosphatases (PTPs), 1 which includes PTPH1 (17), PTPMEG (18), and hPTP1E (19). The latter, also called PTP-BAS, PTPL1, and FAP-1, is a cytosolic PTPase and contains five PDZ domains in addition to a single tyrosine phosphatase catalytic domain. This protein also contains other distinct structural elements including a band 4.1 homology domain and five PEST regions (19 -22). A recent st...