We have isolated a mouse cDNA of 5.7 kb, encoding a new member of the family of receptor-like protein tyrosine phosphatases, termed mRPTP mu. The cDNA predicts a protein of 1432 amino acids (not including signal peptide) with a calculated Mr of 161,636. In addition, we have cloned the human homologue, hRPTP mu, which shows 98.7% amino acid identity to mRPTP mu. The predicted mRPTP mu protein consists of a 722 amino acid extracellular region, containing 13 potential N-glycosylation sites, a single transmembrane domain and a 688 amino acid intracellular part containing 2 tandem repeats homologous to the catalytic domains of other tyrosine phosphatases. The N-terminal extracellular part contains a region of about 170 amino acids with no sequence similarities to known proteins, followed by one Ig-like domain and 4 fibronectin type III-like domains. The intracellular part is unique in that the region between the transmembrane domain and the first catalytic domain is about twice as large as in other receptor-like protein tyrosine phosphatases. RNA blot analysis reveals a single transcript, that is most abundant in lung and present in much lower amounts in brain and heart. Transfection of the mRPTP mu cDNA into COS cells results in the synthesis of a protein with an apparent Mr of 195,000, as detected in immunoblots using an antipeptide antibody. The human RPTP mu gene is localized on chromosome 18pter-q11, a region with frequent abnormalities implicated in human cancer.