The human P zero‐related protein (hPZR) has a unique function in regulating cell migration. This activity is dependent on both its cytoplasmic immunoreceptor tyrosine inhibitory motif (ITIM) and its interaction with the tyrosine protein phosphatase, src homology phosphatase‐2 (SHP‐2). Here, using in silico and cDNA cloning approaches, we identify the murine ITIM‐containing hPZR ortholog, mPZR, together with its ITIM‐less isoform, mPZRb. We demonstrate that, like hPZR, these type 1 integral murine transmembrane isoforms are derived by differential splicing from a single gene transcription unit on mouse chromosome 1, and differ only in the sequence of their cytoplasmic domains. Importantly, mPZR mimicks hPZR functionally by accelerating SHP‐2‐mediated cell migration on fibronectin. Interestingly, we further demonstrate that although neither mPZR nor mPZRb is expressed in murine pluripotent embryonic stem cells, they first appear at approximately day 3 of blastocyst formation in vivo and of embryoid body formation in vitro. These studies thus provide the basis for defining the function of the mPZR isoforms in vivo, particularly with respect to their roles in regulating SHP‐2‐dependent cell migration during development. J. Cell. Biochem. 102: 955–969, 2007. © 2007 Wiley‐Liss, Inc.