P0-related
protein (PZR), a Noonan and
Leopard syndrome target, is a member of the transmembrane
Immunoglobulin superfamily. Its cytoplasmic tail contains two immune-
receptor tyrosine-based inhibitory motifs (ITIMs), implicated in adhesion-dependent signaling and regulating cell adhesion and motility. PZR promotes cell migration on the extracellular matrix (ECM) molecule,
fibronectin, by interacting with SHP-2 (Src homology-2 domain-containing
protein tyrosine phosphatase-2), a molecule essential for skeletal development and often mutated in Noonan and
Leopard syndrome patients sharing overlapping
musculoskeletal abnormalities and cardiac defects. To further explore the role of PZR, we assessed the expression of PZR and its ITIM-less
isoform, PZRb, in human bone marrow mesenchymal stromal cells (hBM MSC), and its ability to facilitate adhesion to and spreading and migration on various ECM molecules. Furthermore, using
siRNA knockdown, confocal microscopy, and immunoprecipitation assays, we assessed PZR and PZRb interactions with β1
integrins. PZR was the predominant
isoform in hBM MSC. Migrating hBM MSCs interacted most effectively with
fibronectin and required the association of PZR, but not PZRb, with the
integrin, VLA-5(α5β1), leading to modulation of
focal adhesion kinase phosphorylation and
vinculin levels. This raises the possibility that dysregulation of PZR function may modify hBM MSC migratory behavior, potentially contributing to skeletal abnormalities.