OVEREXPRESSION OF THE TRANSMEMBRANE TYROSINE PHOSPHATASE LAR ACTIVATES THE CASPASE PATHWAY AND INDUCES APOPTOSIS

Background: The protein tyrosine phosphatase family comprises transmem brane receptor-like and cytosolic forms. Although the exact biological functions of these enzymes are largely unknown, they are believed to counter-balance the effects of protein tyrosine kinases. We have previ ously identified and characterized a mammalian transmembrane protein t yrosine phosphatase, called LAR (leukocyte common antigen related gene ), whose expression is often associated with proliferating epithelial cells or epithelial progenitor cells. This study investigates the pote ntial role of LAR in the regulation of cell growth and death in mammal s. Results: We overexpressed in mammalian cells in culture either the full-length wild-type LAR or a truncation mutant containing only the e xtracellular domain of the molecule, and found that whereas the trunca ted LAR could be readily overexpressed in various cell lines, cells ov erexpressing the wild-type LAR were negatively selected. Using an indu cible expression system, we demonstrated that overexpression of the wi ld-type LAR, but not the truncated LAR, activated the caspase pathway directly and induced p53-independent apoptosis. Conclusion: Our data s uggest that LAR might regulate cellular signals essential for cell sur vival. Overproduction of LAR may tilt the balance between the tyrosine phosphorylation and dephosphorylation of proteins whose activities ar e critical for cell survival, and therefore lead to cell death. In add ition, our observations that overexpression of LAR induces cell death without affecting cell adhesion suggest that LAR may activate the casp ase pathway and induce cell death directly. This work is the first exa mple of the involvement of a receptor-like protein tyrosine phosphatas e in cell-death control and provides the basis for searching for molec ules and mechanisms linking signal transduction by protein tyrosine ph osphorylation to the caspase-mediated cell-death pathway.