Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas.
BACKGROUND
LAR is a transmembrane receptor-like protein tyrosine phosphatase (PTP). Genetic studies of Drosophila LAR suggest that LAR may function to regulate cell adhesions or adhesion-mediated signal transduction. The over-expression of LAR in mammalian tissue culture cells does not affect cell adhesion but induces caspase-dependent apoptosis. This study investigates molecular mechanisms of LAR-induced apoptosis by searching for in vivo substrates of LAR which are responsible for LAR-induced apoptosis.


RESULTS
The over-expression of LAR in tissue culture cells specifically decreased the steady state protein level of p130Cas, a multifunctional signal assembly protein in signal transduction, by reducing the tyrosine phosphorylation and protein stability of p130Cas. The reduction of p130Cas protein level could be inhibited by tyrosine phosphatase inhibitors. Phosphatase domain-deleted mutant LARs had no effect on p130Cas. LAR also preferentially dephosphorylated p130Cas in vitro. Subcellularly, LAR and p130Cas were co-localized along stress fibres and at focal adhesions. LAR over-expression eliminated p130Cas from focal adhesions without affecting focal adhesion assembly. Restoring the level of p130Cas alleviated LAR-induced apoptosis.


CONCLUSIONS
p130Cas is an in vivo substrate of LAR. LAR specifically dephosphorylates and destabilizes p130Cas and may play a role in regulating cell adhesion-mediated cell survival. The function of p130Cas in focal adhesions may not be to regulate focal adhesion assembly and cell adhesion but rather to transduce the cell adhesion-generated signals which are essential for cell survival.
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D005786:Gene Expression Regulation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism