The LAR protein tyrosine phosphatase enables PDGF beta-receptor activation through attenuation of the c-Abl kinase activity.

The receptor tyrosine phosphatase (RPTP) LAR negatively regulates the activity of several receptor tyrosine kinases. To investigate if LAR affects the platelet-derived growth factor (PDGF) receptor signaling, mouse embryonic fibroblasts (MEFs) from mice where the LAR phosphatase domains were deleted (LARDeltaP), and wt littermates, were stimulated with 20ng/ml PDGF-BB. In LAR phosphatase deficient MEFs, the phosphorylation of the PDGF beta-receptor was surprisingly reduced, an event that was rescued by re-expression of wt LAR. The decreased phosphorylation of the PDGF beta-receptor was observed independent of ligand concentration and occurred on all tyrosine residues, as determined by immunoblotting analysis using site-selective phosphotyrosine antibodies. This suggests that LAR is required for full PDGF beta-receptor kinase activation. Downstream of receptor activation, phosphorylation of Akt and PLCgamma were decreased in LARDeltaP MEFs, whereas Src and Erk MAP kinase pathways were less affected. The proliferation of LARDeltaP MEFs in response to PDGF-BB was also reduced. The inhibitory effect on the PDGF beta-receptor in LARDeltaP cells was exerted via increased basal activity of c-Abl, since inhibition of c-Abl, by AG957 or siRNA, restored PDGF beta-receptor phosphorylation. These observations suggest that LAR reduces the basal c-Abl activity thereby allowing for PDGF beta-receptor kinase activation