title: The LAR protein tyrosine phosphatase enables PDGF β-receptor activation through attenuation of the c-Abl kinase activity.
abstract: 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 (LARΔP), and wt littermates, were stimulated with 20ng/ml PDGF-BB. In LAR phosphatase deficient MEFs, the phosphorylation of the PDGF β-receptor was surprisingly reduced, an event that was rescued by re-expression of wt LAR. The decreased phosphorylation of the PDGF β-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 β-receptor kinase activation. Downstream of receptor activation, phosphorylation of Akt and PLCγ were decreased in LARΔP MEFs, whereas Src and Erk MAP kinase pathways were less affected. The proliferation of LARΔP MEFs in response to PDGF-BB was also reduced. The inhibitory effect on the PDGF β-receptor in LARΔP cells was exerted via increased basal activity of c-Abl, since inhibition of c-Abl, by AG957 or siRNA, restored PDGF β-receptor phosphorylation. These observations suggest that LAR reduces the basal c-Abl activity thereby allowing for PDGF β-receptor kinase activation.
authors.affiliation: Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Johan
authors.initials: J
authors.lastname: Lennartsson
authors.forename: Wiljan
authors.initials: W
authors.lastname: Hendriks
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Carina
authors.initials: C
authors.lastname: Hellberg
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2