Lyn kinase and ZAP70 are substrates of PTPROt in B‐cells: Lyn inactivation by PTPROt sensitizes leukemia cells to VEGF‐R inhibitor pazopanib
- 5 April 2010
- journal article
- research article
- Published by Wiley in Journal of Cellular Biochemistry
- Vol. 110 (4), 846-856
- https://doi.org/10.1002/jcb.22593
Abstract
We have recently shown that the gene encoding the truncated form of protein tyrosine phosphatase receptor‐type O (PTPROt) expressed predominantly in hematopoietic cells is epigenetically silenced in human primary chronic lymphocytic leukemia (B‐CLL). To determine whether increased phosphorylation of the PTPROt substrates following PTPROt suppression alters signal transduction pathway(s) that impart a growth advantage to the leukemic lymphocytes, it is critical to discern the key substrates of PTPROt. Here, we used substrate‐trapping assay to identify two novel substrates of PTPROt, the tyrosine kinases Lyn and ZAP70. Both Lyn and ZAP70 were dephosphorylated by wild‐type PTPROt, but not by its catalytic site (CS) mutant. A critical phosphorylation site in Lyn, Y397, essential for its activity was dephosphorylated by PTPROt. Consequently, the activity of Lyn kinase was compromised when co‐expressed with PTPROt‐WT compared to vector control or upon co‐expression with PTPROt‐CS. Ectopic expression of PTPROt in Raji cells reduced phosphorylation of Lyn in the absence of any change in its protein levels. These results have revealed the physiological importance of PTPROt in regulating B‐cell receptor signaling at Lyn kinase. Further, ectopic expression of PTPROt also sensitized the cells to the VEGF‐R inhibitor Pazopanib. J. Cell. Biochem. 110: 846–856, 2010.Keywords
This publication has 44 references indexed in Scilit:
- Targeted Transgenic Expression of an Osteoclastic Transmembrane Protein-tyrosine Phosphatase in Cells of Osteoclastic Lineage Increases Bone Resorption and Bone Loss in Male Young Adult MicePublished by Elsevier BV ,2009
- CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cellsImmunological Reviews, 2009
- PTPROt Inactivates the Oncogenic Fusion Protein BCR/ABL and Suppresses Transformation of K562 CellsPublished by Elsevier BV ,2009
- ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemiaBlood, 2008
- Methylation and Silencing of Protein Tyrosine Phosphatase Receptor Type O in Chronic Lymphocytic LeukemiaClinical Cancer Research, 2007
- Protein tyrosine phosphatase function: the substrate perspectiveBiochemical Journal, 2007
- Role of Protein Tyrosine Phosphatases in CancerProgress in Nucleic Acid Research and Molecular Biology, 2006
- Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivoBlood, 2004
- Hepatocyte Growth Factor Receptor Tyrosine Kinase Met Is a Substrate of the Receptor Protein-tyrosine Phosphatase DEP-1Journal of Biological Chemistry, 2003
- Protein Tyrosine Phosphatase φ Regulates Paxillin Tyrosine Phosphorylation and Mediates Colony-Stimulating Factor 1-Induced Morphological Changes in MacrophagesMolecular and Cellular Biology, 2001