Lyn kinase and ZAP70 are substrates of PTPROt in B-cells: Lyn inactivation by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib

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BlankLyn kinase and ZAP70 are substrates of PTPROt in B-cells: Lyn inactivation

by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib.

T Motiwala, J Datta, H Kutay, S Roy, and ST

J Cell Biochem, April 5, 2010; .

Department of Molecular and Cellular Biochemistry, College of Medicine, Ohio

State University, Columbus, Ohio 43210.

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.

© 2010 Wiley-Liss, Inc.

PMID: 20564182