Submitted March 30, 2006
Accepted July 10, 2006
Protein Tyrosine Phosphatase Receptor-Type O Truncated (PTPROt) Regulates SYK Phosphorylation, Proximal B-Cell Receptor Signaling and Cellular Proliferation
Linfeng Chen, Przemyslaw Juszczynski, Kunihiko Takeyama, Ricardo C.T. Aguiar, and Margaret A. Shipp*
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
* Corresponding author; email: margaret_shipp{at}dfci.harvard.edu.
The strength and duration of B-cell receptor (BCR) signaling depends upon the balance between protein tyrosine kinase (PTK) activation and protein tyrosine phosphatase (PTP) inhibition. BCR-dependent activation of the SYK PTK initiates downstream signaling events and amplifies the original BCR signal. Although BCR-associated SYK phosphorylation is clearly regulated by PTPs, SYK has not been identified as a direct PTP substrate. Herein, we demonstrate that SYK is a major substrate of a tissue-specific and developmentally regulated PTP, PTPROt. PTPROt is a member of the PTPRO family (also designated GLEPP, PTP-
, PTP-oc and PTPu2), a group of highly conserved receptor-type PTPs that are thought to function as tumor suppressor genes. The overexpression of PTPROt inhibited BCR-triggered SYK tryosyl phosphorylation, activation of the associated adaptor proteins SHC and BLNK, and downstream signaling events including calcium mobilization and MAPK/ERK activation. PTPROt overexpression also inhibited lymphoma cell proliferation and induced apoptosis in the absence of BCR crosslinking, suggesting that the phosphatase modulates tonic BCR signaling.
