Protein tyrosine phosphatase receptor-type O truncated (PTPROt) regulates SYK phosphorylation, proximal B-cell-receptor signaling, and cellular proliferation.
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, PTP receptor-type O truncated (PTPROt). PTPROt is a member of the PTPRO family (also designated GLEPP, PTP-Ø, 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 tyrosyl phosphorylation, activation of the associated adaptor proteins SHC and BLNK, and downstream signaling events, including calcium mobilization and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activation. PTPROt overexpression also inhibited lymphoma cell proliferation and induced apoptosis in the absence of BCR cross-linking, suggesting that the phosphatase modulates tonic BCR signaling.
Chen
Linfeng
L
Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
Juszczynski
Przemyslaw
P
Takeyama
Kunihiko
K
Aguiar
Ricardo C T
RC
Shipp
Margaret A
MA
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008223:Lymphoma / Q000473:pathology*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D000072377:Syk Kinase
D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C516868:PTPRU protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2