A novel histidine tyrosine phosphatase, TULA-2, associates with Syk and negatively regulates GPVI signaling in platelets.
T-cell ubiquitin ligand-2 (TULA-2) is a recently discovered histidine tyrosine phosphatase thought to be ubiquitously expressed. In this work, we have investigated whether TULA-2 has a key role in platelet glycoprotein VI (GPVI) signaling. This study indicates that TULA-2 is expressed in human and murine platelets and is able to associate with Syk and dephosphorylate it. Ablation of TULA-2 resulted in hyperphosphorylation of Syk and its downstream effector phospholipase C-γ2 as well as enhanced GPVI-mediated platelet functional responses. In addition, shorter bleeding times and a prothrombotic phenotype were observed in mice lacking TULA-2. We therefore propose that TULA-2 is the primary tyrosine phosphatase mediating the dephosphorylation of Syk and thus functions as a negative regulator of GPVI signaling in platelets.
Thomas
Dafydd H
DH
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Getz
Todd M
TM
Newman
Tiffanny N
TN
Dangelmaier
Carol A
CA
Carpino
Nick
N
Kunapuli
Satya P
SP
Tsygankov
Alexander Y
AY
Daniel
James L
JL
D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase
D047908:Intracellular Signaling Peptides and Proteins; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse; C489397:UBASH3B protein, human; D051966:Phospholipase C gamma; D002118:Calcium