TULA-2 Protein Phosphatase Suppresses Activation of Syk through the GPVI Platelet Receptor for Collagen by Dephosphorylating Tyr(P)346, a Regulatory Site of Syk

J Biol Chem. 2016 Oct 21;291(43):22427-22441. doi: 10.1074/jbc.M116.743732. Epub 2016 Sep 8.


Protein-tyrosine phosphatase TULA-2 has been shown to regulate receptor signaling in several cell types, including platelets. Platelets are critical for maintaining vascular integrity; this function is mediated by platelet aggregation in response to recognition of the exposed basement membrane collagen by the GPVI receptor, which is non-covalently associated with the signal-transducing FcRγ polypeptide chain. Our previous studies suggested that TULA-2 plays an important role in negatively regulating signaling through GPVI-FcRγ and indicated that the tyrosine-protein kinase Syk is a key target of the regulatory action of TULA-2 in platelets. However, the molecular basis of the down-regulatory effect of TULA-2 on Syk activation via FcRγ remained unclear. In this study, we demonstrate that suppression of Syk activation by TULA-2 is mediated, to a substantial degree, by dephosphorylation of Tyr(P)346, a regulatory site of Syk, which becomes phosphorylated soon after receptor ligation and plays a critical role in initiating the process that yields fully activated Syk. TULA-2 is capable of dephosphorylating Tyr(P)346 with high efficiency, thus controlling the overall activation of Syk, but is less efficient in dephosphorylating other regulatory sites of this kinase. Therefore, dephosphorylation of Tyr(P)346 may be considered an important "checkpoint" in the regulation of Syk activation process. Putative biological functions of TULA-2-mediated dephosphorylation of Tyr(P)346 may include deactivation of receptor-activated Syk or suppression of Syk activation by suboptimal stimulation.

Keywords: GPVI receptor; ITAM; TULA-2; platelet; protein phosphorylation; signaling; spleen tyrosine kinase (Syk); tyrosine-protein kinase (tyrosine kinase); tyrosine-protein phosphatase (tyrosine phosphatase).

MeSH terms

  • Animals
  • Blood Platelets / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Phosphorylation / physiology
  • Platelet Membrane Glycoproteins / genetics
  • Platelet Membrane Glycoproteins / metabolism*
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Syk Kinase / genetics
  • Syk Kinase / metabolism*


  • Platelet Membrane Glycoproteins
  • platelet membrane glycoprotein VI
  • Syk Kinase
  • Syk protein, mouse
  • Protein Tyrosine Phosphatases
  • TULA-2 protein, mouse