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.

Reppschläger, Kevin; Gosselin, Jeanne; Dangelmaier, Carol; Thomas, Dafydd; Carpino, Nick; McKenzie, Steven E.; Kunapuli, Satya P.; Tsygankov, Alexander Y.

doi:10.1074/jbc.a116.743732

Cited by 5 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A positive effect of dKO on TCR‐induced tyrosine phosphorylation of Zap‐70 in T cells (Carpino et al, ; Mikhailik et al, ) and the dependence of this effect on the phosphatase activity of TULA‐2 shown in reconstitution experiments using the inactivated form of TULA‐2 (Mikhailik et al, ) argue that the effect of TULA‐family proteins, at least that of TULA‐2, depends on the PTP activity. These results are in agreement with findings made in platelets and platelet signaling‐mimicking systems in which the key role of PTP activity of TULA‐2 has been demonstrated (X. Chen et al, ; Reppschlager et al, ; Thomas et al, ). A substantial degree of sequence similarity between TULA and TULA‐2 (Figure and Table ) and especially the conserved nature of the amino acid residues essential for their enzymatic activity (Y. Chen, Jakoncic, Carpino, et al, ; Y. Chen, Jakoncic, Parker, et al, ) support the idea that the regulatory effects of both TULA and TULA‐2 depend on their PTP activity.…”

Section: Functions Of Ubash3/tula‐family Proteinssupporting

confidence: 92%

“…The data on TULA‐2 substrate specificity suggested that Syk pY346 is the best substrate site of TULA‐2 on Syk, while Syk pY519/pY520 (murine numbering is used in both cases) is insensitive to TULA‐2‐dependent hydrolysis (X. Chen et al, ). Considering that pY346 is a key regulatory site of Syk (Gradler et al, ; Groesch et al, ; Hong, Yankee, Harrison, & Geahlen, ; Simon, Vanes, Geahlen, & Tybulewicz, ; Tsang et al, ), the role of this site in the downregulation of Syk and Syk‐mediated signaling by TULA‐2 has been evaluated in a study that utilized (a) platelets and (b) cells mimicking platelet GPVI signaling by coexpression of a chimeric receptor containing the cytoplasmic tail of FcRγ, the signal‐transducing part of the GPVI complex, TULA‐2 and Syk—either WT or mutant, lacking several potentially important regulatory tyrosine sites in various combinations (Reppschlager et al, ). First, this study demonstrated that Syk is the primary target of TULA‐2 in platelets and that a decrease in tyrosine phosphorylation of proteins mediating GPVI signaling is a result of TULA‐2‐dependent downregulation of Syk, which is essential for triggering this entire pathway (Figure ).…”

Section: Functions Of Ubash3/tula‐family Proteinsmentioning

confidence: 99%

See 1 more Smart Citation

TULA‐family proteins: Jacks of many trades and then some

Tsygankov

2018

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

UBASH3/STS/TULA is a novel two-member family, which exerts several key regulatory effects in multiple cell types. UBASH3B/STS-1/TULA-2 is a highly active protein tyrosine phosphatase; its major target appears to be a specific regulatory site of protein tyrosine kinases of the Syk family, dephosphorylation of which inhibits Syk and Zap-70 kinases and suppresses receptor signaling mediated by these kinases. UBASH3A/STS-2/TULA exhibits substantial homology to UBASH3B/STS-1/TULA-2, but possesses only a small fraction of phosphatase activity of UBASH3B/STS-1/TULA-2, and thus, its regulatory effect may be based also on the phosphatase-independent mechanisms. Critical physiologic effects of these proteins have been demonstrated in T lymphocytes, platelets, stem cells, and other important cell types. These proteins have also been shown to play a key role in such pathologic conditions as autoimmunity, cancer, and thrombosis. The review focuses on the recent studies of this important family of cellular regulators.

show abstract

Section: Functions Of Ubash3/tula‐family Proteinssupporting

confidence: 92%

Section: Functions Of Ubash3/tula‐family Proteinsmentioning

confidence: 99%

TULA‐family proteins: Jacks of many trades and then some

Tsygankov

2018

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…46 In platelets, SYK is primarily dephosphorylated by UBASH3B/TULA-2, inducing a negative regulation of GPVI signaling. 43,47 Notably, the regulated phosphorylation site is within the ubiquitin binding domain and thus could potentially modulate binding of ubiquitinated proteins.…”

Section: Ubiquitin Signaling Pathwaysmentioning

confidence: 99%

Temporal quantitative phosphoproteomics of ADP stimulation reveals novel central nodes in platelet activation and inhibition

Beck

Geiger²,

Gambaryan

et al. 2017

Blood

112

160

View full text Add to dashboard Cite

Key Points• Temporal profiles of .4000 phosphopeptides after stimulating human platelets (a) with ADP and (b) consecutively with ADP and Iloprost.• Reciprocal phosphorylation profiles of ADP and Iloprost point to central players of platelet homeostasis.Adenosine diphosphate (ADP) enhances platelet activation by virtually any other stimulant to complete aggregation. It binds specifically to the G-protein-coupled membrane receptors P2Y1 and P2Y12, stimulating intracellular signaling cascades, leading to integrin aIIbb3 activation, a process antagonized by endothelial prostacyclin. P2Y12 inhibitors are among the most successful antiplatelet drugs, however, show remarkable variability in efficacy. We reasoned whether a more detailed molecular understanding of ADP-induced protein phosphorylation could identify (1) critical hubs in platelet signaling toward aggregation and (2) novel molecular targets for antiplatelet treatment strategies. We applied quantitative temporal phosphoproteomics to study ADP-mediated signaling at unprecedented molecular resolution. Furthermore, to mimic the antagonistic efficacy of endothelial-derived prostacyclin, we determined how Iloprost reverses ADP-mediated signaling events. We provide temporal profiles of 4797 phosphopeptides, 608 of which showed significant regulation. Regulated proteins are implicated in well-known activating functions such as degranulation and cytoskeletal reorganization, but also in less well-understood pathways, involving ubiquitin ligases and GTPase exchange factors/GTPaseactivating proteins (GEF/GAP). Our data demonstrate that ADP-triggered phosphorylation occurs predominantly within the first 10 seconds, with many short rather than sustained changes. For a set of phosphorylation sites (eg, PDE3A Ser312 , CALDAG-GEFI Ser587 , ENSA Ser109 ), we demonstrate an inverse regulation by ADP and Iloprost, suggesting that these are central modulators of platelet homeostasis. This study demonstrates an extensive spectrum of human platelet protein phosphorylation in response to ADP and Iloprost, which inversely overlap and represent major activating and inhibitory pathways. (Blood. 2017;129(2):e1-e12)

show abstract

“…Given that DUSP3 positively regulates Syk and hence CLEC-2 signaling, it might be positively regulated by GPCRs. Another possible phosphatase could be T-cell ubiquitin ligand-2 (TULA-2), which dephosphorylates Syk at Tyr-346, thereby inactivating Syk (39,40). Hence, in a possible scenario, the G q -PLC␤-PKC pathway might lead to inhibition of TULA-2 by a PKC-dependent phosphorylation, thereby blocking its negative regulatory activity on Syk.…”

Section: Novel Cross-talk Mechanism In Plateletsmentioning

confidence: 99%

Gq pathway regulates proximal C-type lectin-like receptor-2 (CLEC-2) signaling in platelets

Badolia¹,

Inamdar²,

Manne³

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Platelets play a key role in the physiological hemostasis or pathological process of thrombosis. Rhodocytin, an agonist of the C-type lectin-like receptor-2 (CLEC-2), elicits powerful platelet activation signals in conjunction with Src family kinases (SFKs), spleen tyrosine kinase (Syk), and phospholipase γ2 (PLCγ2). Previous reports have shown that rhodocytin-induced platelet aggregation depends on secondary mediators such as thromboxane A2 (TxA2) and ADP, which are agonists for G-protein-coupled receptors (GPCRs) on platelets. How the secondary mediators regulate CLEC-2-mediated platelet activation in terms of signaling is not clearly defined. In this study, we report that CLEC-2-induced Syk and PLCγ2 phosphorylation is potentiated by TxA2 and that TxA2 plays a critical role in the most proximal event of CLEC-2 signaling, the CLEC-2 receptor tyrosine phosphorylation. We show that the activation of other GPCRs, such as the ADP receptors and protease-activated receptors, can also potentiate CLEC-2 signaling. By using the specific G inhibitor, UBO-QIC, or G knock-out murine platelets, we demonstrate that G signaling, but not other G-proteins, is essential for GPCR-induced potentiation of Syk phosphorylation downstream of CLEC-2. We further elucidated the signaling downstream of G and identified an important role for the PLCβ-PKCα pathway, possibly regulating activation of SFKs, which are crucial for initiation of CLEC-2 signaling. Together, these results provide evidence for novel G-PLCβ-PKCα-mediated regulation of proximal CLEC-2 signaling by G-coupled receptors.

show abstract

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.

Cited by 5 publications

References 0 publications

TULA‐family proteins: Jacks of many trades and then some

TULA‐family proteins: Jacks of many trades and then some

Temporal quantitative phosphoproteomics of ADP stimulation reveals novel central nodes in platelet activation and inhibition

Gq pathway regulates proximal C-type lectin-like receptor-2 (CLEC-2) signaling in platelets

Contact Info

Product

Resources

About