TULA proteins regulate activity of the protein tyrosine kinase Syk
TULA proteins regulate activity of the protein tyrosine kinase Syk
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DOI：
10.1002/jcb.21678
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发表时间：
2008-06-01
影响因子：
4
通讯作者：
Tsygankov, Alexander Y.
中科院分区：
文献类型：
--
作者：
Agrawal, Rachana;Carpino, Nick;Tsygankov, Alexander Y.
TULA 属于两个成员家族：TULA (STS-2) 是一种淋巴蛋白，而 STS-1/TULA-2 则广泛表达。 TULA 蛋白参与蛋白酪氨酸激酶 (PTK) 介导的信号传导调节。最初的实验并未完全揭示这些效应的分子机制，但表明两种 TULA 蛋白以相似的方式发挥作用。最近的研究表明，STS-1/TULA-2 可以使 PTK 去磷酸化。在这项研究中，我们分析了 TULA 蛋白对 Syk 的影响，Syk 是一种在淋巴信号传导中发挥重要作用的 PTK。首先，我们已经证明 TULA-2 在体内和体外都能降低 Syk 的酪氨酸磷酸化，并且 TULA-2 的完整磷酸酶结构域对于这种作用至关重要。我们还表明 TULA-2 表现出一定程度的底物特异性。我们的结果还表明，灭活的 TULA-2 会增加共转染细胞中 Syk 的酪氨酸磷酸化，从而过度表达这些蛋白质，从而作为显性失活形式抑制内源性 TULA-2 引起的 Syk 去磷酸化。此外，我们已经证明，与 TULA-2 相比，TULA 的磷酸酶活性可以忽略不计，并且这一发现与过表达 TULA 的细胞中 Syk 酪氨酸磷酸化的增加相关。这一结果与失活的 TULA-2 的显性负效应一致，认为 TULA 在该系统中充当 TULA-2 依赖性去磷酸化的负调节因子。总而言之，我们的研究结果表明 TULA 蛋白可能对 PTK 介导的信号传导产生相反的影响，并表明可能存在基于此特征的调节机制。
TULA belongs to a two-member family: TULA (STS-2) is a lymphoid protein, whereas STS-1/TULA-2 is expressed ubiquitously. TULA proteins were implicated in the regulation of signaling mediated by protein tyrosine kinases (PTKs). The initial experiments did not fully reveal the molecular mechanism of these effects, but suggested that both TULA proteins act in a similar fashion. It was shown recently that STS-1/TULA-2 dephosphorylates PTKs. In this study, we analyzed the effects of TULA proteins on Syk, a PTK playing an important role in lymphoid signaling. First, we have shown that TULA-2 decreases tyrosine phosphorylation of Syk in vivo and in vitro and that the intact phosphatase domain of TULA-2 is essential for this effect. We have also shown that TULA-2 exhibits a certain degree of substrate specificity. Our results also indicate that inactivated TULA-2 increases tyrosine phosphorylation of Syk in cells co-transfected to overexpress these proteins, thus acting as a dominant-negative form that suppresses dephosphorylation of Syk caused by endogenous TULA-2. Furthermore, we have demonstrated that phosphatase activity of TULA is negligible as compared to that of TULA-2 and that this finding correlates with an increase in Syk tyrosine phosphorylation in cells overexpressing TULA. This result is consistent with the dominant-negative effect of inactivated TULA-2, arguing that TULA acts in this system as a negative regulator of TULA-2-dependent dephosphorylation. To summarize, our findings indicate that TULA proteins may exert opposite effects on PTK-mediated signaling and suggest that a regulatory mechanism based on this feature may exist.