State Key Laboratory of Molecular and Cellular Biology, Institute of Molecular Biology and Genetics, 150 Zabolotnogo Street, Kyiv 03680, Ukraine.
Cell Signal. 2013 Jan;25(1):33-40. doi: 10.1016/j.cellsig.2012.09.011. Epub 2012 Sep 10.
Latent Membrane Protein 2A (LMP2A) is an Epstein-Barr virus-encoded protein that is important for the maintenance of latent infection. Its activity affects cellular differentiation, migration, proliferation and B cell survival. LMP2A resembles a constitutively activated B cell antigen receptor and exploits host kinases to activate a set of downstream signaling pathways. In the current study we demonstrate the interaction of LMP2A with intersectin 1 (ITSN1), a key endocytic adaptor protein. This interaction occurs via both the N- and C-tails of LMP2A and is mediated by the SH3 domains of ITSN1. Additionally, we identified the Shb adaptor and the Syk kinase as novel binding ligands of ITSN1. The Shb adaptor interacts simultaneously with the phosphorylated tyrosines of LMP2A and the SH3 domains of ITSN1 and mediates indirect interaction of ITSN1 to LMP2A. Syk kinase promotes phosphorylation of both ITSN1 and Shb adaptors in LMP2A-expressing cells. In contrast to ITSN1, Shb phosphorylation depends additionally on Lyn kinase activity. Considering that Shb and ITSN1 are implicated in various receptor tyrosine kinase signaling, our results indicate that LMP2A can affect a number of signaling pathways by regulating the phosphorylation of the ITSN1 and Shb adaptors.
潜伏膜蛋白 2A（LMP2A）是 Epstein-Barr 病毒编码的一种蛋白，对于维持潜伏感染至关重要。其活性影响细胞分化、迁移、增殖和 B 细胞存活。LMP2A 类似于组成性激活的 B 细胞抗原受体，并利用宿主激酶激活一系列下游信号通路。在本研究中，我们证明了 LMP2A 与交叉蛋白 1（ITSN1）的相互作用，ITSN1 是一种关键的内吞衔接蛋白。这种相互作用通过 LMP2A 的 N 端和 C 端发生，并由 ITSN1 的 SH3 结构域介导。此外，我们还确定了 Shb 衔接蛋白和 Syk 激酶是 ITSN1 的新结合配体。Shb 衔接蛋白同时与 LMP2A 的磷酸化酪氨酸和 ITSN1 的 SH3 结构域相互作用，并介导 ITSN1 与 LMP2A 的间接相互作用。Syk 激酶促进 LMP2A 表达细胞中 ITSN1 和 Shb 衔接蛋白的磷酸化。与 ITSN1 不同，Shb 磷酸化还依赖于 Lyn 激酶活性。考虑到 Shb 和 ITSN1 参与各种受体酪氨酸激酶信号转导，我们的结果表明，LMP2A 可以通过调节 ITSN1 和 Shb 衔接蛋白的磷酸化来影响许多信号通路。
