Raguz Josipa, Wagner Sebastian, Dikic Ivan, Hoeller Daniela
Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
FEBS Lett. 2007 Oct 2;581(24):4767-72. doi: 10.1016/j.febslet.2007.08.077. Epub 2007 Sep 11.
Suppressor of T-cell receptor signalling 1 and 2 (Sts-1 and 2) negatively regulate the endocytosis of receptor tyrosine kinases. The UBA domain of Sts-2 and SH3-dependent Cbl-binding are required for this function. Sts-1 and -2 also possess a PGM domain, which was recently reported to exhibit tyrosine phosphatase activity. Here, we demonstrate that the PGM of Sts-1, but not of Sts-2, dephosphorylates the EGFR at multiple tyrosines thereby terminating its signalling and endocytosis. In contrast to Sts-2 the UBA of Sts-1 did not contribute significantly to receptor stabilization. Thus, although Sts-1 and Sts-2 are structurally highly homologous and both inhibit ligand-induced EGFR degradation, their mechanisms of action differ significantly. As a consequence, Sts-1-containing receptor complexes are inactive, whereas Sts-2-containing complexes are signalling competent.
T细胞受体信号传导抑制因子1和2（Sts-1和2）对受体酪氨酸激酶的内吞作用起负向调节作用。Sts-2的泛素结合结构域（UBA）和依赖SH3的Cbl结合对于该功能是必需的。Sts-1和-2还具有一个磷酸甘油酸变位酶（PGM）结构域，最近有报道称该结构域具有酪氨酸磷酸酶活性。在此，我们证明Sts-1的PGM结构域而非Sts-2的PGM结构域可使表皮生长因子受体（EGFR）的多个酪氨酸去磷酸化，从而终止其信号传导和内吞作用。与Sts-2不同，Sts-1的UBA结构域对受体稳定性的贡献不大。因此，尽管Sts-1和Sts-2在结构上高度同源且都抑制配体诱导的EGFR降解，但其作用机制却有显著差异。结果，含有Sts-1的受体复合物无活性，而含有Sts-2的复合物具有信号传导能力。
