Aman M J, Migone T S, Sasaki A, Ascherman D P, Zhu M h, Soldaini E, Imada K, Miyajima A, Yoshimura A, Leonard W J
Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1674, USA.
J Biol Chem. 1999 Oct 15;274(42):30266-72. doi: 10.1074/jbc.274.42.30266.
CIS is a cytokine-induced SH2-containing protein that was originally cloned as an interleukin (IL)-3-inducible gene. CIS is known to associate with the IL-3 receptor beta chain and erythropoietin receptor and to inhibit signaling mediated by IL-3 and erythropoietin. We now demonstrate that CIS also interacts with the IL-2 receptor beta chain (IL-2Rbeta). This interaction requires the A region of IL-2Rbeta (residues 313-382), which also mediates the association of IL-2Rbeta with Lck and Jak3. Correspondingly, CIS inhibits functions associated with both of these kinases: Lck-mediated phosphorylation of IL-2Rbeta and IL-2-mediated activation of Stat5. Thus, we demonstrate that CIS can negatively control at least two independent IL-2 signaling pathways. Although a functional SH2 binding domain of CIS was not required for its interaction with IL-2Rbeta in vitro, its phosphotyrosine binding capability was essential for the inhibitory action of CIS. On this basis, we have generated a mutant form of CIS protein with an altered SH2 domain that acts as a dominant negative and should prove useful in further understanding CIS action.
CIS是一种细胞因子诱导的含SH2蛋白，最初作为白细胞介素（IL）-3诱导基因被克隆。已知CIS与IL-3受体β链和促红细胞生成素受体相关联，并抑制由IL-3和促红细胞生成素介导的信号传导。我们现在证明CIS也与IL-2受体β链（IL-2Rβ）相互作用。这种相互作用需要IL-2Rβ的A区域（第313 - 382位氨基酸残基），该区域也介导IL-2Rβ与Lck和Jak3的结合。相应地，CIS抑制与这两种激酶相关的功能：Lck介导的IL-2Rβ磷酸化和IL-2介导的Stat5激活。因此，我们证明CIS可以负向控制至少两条独立的IL-2信号通路。虽然在体外CIS与IL-2Rβ相互作用不需要其功能性SH2结合结构域，但其磷酸酪氨酸结合能力对于CIS的抑制作用至关重要。在此基础上，我们构建了一种具有改变的SH2结构域的CIS蛋白突变体形式，其作为显性负性突变体，在进一步理解CIS作用方面应具有重要价值。
