Nakamura K, Cambier J C
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
J Immunol. 1998 Jul 15;161(2):684-91.
Accumulating evidence indicates that the Src homology 2-containing tyrosine phosphatase 2 (SHP-2) plays an important role in signal transduction through receptor tyrosine kinase and cytokine receptors. In most models, SHP-2 appears to be a positive mediator of signaling. However, coligation of Fc gamma RIIB1 with B cell Ag receptors (BCR) inhibits BCR-mediated signaling by a mechanism that may involve recruitment of phosphatases SHP-1, SHP-2, and the SH2 containing inositol 5'phosphatase (SHIP) to the phosphorylated Fc gamma RIIB1 immunoreceptor tyrosine-based inhibitory motif. The role of SHP-2 in BCR-mediated cell activation and in Fc gamma RIIB1-mediated inhibitory signaling is unclear. In this study we assessed the association of SHP-2 with phosphotyrosine-containing cellular protein(s) before and after stimulation through these receptors. BCR stimulation induced the association of SHP-2 with a single major tyrosyl-phosphorylated molecule (pp120) that had an apparent molecular mass of 120 kDa. Coligation of Fc gamma RIIB1 with BCR led to a rapid decrease in SHP-2 association with pp120. Analysis of the subcellular localization of pp120 showed that the complex of SHP-2 and tyrosyl-phosphorylated p120 occurs predominantly in the cytosol. Furthermore, the binding of the two molecules was mediated by the interaction of tyrosyl-phosphorylated p120 with the SHP-2 N-terminal SH2 domain. These findings indicate that SHP-2 and pp120 function in BCR signaling, and this function may be inhibited by Fc gamma RIIB1 signaling.
越来越多的证据表明，含Src同源2结构域的酪氨酸磷酸酶2（SHP-2）在通过受体酪氨酸激酶和细胞因子受体的信号转导中起重要作用。在大多数模型中，SHP-2似乎是信号传导的正向介质。然而，FcγRIIB1与B细胞抗原受体（BCR）的共连接通过一种可能涉及将磷酸酶SHP-1、SHP-2和含SH2的肌醇5'磷酸酶（SHIP）募集到磷酸化的FcγRIIB1免疫受体酪氨酸抑制基序的机制来抑制BCR介导的信号传导。SHP-2在BCR介导的细胞活化和FcγRIIB1介导的抑制性信号传导中的作用尚不清楚。在本研究中，我们评估了在通过这些受体刺激之前和之后SHP-2与含磷酸酪氨酸的细胞蛋白之间的关联。BCR刺激诱导SHP-2与单个主要的酪氨酸磷酸化分子（pp120）结合，该分子的表观分子量为120 kDa。FcγRIIB1与BCR的共连接导致SHP-2与pp120的结合迅速减少。对pp120亚细胞定位的分析表明，SHP-2和酪氨酸磷酸化的p120复合物主要出现在细胞质中。此外，这两个分子的结合是由酪氨酸磷酸化的p120与SHP-2 N端SH2结构域的相互作用介导的。这些发现表明，SHP-2和pp120在BCR信号传导中起作用，并且这种作用可能被FcγRIIB1信号传导抑制。
