SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1*
SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1*
复制标题
SHP-2 通过磷脂酶 Cγ1* 的磷酸化调节 Interleukin-1 诱导的 Ca2+ 通量和 ERK 激活
DOI：
10.1074/jbc.m410462200
复制
发表时间：
2005
影响因子：
4.8
通讯作者：
C. McCulloch
中科院分区：
文献类型：
--
作者：
Qin Wang;G. Downey;M. T. Herrera;A. Kapus;C. McCulloch
白细胞介素-1（IL-1）信号传导依赖于粘着斑，粘着斑是富含酪氨酸激酶和磷酸酶的结构。由于非受体酪氨酸磷酸酶Src同源2结构域的蛋白酪氨酸磷酸酶-2（SHP-2）在粘着斑中富集，并且IL-1诱导的ERK激活需要增加的Ca 2+，我们确定SHP-2是否调节IL-1诱导的Ca 2+信号传导。在SHP-2缺陷的成纤维细胞中，IL-1诱导的Ca 2+信号传导和ERK激活与表达SHP-2的细胞相比显著减少。IL-1诱导的Ca 2+释放从内质网发生在附近的粘着斑，并强烈抑制磷脂酶C（PLC）的催化活性的阻断。免疫沉淀和免疫染色显示，SHP-2、内质网特异性蛋白钙连接蛋白和PLCγ1与局灶性粘连相关;然而，这些相关性和IL-1诱导的ERK激活在细胞接种在非整合素基质上后消失。IL-1促进SHP-2和PLCγ1的磷酸化。IL-1诱导的PLCγ1磷酸化在SHP-2缺陷细胞中减弱，但通过稳定转染SHP-2恢复。BAPTA/AM（1，2-bis（2-aminophenoxy）ethane-N，N，N′，N′-tetraacetic acid tetrakis（acetoxymethyl ester））阻断IL-1诱导的SHP-2和PLCγ1的磷酸化，表明Ca 2+、SHP-2和PLCγ1在IL-1信号转导中相互依赖的相互作用。SHP-2在IL-1诱导的PLCγ1磷酸化过程中起重要作用，从而增强IL-1诱导的Ca ~（2+）释放和ERK激活。与内质网共定位的局灶性粘连可能提供ERK激活所需的分子分期位点。
Interleukin-1 (IL-1) signaling is dependent on focal adhesions, structures that are enriched with tyrosine kinases and phosphatases. Because the non-receptor tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) is enriched in focal adhesions and IL-1-induced ERK activation requires increased Ca2+, we determined whether SHP-2 modulates IL-1-induced Ca2+ signaling. In SHP-2-deficient fibroblasts, IL-1-induced Ca2+ signaling and ERK activation were markedly diminished compared with cells expressing SHP-2. IL-1-induced Ca2+ release from the endoplasmic reticulum occurred in the vicinity of focal adhesions and was strongly inhibited by the blockage of phospholipase C (PLC) catalytic activity. Immunoprecipitation and immunostaining showed that SHP-2, the endoplasmic reticulum-specific protein calnexin, and PLCγ1 were associated with focal adhesions; however, these associations and IL-1-induced ERK activation dissipated after cells were plated on non-integrin substrates. IL-1 promoted phosphorylation of SHP-2 and PLCγ1. IL-1-induced phosphorylation of PLCγ1 was diminished in SHP-2-deficient cells but was restored by stable transfection with SHP-2. BAPTA/AM (1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester)) blocked IL-1-induced phosphorylation of SHP-2 and PLCγ1, indicating mutually dependent interactive roles for Ca2+, SHP-2, and PLCγ1 in IL-1 signaling. We conclude that SHP-2 is critical for IL-1-induced phosphorylation of PLCγ1 and thereby enhances IL-1-induced Ca2+ release and ERK activation. Focal adhesions co-localizing with the endoplasmic reticulum may provide molecular staging sites required for ERK activation.
影响因子：
5.3
作者：
E. Oh;Haihua Gu;T. M. Saxton;J. Timms;S. Hausdorff;E. Frevert;B. Kahn;T. Pawson;B. Neel;Sheila M. Thomas
通讯作者：
E. Oh;Haihua Gu;T. M. Saxton;J. Timms;S. Hausdorff;E. Frevert;B. Kahn;T. Pawson;B. Neel;Sheila M. Thomas