Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2
Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2
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DOI：
10.1042/bj20040103
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发表时间：
2004-09-01
影响因子：
4.1
通讯作者：
Bertoglio, J
中科院分区：
文献类型：
--
作者：
Arnaud, M;Mzali, R;Bertoglio, J
Gab2（Grb2 相关结合物-2）是 IRS（胰岛素受体底物）/Gab 衔接蛋白家族的成员，响应细胞因子或生长因子刺激而发生酪氨酸磷酸化，并作为许多信号转导效应子的对接平台，包括包含酪氨酸磷酸酶 SHP-2 [SH2 (Src 同源性 2) 结构域 酪氨酸磷酸酶]。在此，我们报道，在IL-2（白细胞介素2）刺激人T淋巴细胞后，SHP-2分别通过其N端和C端SH2结构域结合人Gab2的酪氨酸残基614和643。然而，Tyr-614 突变为苯丙氨酸就足以阻止 Gab2 募集 SHP-2。 Gab2 Tyr-614 --> Phe (Y614F) 突变体的表达（SHP-2 关联有缺陷）可阻止 ERK（细胞外信号调节激酶）激活和由 c-fos SRE（血清反应元件）驱动的荧光素酶报告质粒的表达，表明 SHP-2 与 Gab2 的相互作用是响应 IL-2 的 ERK 激活所必需的。对 IL-2 依赖性 SRE 诱导的进一步研究表明，RhoA GTPase 组成型活性突变体的表达与 IL-2 协同促进 SRE 驱动的转录，而显性失活突变体则降低 IL-2 反应。因此，响应 IL-2，SRE 的完全诱导需要分别针对 Ets-box 和 CArG-box 的 ERK 依赖性和 Rho 依赖性信号。我们还报道，Gab2/SHP-2 和 RhoA 之间对于 IL-2 依赖性 CArG 盒驱动转录的协同作用取决于 MEK（丝裂原激活蛋白激酶/ERK 激酶）激活，并且可能涉及血清反应因子共激活剂 MAL 的调节。因此，我们的研究为 Gab2 和 SHP-2 在 IL-2 信号转导中的作用提供了新的见解。
Gab2 (Grb2-associated binder-2), a member of the IRS (insulin receptor substrate)/Gab family of adapter proteins, undergoes tyrosine phosphorylation in response to cytokine or growth factor stimulation and serves as a docking platform for many signal-transduction effectors, including the tyrosine phosphatase SHP-2 [SH2 (Src homology 2)-domain-containing tyrosine phosphatase]. Here, we report that, following IL-2 (interleukin-2) stimulation of human T lymphocytes, SHP-2 binds tyrosine residues 614 and 643 of human Gab2 through its N- and C-terminal SH2 domains respectively. However, the sole mutation of Tyr-614 into phenylalanine is sufficient to prevent Gab2 from recruiting SHP-2. Expression of the Gab2 Tyr-614 --> Phe (Y614F) mutant, defective in SHP-2 association, prevents ERK (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos SRE (serum response element), indicating that interaction of SHP-2 with Gab2 is required for ERK activation in response to IL-2. Further investigation of IL-2-dependent induction of SRE showed that expression of a constitutively active mutant of the RhoA GTPase synergizes with IL-2 for SRE-driven transcription, whereas a dominant-negative mutant reduces the IL-2 response. Thus, in response to IL-2, full induction of the SRE requires ERK-dependent as well as Rho-dependent signals that target the Ets-box and the CArG-box respectively. We also report that the synergy between Gab2/SHP-2 and RhoA for IL-2-dependent CArG-box-driven transcription depends upon MEK (mitogen-activated protein kinase/ERK kinase) activation, and is likely to involve regulation of the serum response factor co-activator MAL. Our studies thus provide new insights into the role of Gab2 and SHP-2 in IL-2 signal transduction.