Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade
Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade
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DOI：
10.1128/mcb.22.12.4073-4085.2002
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发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Feig, LA
中科院分区：
文献类型：
--
作者：
Buchsbaum, RJ;Connolly, BA;Feig, LA
Tiam 1和Ras-GRF 1是激活Rac GT3的鸟嘌呤核苷酸交换因子（GEF）。这两种GEF具有相似的N-末端区域，其含有普列克底物蛋白同源结构域，随后是卷曲螺旋和一起起作用以允许调节GEF活性的额外序列。在这里，我们表明，这两种蛋白质的N-末端区域结合到支架蛋白IB 2/JIP 2。IB 2/JIP 2是p38促分裂原活化蛋白（MAP）激酶级联的支架，因为它结合Rac靶标MLK 3、MAP激酶激酶MKK 3和p38 MAP激酶。IB 2/JIP 2在细胞中的表达增强了Tiam 1或Ras-GRF 1激活p38 MAP激酶级联而不是JNK MAP激酶级联的能力。此外，Tiam 1或Ras-GRF 1与IB 2/JIP 2的结合增加了细胞中p38 MAP激酶信号盒组分与IB 2/JIP 2的结合，并激活支架相关的p38。这些发现意味着Tiam 1和Ras-GRF 1可以通过它们与结合许多已知Rac效应子途径之一的组分的支架形成复合物的能力来促进Rac信号传导特异性。
Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.