Uncoupling ligand-dependent and -independent mechanisms for mitogen-activated protein kinase activation by the murine Ron receptor tyrosine kinase.
Uncoupling ligand-dependent and -independent mechanisms for mitogen-activated protein kinase activation by the murine Ron receptor tyrosine kinase.
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鼠 Ron 受体酪氨酸激酶解偶联丝裂原激活蛋白激酶激活的配体依赖性和非依赖性机制。
DOI：
10.1074/jbc.m505737200
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Correll,PamelaH
中科院分区：
文献类型：
--
作者：
Wei,Xin;Ni,Shuang;Correll,PamelaH
受体酪氨酸激酶 (RTK) 通过同源生长因子受体诱导的二聚化和自磷酸化激活下游信号传导。 RTK 的过度表达可由于在没有配体的情况下二聚化增加而导致组成型激活，并且下游信号被认为与配体诱导的信号相同。我们已经证明，鼠 Ron (mRon) 受体酪氨酸激酶表现出独立于两个对接位点酪氨酸的 MAP 激酶途径的组成型激活，而在没有这些酪氨酸的情况下，响应配体（巨噬细胞刺激蛋白）的该途径的激活被消除。此外，我们还确定了激酶结构域内的三个酪氨酸（Tyr-1175、Tyr-1265 和 Tyr-1294），它们在 mRon 控制组成型 Erk 激活中发挥着关键但重叠的作用。这三个酪氨酸的苯丙氨酸突变导致受体无法组成性激活 Erk 通路，但保留了响应配体刺激而诱导 Erk 磷酸化的能力。 mRon 激活 MAP 激酶途径的能力取决于 c-Src 活性，我们已经证明 c-Src 与 mRon 发生共免疫沉淀。当 MAP 激酶激活所需的三个酪氨酸发生突变时，c-Src 无法与 mRon 相互作用，而单独存在这些酪氨酸中的任何一个都会恢复 Erk 磷酸化和 c-Src 的募集。因此，mRon 的配体依赖性和非依赖性活性可以通过选择性酪氨酸组的改变而解偶联。
Receptor tyrosine kinases (RTKs) activate downstream signaling through cognate growth factor receptor-induced dimerization and autophosphorylation. Overexpression of RTKs can lead to constitutive activation due to increased dimerization in the absence of ligand, and downstream signals are presumed to be the same as the ligand-induced signals. We have shown that the murine Ron (mRon) receptor tyrosine kinase exhibits constitutive activation of the MAP kinase pathway that is independent of the two docking site tyrosines, whereas activation of this pathway in response to ligand (macrophage-stimulating protein) is abolished in the absence of these tyrosines. Furthermore, we identified three tyrosines (Tyr-1175, Tyr-1265, and Tyr-1294) within the kinase domain that play critical but overlapping roles in controlling constitutive Erk activation by mRon. Phenylalanine mutations at these three tyrosines results in a receptor that fails to constitutively activate the Erk pathway but retains the ability to induce Erk phosphorylation in response to ligand stimulation. The ability of mRon to activate the MAP kinase pathway is dependent on c-Src activity, and we have shown that c-Src co-immunoprecipitates with mRon. c-Src fails to interact with mRon when the three tyrosines required for MAP kinase activation are mutated, whereas the presence of any one of these tyrosines alone restores Erk phosphorylation and recruitment of c-Src. Thus, the ligand-dependent and -independent activity of mRon can be uncoupled through the alteration of selective sets of tyrosines.