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首页> 外文期刊>Molecular and Cellular Biology >Activation of the Ras/Mitogen-Activated Protein Kinase Pathway by Kinase-Defective Epidermal Growth Factor Receptors Results in Cell Survival but Not Proliferation
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Activation of the Ras/Mitogen-Activated Protein Kinase Pathway by Kinase-Defective Epidermal Growth Factor Receptors Results in Cell Survival but Not Proliferation

机译：激酶缺陷表皮生长因子受体对Ras /丝裂原活化的蛋白激酶途径的激活导致细胞存活，但不增殖

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Signalling by the epidermal growth factor (EGF) receptor (EGFR) has been studied intensively, but for most cell types the analysis is complicated by the fact that EGFR not only homodimerizes but can also form heterodimers with other EGFR family members. Heterodimerization is a particular problem in the study of EGFR mutants, where the true phenotype of the mutants is confounded by the contribution of the heterodimer partner to signal transduction. We have made use of the murine hemopoietic cell line BaF/3, which does not express EGFR family members, to express wild-type (WT) EGFR, three kinase-defective EGFR mutants (V741G, Y740F, and K721R), or a C-terminally truncated EGFR (CT957) and have measured their responses to EGF. We found that under the appropriate conditions EGF can stimulate cell proliferation of BaF/3 cells expressing WT or CT957 EGFRs but not that of cells expressing the kinase-defective mutants. However, EGF promotes the survival of BaF/3 cells expressing either of the kinase-defective receptors (V741G and Y740F), indicating that these receptors can still transmit a survival signal. Analysis of the early signalling events by the WT, V741G, and Y740F mutant EGF receptors indicated that EGF stimulates comparable levels of Shc phosphorylation, Shc–GRB-2 association, and activation of Ras, B-Raf, and Erk-1. Blocking the mitogen-activated protein kinase (MAPK) signalling pathway with the specific inhibitor PD98059 abrogates completely the EGF-dependent survival of cells expressing the kinase-defective EGFR mutants but has no effect on the EGF-dependent proliferation mediated by WT and CT957 EGFRs. Similarly, the Src family kinase inhibitor PP1 abrogates EGF-dependent survival without affecting proliferation. However blocking phosphatidylinositol-3-kinase or JAK-2 kinase with specific inhibitors does arrest growth factor-dependent cell proliferation. Thus, EGFR-mediated mitogenic signalling in BaF/3 cells requires an intact EGFR tyrosine kinase activity and appears to depend on the activation of both the JAK-2 and PI-3 kinase pathways. Activation of the Src family of kinases or of the Ras/MAPK pathway can, however, be initiated by a kinase-impaired EGFR and is linked to survival.
机译：对表皮生长因子（EGF）受体（EGFR）的信号进行了深入研究，但是对于大多数细胞类型，由于EGFR不仅同型二聚体，而且还可以与其他EGFR家族成员形成异二聚体，因此分析变得复杂。异二聚体化是EGFR突变体研究中的一个特殊问题，其中突变体的真正表型因异二聚体伴侣对信号转导的贡献而被混淆。我们利用了不表达EGFR家族成员的鼠造血细胞系BaF / 3来表达野生型（WT）EGFR，三个激酶缺陷型EGFR突变体（V741G，Y740F和K721R）或C -末端截短的EGFR（CT957），并测量了其对EGF的反应。我们发现，在适当的条件下，EGF可以刺激表达WT或CT957 EGFR的BaF / 3细胞的细胞增殖，但不能刺激表达激酶缺陷型突变体的细胞的增殖。然而，EGF促进表达任何一种激酶缺陷受体（V741G和Y740F）的BaF / 3细胞的存活，表明这些受体仍可以传递存活信号。 WT，V741G和Y740F突变EGF受体对早期信号事件的分析表明，EGF刺激可比较水平的Shc磷酸化，Shc–GRB-2缔合以及Ras，B-Raf和Erk-1的活化。用特异性抑制剂PD98059阻断有丝分裂原激活的蛋白激酶（MAPK）信号通路完全消除了表达激酶缺陷型EGFR突变体的细胞的EGF依赖性存活，但对由WT和CT957 EGFR介导的EGF依赖性增殖没有影响。同样，Src家族激酶抑制剂PP1消除了EGF依赖的生存，而不会影响增殖。然而，用特异性抑制剂阻断磷脂酰肌醇-3-激酶或JAK-2激酶确实会阻止生长因子依赖性细胞增殖。因此，BaF / 3细胞中EGFR介导的促有丝分裂信号传导需要完整的EGFR酪氨酸激酶活性，并且似乎依赖于JAK-2和PI-3激酶途径的激活。然而，激酶的Src家族或Ras / MAPK途径的激活可以由激酶受损的EGFR启动，并与生存有关。

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