EGFR Tyrosine 845 Phosphorylation-Dependent Proliferation and Transformation of Breast Cancer Cells Require Activation of p38 MAPK
EGFR Tyrosine 845 Phosphorylation-Dependent Proliferation and Transformation of Breast Cancer Cells Require Activation of p38 MAPK
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DOI：
10.1593/tlo.12163
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发表时间：
2012-10-01
影响因子：
5
通讯作者：
Boerner, Julie L.
中科院分区：
文献类型：
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作者：
Mueller, Kelly L.;Powell, Katelyn;Boerner, Julie L.
在几种模型系统中，c-Src对酪氨酸845上的表皮生长因子受体（EGFR）的磷酸化已被证明对细胞增殖和迁移很重要。EGFR和Src家族激酶（SFK）之间的这种相互作用是细胞模型和临床中EGFR抑制剂耐药的一种机制。在这里，我们表明，EGFR上的酪氨酸845的磷酸化是必需的增殖和转化使用几种乳腺癌细胞模型。EGFR-Y845 F的过表达或用SFK抑制剂达沙替尼处理细胞废除了酪氨酸845磷酸化，但对其他EGFR磷酸化位点或EGFR激酶活性几乎没有影响。消除Y845磷酸化抑制细胞增殖和转化，即使细胞外信号调节激酶（ERK）和Akt在这些条件下保持活性。重要的是，共转染丝裂原活化蛋白激酶（MAPK）激酶3和p38 MAPK恢复细胞增殖的EGFR酪氨酸845磷酸化的情况下。综上所述，这些数据证明了EGFR酪氨酸845磷酸化下游的p38 MAPK信号转导在乳腺癌细胞增殖和转化调节中的新作用，并暗示SFK抑制剂作为克服乳腺癌中EGFR酪氨酸激酶抑制剂耐药性的潜在治疗机制。
Phosphorylation of epidermal growth factor receptor (EGFR) on tyrosine 845 by c-Src has been shown to be important for cell proliferation and migration in several model systems. This cross talk between EGFR and Src family kinases (SFKs) is one mechanism for resistance to EGFR inhibitors both in cell models and in the clinic. Here, we show that phosphorylation of tyrosine 845 on EGFR is required for proliferation and transformation using several cell models of breast cancer. Overexpression of EGFR-Y845F or treating cells with the SFK inhibitor dasatinib abrogated tyrosine 845 phosphorylation, yet had little to no effect on other EGFR phosphorylation sites or EGFR kinase activity. Abrogation of Y845 phosphorylation inhibited cell proliferation and transformation, even though extracellular signal-regulated kinase (ERK) and Akt remained active under these conditions. Importantly, cotransfection of mitogen-activated protein kinase (MAPK) kinase 3 and p38 MAPK restored cell proliferation in the absence of EGFR tyrosine 845 phosphorylation. Taken together, these data demonstrate a novel role for p38 MAPK signaling downstream of EGFR tyrosine 845 phosphorylation in the regulation of breast cancer cell proliferation and transformation and implicate SFK inhibitors as a potential therapeutic mechanism for overcoming EGFR tyrosine kinase inhibitor resistance in breast cancer.