Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Salamanca, Spain.
Mol Cell Biol. 2010 Oct;30(19):4687-97. doi: 10.1128/MCB.01581-09. Epub 2010 Aug 2.
The epidermal growth factor (EGF)-ErbB-mitogen-activated protein kinase (MAPK) transcription signaling pathway is altered in many types of carcinomas, and this pathway can be regulated by new protein-protein interactions. Vaccinia-related kinase (VRK) proteins are Ser-Thr kinases that regulate several signal transduction pathways. In this work, we study the effect of VRK2 on MAPK signaling using breast cancer as a model. High levels of VRK2 inhibit EGF and ErbB2 activation of transcription by the serum response element (SRE). This effect is also detected in response to H-Ras(G12V) or B-Raf(V600E) oncogenes and is accompanied by a reduction in phosphorylated extracellular signal-regulated kinase (ERK) levels, p90RSK levels, and SRE-dependent transcription. Furthermore, VRK2 knockdown has the opposite effect, increasing the transcriptional response to stimulation with EGF and leading to increased levels of ERK phosphorylation. The molecular mechanism lies between MAPK/ERK kinase (MEK) and ERK, since MEK remains phosphorylated while ERK phosphorylation is blocked by VRK2A. This inhibition of the ERK signaling pathway is a consequence of a direct protein-protein interaction between VRK2A, MEK, and kinase suppressor of Ras 1 (KSR1). Identification of new correlations in human cancer can lead to a better understanding of the biology of individual tumors. ErbB2 and VRK2 protein levels were inversely correlated in 136 cases of human breast carcinoma. In ErbB2(+) tumors, there is a significant reduction in the VRK2 level, suggesting a role for VRK2A in ErbB2-MAPK signaling. Thus, VRK2 downregulation in carcinomas permits signal transmission through the MEK-ERK pathway without affecting AKT signaling, causing a signal imbalance among pathways that contributes to the phenotype of breast cancer.
表皮生长因子 (EGF)-表皮生长因子受体 (ErbB)-丝裂原活化蛋白激酶 (MAPK) 转录信号通路在许多类型的癌中发生改变，并且该通路可以通过新的蛋白-蛋白相互作用进行调节。痘苗病毒相关激酶 (VRK) 蛋白是 Ser-Thr 激酶，可调节几种信号转导途径。在这项工作中，我们使用乳腺癌作为模型研究 VRK2 对 MAPK 信号转导的影响。高水平的 VRK2 抑制 EGF 和 ErbB2 通过血清反应元件 (SRE) 的转录激活。这种作用也在响应 H-Ras(G12V) 或 B-Raf(V600E) 癌基因时被检测到，并伴随着磷酸化细胞外信号调节激酶 (ERK) 水平、p90RSK 水平和 SRE 依赖性转录的降低。此外，VRK2 敲低具有相反的效果，增加了对 EGF 刺激的转录反应，并导致 ERK 磷酸化水平增加。分子机制位于 MAPK/ERK 激酶 (MEK) 和 ERK 之间，因为 VRK2A 使 MEK 保持磷酸化，而 ERK 磷酸化被 VRK2A 阻断。ERK 信号通路的这种抑制是 VRK2A、MEK 和 Ras 激酶抑制剂 1 (KSR1) 之间直接蛋白-蛋白相互作用的结果。在人类癌症中鉴定新的相关性可以更好地理解个体肿瘤的生物学。在 136 例人类乳腺癌中，ErbB2 和 VRK2 蛋白水平呈负相关。在 ErbB2(+)肿瘤中，VRK2 水平显著降低，提示 VRK2A 在 ErbB2-MAPK 信号转导中发挥作用。因此，癌组织中 VRK2 的下调允许通过 MEK-ERK 途径进行信号传递，而不影响 AKT 信号，导致途径之间的信号失衡，这有助于乳腺癌的表型。
