Hyperactivation of MEK/ERK pathway by Ca2+/calmodulin-dependent protein kinase kinase 2 promotes cellular proliferation by activating cyclin-dependent kinases and minichromosome maintenance protein in gastric cancer cells,Molecular Carcinogenesis

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Hyperactivation of MEK/ERK pathway by Ca2+/calmodulin-dependent protein kinase kinase 2 promotes cellular proliferation by activating cyclin-dependent kinases and minichromosome maintenance protein in gastric cancer cells
Molecular Carcinogenesis ( IF 3.0 ) Pub Date : 2021-08-26 , DOI: 10.1002/mc.23343
Mohd A Najar ₁ , Anjana Aravind ₁ , Shobha Dagamajalu ₁ , David Sidransky ₂ , Hassan Ashktorab ₃ , Duane T Smoot ₄ , Harsha Gowda _{1,

5,

6} , T S Keshava Prasad ₁ , Prashant K Modi ₁ , Aditi Chatterjee _{1,

5,

6}

Affiliation

Although CAMKK2 is overexpressed in several cancers, its role and relevant downstream signaling pathways in gastric cancer (GC) are poorly understood. Treatment of AGS GC cells with a CAMKK2 inhibitor, STO-609, resulted in decreased cell proliferation, cell migration, invasion, colony-forming ability, and G1/S-phase arrest. Quantitative phosphoproteomics in AGS cells with the CAMKK2 inhibitor led to the identification of 9603 unique phosphosites mapping to 3120 proteins. We observed decreased phosphorylation of 1101 phosphopeptides (1.5-fold) corresponding to 752 proteins upon CAMKK2 inhibition. Bioinformatics analysis of hypo-phosphorylated proteins revealed enrichment of MAPK1/MAPK3 signaling. Kinase enrichment analysis of hypo-phosphorylated proteins using the X2K Web tool identified ERK1, cyclin-dependant kinase 1 (CDK1), and CDK2 as downstream substrates of CAMKK2. Moreover, inhibition of CAMKK2 and MEK1 resulted in decreased phosphorylation of ERK1, CDK1, MCM2, and MCM3. Immunofluorescence results were in concordance with our mass spectroscopy data and Western blot analysis results. Taken together, our data reveal the essential role of CAMKK2 in the pathobiology of GC through the activation of the MEK/ERK1 signaling cascade.

中文翻译：

Ca2+/钙调蛋白依赖性蛋白激酶激酶2对MEK/ERK通路的过度激活通过激活胃癌细胞中的细胞周期蛋白依赖性激酶和微染色体维持蛋白促进细胞增殖

尽管 CAMKK2 在多种癌症中过度表达，但对其在胃癌 (GC) 中的作用和相关下游信号通路知之甚少。用 CAMKK2 抑制剂 STO-609 处理 AGS GC 细胞导致细胞增殖、细胞迁移、侵袭、集落形成能力和 G1/S 期停滞降低。使用 CAMKK2 抑制剂在 AGS 细胞中进行定量磷酸化蛋白质组学，鉴定了 9603 个独特的磷酸化位点，映射到 3120 个蛋白质。我们观察到 1101 种磷酸化肽（1.5 倍）在 CAMKK2 抑制后对应于 752 种蛋白质的磷酸化降低。低磷酸化蛋白的生物信息学分析揭示了 MAPK1/MAPK3 信号的富集。使用 X2K Web 工具对低磷酸化蛋白质的激酶富集分析鉴定了 ERK1、细胞周期蛋白依赖性激酶 1 (CDK1)、和 CDK2 作为 CAMKK2 的下游底物。此外，CAMKK2 和 MEK1 的抑制导致 ERK1、CDK1、MCM2 和 MCM3 的磷酸化降低。免疫荧光结果与我们的质谱数据和蛋白质印迹分析结果一致。总之，我们的数据通过激活 MEK/ERK1 信号级联反应揭示了 CAMKK2 在 GC 病理生物学中的重要作用。

更新日期：2021-10-14

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