Analysis of Kinase Gene Expression Patterns across 5681 Human Tissue Samples Reveals Functional Genomic Taxonomy of the Kinome

Abstract

Kinases play key roles in cell signaling and represent major targets for drug development, but the regulation of their activation and their associations with health and disease have not been systematically analyzed. Here, we carried out a bioinformatic analysis of the expression levels of 459 human kinase genes in 5681 samples consisting of 44 healthy and 55 malignant human tissues. Defining the tissues where the kinase genes were transcriptionally active led to a functional genomic taxonomy of the kinome and a classification of human tissues and disease types based on the similarity of their kinome gene expression. The co-expression network around each of the kinase genes was defined in order to determine the functional context, i.e. the biological processes that were active in the cells and tissues where the kinase gene was expressed. Strong associations for individual kinases were found for mitosis (69 genes, including AURKA and BUB1), cell cycle control (73 genes, including PLK1 and AURKB), DNA repair (49 genes, including CHEK1 and ATR), immune response (72 genes, including MATK), neuronal (131 genes, including PRKCE) and muscular (72 genes, including MYLK2) functions. We then analyzed which kinase genes gain or lose transcriptional activity in the development of prostate and lung cancers and elucidated the functional associations of individual cancer associated kinase genes. In summary, we report here a systematic classification of kinases based on the bioinformatic analysis of their expression in human tissues and diseases, as well as grouping of tissues and tumor types according to the similarity of their kinome transcription.

Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression

“…CHEK1 is required for cell cycle arrest in response to DNA damage and may also regulate cell cycle (44). A decline in CHEK1 expression was reported in prostate cancer (45) and compound loss of CHEK1 and PTEN triggers progression from high grade prostatic intraepithelial neoplasia to invasive prostate carcinoma (46). CHEK1 knockdown increased LNCaP cellular proliferation but bicalutamide was still able to suppress proliferation (Figure 4H).…”

VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage

“…22 Analysis of VRK1 expression has revealed that it is associated to cell cycle and chromatin remodeling biological processes. 23 VRK1 is one of the most abundant kinases within nuclei of human cells. 24 Several processes implicating, or requiring, chromatin remodeling have been associated to VRK1.…”

Targeting MPS1 Enhances Radiosensitization of Human Glioblastoma by Modulating DNA Repair Proteins

“…MPS1 functions in several aspects of cell cycle control, including mitotic spindle assembly checkpoint activation, proper mitotic progression, centrosome duplication, chromosome alignment, error correction of kinetochore-microtubule attachment, and recruitment of SAC components to kinetochores (8–10). Like many cell-cycle regulators, MPS1 transcription is deregulated in a variety of human tumors and elevated MPS1 mRNA levels are found in several human cancers, including thyroid papillary carcinoma, breast cancer, gastric cancer, bronchogenic carcinoma, and lung cancers (6, 11, 12). Furthermore, high levels of MPS1 correlate with a more aggressive histological grade in breast cancers (13).…”