Table S2. List of the Hits Kinases Chosen for Validation and Their Known Functions

Table S2. List of the hits kinases chosen for validation and their known functions

kinase Known biological functions MAPK3 Signal transduction, regulates most biological functions MAPK1 Signal transduction, regulates most biological functions Upstream activator of JNK and p38MAPK pathways, mediator of environmental MAP3K4 stresses; required during development (1) response to cellular stress and proinflammatory cytokines, activated by MAPK1, MAPKAPK5 MAPK14/p38-alpha, and MAPK11/p38-beta (2) mediates the cell responses to proinflammatory cytokines and environmental MA2K7 stresses; activates JNK1/2 (3) P38MAPKα stress related transcription and cell cycle regulation; antagonist of JNK/c-jun MAPK14 pathway in controlling proliferation of normal and cancer cells (4, 5) JNK1, activated by various stressful stimuli involved in initiation and progression of MAPK8 hepatocellular carcinoma. Involved in telomerase regulation (6) RPS6KA4 MSK2; regulated by CK2 in p38-dependent manner in response to UV (7) Important for cell proliferation in colorectal cancer (8); over-expressed in several ERK8 human cancers (9, 10) Controller of mitosis, regulates centrosome separation; over-expressed in cancer (11- NEK2 13) Mitotic spindle assembly; works with NEK6 and is regulated by NEK9. Over- NEK7 expressed in cancer (14-16) Closely related to NEK9; mainly involved in cilia biology (17); expressed in breast NEK8 cancer and pancreatic cancer (18, 19) Central regulator of mitosis, chromosome segregation and cytokinesis; over- AURKB expressed in cancer (20-22). Involved in telomerase regulation via surviving (23) CCRK Cell proliferation, regulates cdk2, cyc E and cyc D1 (24, 25) phospholipid-dependent protein kinase, important for T-cell activation; required for the PRKCQ activation of NF-kappaB and AP (26). Known telomerase regulator (27). Signal transduction in response to FGF, specific function unknown, over-expressed in FGFR4 cancer PNKP DNA repair BER (28) CHEK2 Cell cycle checkpoints, DNA repair, downstream effector of ATM/ATR CHEK1 Signal transduction, regulates most biological functions SRC Oncogene, known telomerase regulator (29) MET Oncogene JAK2 Involved in cytokine receptor signaling pathways and response to gamma interferon PKIB Regulator of PKA-C kinase, potential therapeutic target in prostate cancer (30) YWHAQ Member of 14-3-3 family, Associated with poor prognosis in soft tissue sarcomas (31) AKAP8 Scaffolding protein family, Important for PKA localization (32) CAMK2G Expression increased in heart failure (33)

References

1. Abell AN, Granger DA, Johnson GL. MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3beta. J Biol Chem 2007;282:30476-84. 2. Shiryaev A, Moens U. Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: menage a trois or menage a quatre? Cell Signal;22:1185-92. 3. Wang X, Destrument A, Tournier C. Physiological roles of MKK4 and MKK7: insights from animal models. Biochim Biophys Acta 2007;1773:1349-57. 4. Hui L, Bakiri L, Mairhorfer A, et al. p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet 2007;39:741-9. 5. Hui L, Bakiri L, Stepniak E, Wagner EF. p38alpha: a suppressor of cell proliferation and tumorigenesis. Cell Cycle 2007;6:2429-33. 6. Chen F, Beezhold K, Castranova V. JNK1, a potential therapeutic target for hepatocellular carcinoma. Biochim Biophys Acta 2009;1796:242-51. 7. Jacks KA, Kock CA. Differential regulation of mitogen- and stress-activated protein kinase-1 and -2 (MSK1 and MSK2) by CK2 following UV radiation. J Biol Chem 2010;285:1661-70. 8. Xu YM, Zhu F, Cho YY, et al. Extracellular signal-regulated kinase 8-mediated c-Jun phosphorylation increases tumorigenesis of human colon cancer. Cancer Res 2010;70:3218-27. 9. Abe MK, Saelzler MP, Espinosa R, 3rd, et al. ERK8, a new member of the mitogen-activated protein kinase family. J Biol Chem 2002;277:16733-43. 10. Partheen K, Levan K, Osterberg L, Horvath G. Expression analysis of stage III serous ovarian adenocarcinoma distinguishes a sub-group of survivors. Eur J Cancer 2006;42:2846-54. 11. Hayward DG, Clarke RB, Faragher AJ, Pillai MR, Hagan IM, Fry AM. The centrosomal kinase Nek2 displays elevated levels of protein expression in human breast cancer. Cancer Res 2004;64:7370-6. 12. Kan Z, Jaiswal BS, Stinson J, et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature;466:869-73. 13. Tsunoda N, Kokuryo T, Oda K, et al. Nek2 as a novel molecular target for the treatment of breast carcinoma. Cancer Sci 2009;100:111-6. 14. Jee HJ, Kim AJ, Song N, et al. Nek6 overexpression antagonizes p53-induced senescence in human cancer cells. Cell Cycle;9:4703-10. 15. O'Regan L, Fry AM. The Nek6 and Nek7 protein kinases are required for robust mitotic spindle formation and cytokinesis. Mol Cell Biol 2009;29:3975-90. 16. Salem H, Rachmin I, Yissachar N, et al. Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy. Oncogene;29:4046-57. 17. Sohara E, Luo Y, Zhang J, Manning DK, Beier DR, Zhou J. Nek8 regulates the expression and localization of polycystin-1 and polycystin-2. J Am Soc Nephrol 2008;19:469-76. 18. Bowers AJ, Boylan JF. Nek8, a NIMA family kinase member, is overexpressed in primary human breast tumors. Gene 2004;328:135-42. 19. Carter H, Samayoa J, Hruban RH, Karchin R. Prioritization of driver mutations in pancreatic cancer using cancer-specific high-throughput annotation of somatic mutations (CHASM). Cancer Biol Ther;10:582-7. 20. Lok W, Klein RQ, Saif MW. Aurora kinase inhibitors as anti-cancer therapy. Anticancer Drugs;21:339-50. 21. Katayama H, Brinkley WR, Sen S. The Aurora kinases: role in cell transformation and tumorigenesis. Cancer Metastasis Rev 2003;22:451-64. 22. Gully CP, Zhang F, Chen J, et al. Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. Mol Cancer;9:42. 23. Furuya M, Tsuji N, Kobayashi D, Watanabe N. Interaction between survivin and aurora-B kinase plays an important role in survivin-mediated up-regulation of human telomerase reverse transcriptase expression. Int J Oncol 2009;34:1061-8. 24. An X, Ng SS, Xie D, et al. Functional characterisation of cell cycle-related kinase (CCRK) in colorectal cancer carcinogenesis. Eur J Cancer;46:1752-61. 25. Wu GQ, Xie D, Yang GF, et al. Cell cycle-related kinase supports ovarian carcinoma cell proliferation via regulation of cyclin D1 and is a predictor of outcome in patients with ovarian carcinoma. Int J Cancer 2009;125:2631- 42. 26. Gruber T, Pfeifhofer-Obermair C, Baier G. PKCtheta is necessary for efficient activation of NFkappaB, NFAT, and AP-1 during positive selection of thymocytes. Immunol Lett;132:6-11. 27. Sheng WY, Chen YR, Wang TC. A major role of PKC theta and NFkappaB in the regulation of hTERT in human T lymphocytes. FEBS Lett 2006;580:6819-24. 28. Allinson SL. DNA end-processing enzyme polynucleotide kinase as a potential target in the treatment of cancer. Future Oncol;6:1031-42. 29. Haendeler J, Hoffmann J, Brandes RP, Zeiher AM, Dimmeler S. Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707. Mol Cell Biol 2003;23:4598-610. 30. Chung S, Furihata M, Tamura K, et al. Overexpressing PKIB in prostate cancer promotes its aggressiveness by linking between PKA and Akt pathways. Oncogene 2009;28:2849-59. 31. Vazquez A, Grochola LF, Bond EE, et al. Chemosensitivity profiles identify polymorphisms in the p53 network genes 14-3-3tau and CD44 that affect sarcoma incidence and survival. Cancer Res;70:172-80. 32. Welch EJ, Jones BW, Scott JD. Networking with AKAPs: context-dependent regulation of anchored enzymes. Mol Interv;10:86-97. 33. Sag CM, Wadsack DP, Khabbazzadeh S, et al. Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure. Circ Heart Fail 2009;2:664-75.

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