Chapter 1
Global Approaches to Understanding Protein Kinase Functions
Jennifer L. Gorman,
James R. Woodgett,
Jennifer L. Gorman
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Search for more papers by this authorJames R. Woodgett
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
University of Toronto, Department of Medical Biophysics, Toronto, Ontario Canada
Search for more papers by this authorJennifer L. Gorman,
James R. Woodgett,
Jennifer L. Gorman
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
Search for more papers by this authorJames R. Woodgett
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
University of Toronto, Department of Medical Biophysics, Toronto, Ontario Canada
Search for more papers by this authorBook Editor(s):Heinz-Bernhard Kraatz,
Sanela Martic,
Heinz-Bernhard Kraatz
University of Toronto, Phys. & Environmental Sciences, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada
Search for more papers by this authorSanela Martic
Oakland University, Dept. of Chemistry, 2200 North Squirrel Road, Rochester, MI 48309, United States
Search for more papers by this authorFirst published: 25 September 2015
Summary
This chapter initially describes the subclasses of protein kinases, provides examples of their roles in disease, and discusses methods for their characterization and functional assignments. It exemplifies the role of key protein kinases in the pathophysiology of two of the chronic diseases that affect tens of millions of people worldwide: Alzheimer's disease (AD) and cancer. Knockdown of kinase expression in cell lines has been instrumental in establishing the complex roles of protein kinases in cellular function in both the normal and disease states. While knockdown of kinase activity through RNAi and chemical inhibitors allows for the assessment of kinase function, ultimately these models do not fully recapitulate the system as a whole with its many interacting cell types. The development of mouse models in which a particular kinase has been deleted provides a more informative method to ascertain their complete biological function.
References
- Hunter, T. (1987) A thousand and one protein kinases. Cell, 50 (6), 823–829.
- Manning, G., Whyte, D.B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298 (5600), 1912–1934.
- Pearce, L.R., Komander, D., and Alessi, D.R. (2010) The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol., 11 (1), 9–22.
- Arencibia, J.M., Pastor-Flores, D., Bauer, A.F., Schulze, J.O., and Biondi, R.M. (2013) AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases. Biochim. Biophys. Acta, 1834 (7), 1302–1321.
- Hanks, S.K. and Hunter, T. (1995) Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J., 9 (8), 576–596.
- Fyffe, C. and Falasca, M. (2013) 3-Phosphoinositide-dependent protein kinase-1 as an emerging target in the management of breast cancer. Cancer Manage. Res., 5, 271–280.
- Sato, S., Fujita, N., and Tsuruo, T. (2002) Interference with PDK1-akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene, 21 (11), 1727–1738.
- Gonzalez, E. and McGraw, T.E. (2009) The akt kinases: isoform specificity in metabolism and cancer. Cell Cycle, 8 (16), 2502–2508.
- Chen, W.S., Xu, P.Z., Gottlob, K., Chen, M.L., Sokol, K., Shiyanova, T., Roninson, I., Weng, W., Suzuki, R., Tobe, K., Kadowaki, T., and Hay, N. (2001) Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev., 15 (17), 2203–2208.
- Garofalo, R.S., Orena, S.J., Rafidi, K., Torchia, A.J., Stock, J.L., Hildebrandt, A.L., Coskran, T., Black, S.C., Brees, D.J., Wicks, J.R., McNeish, J.D., and Coleman, K.G. (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J. Clin. Invest., 112 (2), 197–208.
- Tschopp, O., Yang, Z.Z., Brodbeck, D., Dummler, B.A., Hemmings-Mieszczak, M., Watanabe, T., Michaelis, T., Frahm, J., and Hemmings, B.A. (2005) Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development, 132 (13), 2943–2954.
- Tzivion, G., Dobson, M., and Ramakrishnan, G. (2011) FOXO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim. Biophys. Acta, 1813 (11), 1938–1945.
- Xu, K., Liu, P., and Wei, W. (2014) mTOR signaling in tumorigenesis. Biochim. Biophys. Acta, 1846 (2), 638–654.
- Mochly-Rosen, D., Das, K., and Grimes, K.V. (2012) Protein kinase C, an elusive therapeutic target? Nat. Rev. Drug Discovery, 11 (12), 937–957.
- Urtreger, A.J., Kazanietz, M.G., and Bal de Kier Joffe, E.D. (2012) Contribution of individual PKC isoforms to breast cancer progression. IUBMB Life, 64 (1), 18–26.
- Lang, F., Perrotti, N., and Stournaras, C. (2010) Colorectal carcinoma cells--regulation of survival and growth by SGK1. Int. J. Biochem. Cell Biol., 42 (10), 1571–1575.
- Tessier, M. and Woodgett, J.R. (2006) Role of the phox homology domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3. J. Biol. Chem., 281 (33), 23978–23989.
- Wayman, G.A., Lee, Y.S., Tokumitsu, H., Silva, A.J., and Soderling, T.R. (2008) Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron, 59 (6), 914–931.
- Maier, L.S. and Bers, D.M. (2007) Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart. Cardiovasc. Res., 73 (4), 631–640.
- Stull, J.T., Kamm, K.E., and Vandenboom, R. (2011) Myosin light chain kinase and the role of myosin light chain phosphorylation in skeletal muscle. Arch. Biochem. Biophys., 510 (2), 120–128.
- Gowans, G.J., Hawley, S.A., Ross, F.A., and Hardie, D.G. (2013) AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab., 18 (4), 556–566.
- Grahame Hardie, D. (2014) AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J. Int. Med., 276 (6), 543–559.
- Varjosalo, M., Keskitalo, S., Van Drogen, A., Nurkkala, H., Vichalkovski, A., Aebersold, R., and Gstaiger, M. (2013) The protein interaction landscape of the human CMGC kinase group. Cell Rep., 3 (4), 1306–1320.
- Malumbres, M., Harlow, E., Hunt, T., Hunter, T., Lahti, J.M., Manning, G., Morgan, D.O., Tsai, L.H., and Wolgemuth, D.J. (2009) Cyclin-dependent kinases: a family portrait. Nat. Cell Biol., 11 (11), 1275–1276.
- Day, P.J., Cleasby, A., Tickle, I.J., O'Reilly, M., Coyle, J.E., Holding, F.P., McMenamin, R.L., Yon, J., Chopra, R., Lengauer, C., and Jhoti, H. (2009) Crystal structure of human CDK4 in complex with a D-type cyclin. Proc. Natl. Acad. Sci. U.S.A., 106 (11), 4166–4170.
- Takaki, T., Echalier, A., Brown, N.R., Hunt, T., Endicott, J.A., and Noble, M.E. (2009) The structure of CDK4/cyclin D3 has implications for models of CDK activation. Proc. Natl. Acad. Sci. U.S.A., 106 (11), 4171–4176.
- Malumbres, M. (2014) Cyclin-dependent kinases. Genome Biol., 15 (6), 122.
- Kawauchi, T. (2014) Cdk5 regulates multiple cellular events in neural development, function and disease. Dev. Growth Differ., 56 (5), 335–348.
- Tsai, L.H., Takahashi, T., Caviness, V.S. Jr. and Harlow, E. (1993) Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development, 119 (4), 1029–1040.
- Kim, E.K. and Choi, E.J. (2015) Compromised MAPK signaling in human diseases: an update. Arch. Toxicol., 89 (6), 867–882.
- Burotto, M., Chiou, V.L., Lee, J.M., and Kohn, E.C. (2014) The MAPK pathway across different malignancies: a new perspective. Cancer, 120 (22), 3446–3456.
- Roberts, P.J. and Der, C.J. (2007) Targeting the raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26 (22), 3291–3310.
- Crews, C.M., Alessandrini, A., and Erikson, R.L. (1992) The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science, 258 (5081), 478–480.
- Roskoski, R. Jr. (2010) RAF protein-serine/threonine kinases: structure and regulation. Biochem. Biophys. Res. Commun., 399 (3), 313–317.
- Lee, J.D., Ulevitch, R.J., and Han, J. (1995) Primary structure of BMK1: a new mammalian map kinase. Biochem. Biophys. Res. Commun., 213 (2), 715–724.
- Kato, Y., Chao, T.H., Hayashi, M., Tapping, R.I., and Lee, J.D. (2000) Role of BMK1 in regulation of growth factor-induced cellular responses. Immunol. Res., 21 (2–3), 233–237.
- Keshet, Y. and Seger, R. (2010) The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol. Biol., 661, 3–38.
- Sabio, G. and Davis, R.J. (2014) TNF and MAP kinase signalling pathways. Semin. Immunol., 26 (3), 237–245.
- Davis, R.J. (2000) Signal transduction by the JNK group of MAP kinases. Cell, 103 (2), 239–252.
- Woodgett, J.R. (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J., 9 (8), 2431–2438.
- Ling, L.S., Voskas, D., and Woodgett, J.R. (2013) Activation of PDK-1 maintains mouse embryonic stem cell self-renewal in a PKB-dependent manner. Oncogene, 32 (47), 5397–5408.
- Kockeritz, L., Doble, B., Patel, S., and Woodgett, J.R. (2006) Glycogen synthase kinase-3--an overview of an over-achieving protein kinase. Curr. Drug Targets, 7 (11), 1377–1388.
- Kerkela, R., Kockeritz, L., Macaulay, K., Zhou, J., Doble, B.W., Beahm, C., Greytak, S., Woulfe, K., Trivedi, C.M., Woodgett, J.R., Epstein, J.A., Force, T., and Huggins, G.S. (2008) Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. J. Clin. Invest., 118 (11), 3609–3618.
- MacAulay, K., Doble, B.W., Patel, S., Hansotia, T., Sinclair, E.M., Drucker, D.J., Nagy, A., and Woodgett, J.R. (2007) Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab., 6 (4), 329–337.
- Hoeflich, K.P., Luo, J., Rubie, E.A., Tsao, M.S., Jin, O., and Woodgett, J.R. (2000) Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature, 406 (6791), 86–90.
- Xu, B.E., Lee, B.H., Min, X., Lenertz, L., Heise, C.J., Stippec, S., Goldsmith, E.J., and Cobb, M.H. (2005) WNK1: analysis of protein kinase structure, downstream targets, and potential roles in hypertension. Cell Res., 15 (1), 6–10.
- McCormick, J.A. and Ellison, D.H. (2011) The WNKs: atypical protein kinases with pleiotropic actions. Physiol. Rev., 91 (1), 177–219.
- Ubersax, J.A. and Ferrell, J.E. Jr. (2007) Mechanisms of specificity in protein phosphorylation. Nat. Rev. Mol. Cell Biol., 8 (7), 530–541.
- Lemmon, M.A. and Schlessinger, J. (2010) Cell signaling by receptor tyrosine kinases. Cell, 141 (7), 1117–1134.
- Takeuchi, K. and Ito, F. (2011) Receptor tyrosine kinases and targeted cancer therapeutics. Biol. Pharm. Bull., 34 (12), 1774–1780.
- Schlessinger, J. and Lemmon, M.A. (2003) SH2 and PTB domains in tyrosine kinase signaling. Sci. STKE, 2003 (191), RE12.
- Hunter, T. (2009) Tyrosine phosphorylation: thirty years and counting. Curr. Opin. Cell Biol., 21 (2), 140–146.
- Colicelli, J. (2010) ABL tyrosine kinases: evolution of function, regulation, and specificity. Sci. Signal., 3 (139), re6.
- Kim, L.C., Song, L., and Haura, E.B. (2009) Src kinases as therapeutic targets for cancer. Nat. Rev. Clin. Oncol., 6 (10), 587–595.
- Balabanov, S., Braig, M., and Brummendorf, T.H. (2014) Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia. Drug Discovery Today Technol., 11, 89–99.
- Meijer, L., Flajolet, M., and Greengard, P. (2004) Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol. Sci., 25 (9), 471–480.
- Liu, F., Ma, X.H., Ule, J., Bibb, J.A., Nishi, A., DeMaggio, A.J., Yan, Z., Nairn, A.C., and Greengard, P. (2001) Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proc. Natl. Acad. Sci. U.S.A., 98 (20), 11062–11068.
- Walter, J., Fluhrer, R., Hartung, B., Willem, M., Kaether, C., Capell, A., Lammich, S., Multhaup, G., and Haass, C. (2001) Phosphorylation regulates intracellular trafficking of beta-secretase. J. Biol. Chem., 276 (18), 14634–14641.
- Xiao, J., Tagliabracci, V.S., Wen, J., Kim, S.A., and Dixon, J.E. (2013) Crystal structure of the golgi casein kinase. Proc. Natl. Acad. Sci. U.S.A., 110 (26), 10574–10579.
- Gould, K.L. and Nurse, P. (1989) Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature, 342, 39–45.
- Potter, L.R. (2005) Domain analysis of human transmembrane guanylyl cyclase receptors: implications for regulation. Front. Biosci., 10, 1205–1220.
- Saha, S., Biswas, K.H., Kondapalli, C., Isloor, N., and Visweswariah, S.S. (2009) The linker region in receptor guanylyl cyclases is a key regulatory module: mutational analysis of guanylyl cyclase C. J. Biol. Chem., 284 (40), 27135–27145.
- Oliver, P.M., Fox, J.E., Kim, R., Rockman, H.A., Kim, H.S., Reddick, R.L., Pandey, K.N., Milgram, S.L., Smithies, O., and Maeda, N. (1997) Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc. Natl. Acad. Sci. U.S.A., 94 (26), 14730–14735.
- Lopez, M.J., Wong, S.K., Kishimoto, I., Dubois, S., Mach, V., Friesen, J., Garbers, D.L., and Beuve, A. (1995) Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature, 378 (6552), 65–68.
- Yang, R.B., Robinson, S.W., Xiong, W.H., Yau, K.W., Birch, D.G., and Garbers, D.L. (1999) Disruption of a retinal guanylyl cyclase gene leads to cone-specific dystrophy and paradoxical rod behavior. J. Neurosci., 19 (14), 5889–5897.
- Dowling, R.J., Topisirovic, I., Fonseca, B.D., and Sonenberg, N. (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim. Biophys. Acta, 1804 (3), 433–439.
- Knuutila, S., Bjorkqvist, A.M., Autio, K., Tarkkanen, M., Wolf, M., Monni, O., Szymanska, J., Larramendy, M.L., Tapper, J., Pere, H., El-Rifai, W., Hemmer, S., Wasenius, V.M., Vidgren, V., and Zhu, Y. (1998) DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am. J. Pathol., 152 (5), 1107–1123.
- Tell, V. and Hilgeroth, A. (2013) Recent developments of protein kinase inhibitors as potential AD therapeutics. Front. Cell. Neurosci., 7, 189.
- Giacobini, E. and Becker, R.E. (2007) One hundred years after the discovery of Alzheimer's disease. A turning point for therapy? J. Alzheimers Dis., 12 (1), 37–52.
- Benilova, I., Karran, E., and De Strooper, B. (2012) The toxic abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nat. Neurosci., 15 (3), 349–357.
- Kuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers-Nolten, I., Van Der Werf, K., Subramaniam, V., Braeken, D., Callewaert, G., Bartic, C., D'Hooge, R., Martins, I.C., Rousseau, F., Schymkowitz, J., and De Strooper, B. (2010) Neurotoxicity of Alzheimer's disease abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO J., 29 (19), 3408–3420.
- Avila, J., Lucas, J.J., Perez, M., and Hernandez, F. (2004) Role of tau protein in both physiological and pathological conditions. Physiol. Rev., 84 (2), 361–384.
- Avila, J. (2006) Tau phosphorylation and aggregation in Alzheimer's disease pathology. FEBS Lett., 580 (12), 2922–2927.
- Castro-Alvarez, J.F., Uribe-Arias, S.A., Mejia-Raigosa, D., and Cardona-Gomez, G.P. (2014) Cyclin-dependent kinase 5, a node protein in diminished tauopathy: a systems biology approach. Front. Aging Neurosci., 6, 232.
- Hye, A., Kerr, F., Archer, N., Foy, C., Poppe, M., Brown, R., Hamilton, G., Powell, J., Anderton, B., and Lovestone, S. (2005) Glycogen synthase kinase-3 is increased in white cells early in Alzheimer's disease. Neurosci. Lett., 373 (1), 1–4.
- Kwok, J.B., Loy, C.T., Hamilton, G., Lau, E., Hallupp, M., Williams, J., Owen, M.J., Broe, G.A., Tang, N., Lam, L., Powell, J.F., Lovestone, S., and Schofield, P.R. (2008) Glycogen synthase kinase-3beta and tau genes interact in Alzheimer's disease. Ann. Neurol., 64 (4), 446–454.
- Leroy, K., Yilmaz, Z., and Brion, J.P. (2007) Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol. Appl. Neurobiol., 33 (1), 43–55.
- Hooper, C., Killick, R., and Lovestone, S. (2008) The GSK3 hypothesis of Alzheimer's disease. J. Neurochem., 104 (6), 1433–1439.
- Huang, H.C. and Klein, P.S. (2006) Multiple roles for glycogen synthase kinase-3 as a drug target in Alzheimer's disease. Curr. Drug Targets, 7 (11), 1389–1397.
- Chico, L.K., Van Eldik, L.J., and Watterson, D.M. (2009) Targeting protein kinases in central nervous system disorders. Nat. Rev. Drug Discovery, 8 (11), 892–909.
- Takashima, A., Noguchi, K., Michel, G., Mercken, M., Hoshi, M., Ishiguro, K., and Imahori, K. (1996) Exposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci. Lett., 203 (1), 33–36.
- Ly, P.T., Wu, Y., Zou, H., Wang, R., Zhou, W., Kinoshita, A., Zhang, M., Yang, Y., Cai, F., Woodgett, J., and Song, W. (2013) Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J. Clin. Invest., 123 (1), 224–235.
- Martin, L., Latypova, X., Wilson, C.M., Magnaudeix, A., Perrin, M.L., Yardin, C., and Terro, F. (2013) Tau protein kinases: involvement in Alzheimer's disease. Ageing Res. Rev., 12 (1), 289–309.
- Hernandez, F., Borrell, J., Guaza, C., Avila, J., and Lucas, J.J. (2002) Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments. J. Neurochem., 83 (6), 1529–1533.
- Gomez de Barreda, E., Perez, M., Gomez Ramos, P., de Cristobal, J., Martin-Maestro, P., Moran, A., Dawson, H.N., Vitek, M.P., Lucas, J.J., Hernandez, F., and Avila, J. (2010) Tau-knockout mice show reduced GSK3-induced hippocampal degeneration and learning deficits. Neurobiol. Dis., 37 (3), 622–629.
- Engel, T., Hernandez, F., Avila, J., and Lucas, J.J. (2006) Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3. J. Neurosci., 26 (19), 5083–5090.
- Rockenstein, E., Torrance, M., Adame, A., Mante, M., Bar-on, P., Rose, J.B., Crews, L., and Masliah, E. (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation. J. Neurosci., 27 (8), 1981–1991.
- Stambolic, V., Ruel, L., and Woodgett, J.R. (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol., 6 (12), 1664–1668.
- Oruch, R., Elderbi, M.A., Khattab, H.A., Pryme, I.F., and Lund, A. (2014) Lithium: a review of pharmacology, clinical uses, and toxicity. Eur. J. Pharmacol., 740, 464–473.
- Liu, S.J., Zhang, A.H., Li, H.L., Wang, Q., Deng, H.M., Netzer, W.J., Xu, H., and Wang, J.Z. (2003) Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J. Neurochem., 87 (6), 1333–1344.
- De Ferrari, G.V., Chacon, M.A., Barria, M.I., Garrido, J.L., Godoy, J.A., Olivares, G., Reyes, A.E., Alvarez, A., Bronfman, M., and Inestrosa, N.C. (2003) Activation of wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol. Psychiatry, 8 (2), 195–208.
- King, M.K., Pardo, M., Cheng, Y., Downey, K., Jope, R.S., and Beurel, E. (2014) Glycogen synthase kinase-3 inhibitors: rescuers of cognitive impairments. Pharmacol. Ther., 141 (1), 1–12.
- Fiorentini, A., Rosi, M.C., Grossi, C., Luccarini, I., and Casamenti, F. (2010) Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice. PLoS One, 5 (12), e14382.
- Hampel, H., Ewers, M., Burger, K., Annas, P., Mortberg, A., Bogstedt, A., Frolich, L., Schroder, J., Schonknecht, P., Riepe, M.W., Kraft, I., Gasser, T., Leyhe, T., Moller, H.J., Kurz, A., and Basun, H. (2009) Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J. Clin. Psychiatry, 70 (6), 922–931.
- Sereno, L., Coma, M., Rodriguez, M., Sanchez-Ferrer, P., Sanchez, M.B., Gich, I., Agullo, J.M., Perez, M., Avila, J., Guardia-Laguarta, C., Clarimon, J., Lleo, A., and Gomez-Isla, T. (2009) A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol. Dis., 35 (3), 359–367.
- Hu, S., Begum, A.N., Jones, M.R., Oh, M.S., Beech, W.K., Beech, B.H., Yang, F., Chen, P., Ubeda, O.J., Kim, P.C., Davies, P., Ma, Q., Cole, G.M., and Frautschy, S.A. (2009) GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals. Neurobiol. Dis., 33 (2), 193–206.
- Shah, K. and Lahiri, D.K. (2014) Cdk5 activity in the brain – multiple paths of regulation. J. Cell Sci., 127(Pt. 11), 2391–2400.
- Patrick, G.N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L.H. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 402 (6762), 615–622.
- Sengupta, A., Kabat, J., Novak, M., Wu, Q., Grundke-Iqbal, I., and Iqbal, K. (1998) Phosphorylation of tau at both thr 231 and ser 262 is required for maximal inhibition of its binding to microtubules. Arch. Biochem. Biophys., 357 (2), 299–309.
- Cruz, J.C., Tseng, H.C., Goldman, J.A., Shih, H., and Tsai, L.H. (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron, 40 (3), 471–483.
- Piedrahita, D., Hernandez, I., Lopez-Tobon, A., Fedorov, D., Obara, B., Manjunath, B.S., Boudreau, R.L., Davidson, B., Laferla, F., Gallego-Gomez, J.C., Kosik, K.S., and Cardona-Gomez, G.P. (2010) Silencing of CDK5 reduces neurofibrillary tangles in transgenic Alzheimer's mice. J. Neurosci., 30 (42), 13966–13976.
- Wen, Y., Planel, E., Herman, M., Figueroa, H.Y., Wang, L., Liu, L., Lau, L.F., Yu, W.H., and Duff, K.E. (2008) Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J. Neurosci., 28 (10), 2624–2632.
- Perry, G., Roder, H., Nunomura, A., Takeda, A., Friedlich, A.L., Zhu, X., Raina, A.K., Holbrook, N., Siedlak, S.L., Harris, P.L., and Smith, M.A. (1999) Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. Neuroreport, 10 (11), 2411–2415.
- Ploia, C., Antoniou, X., Sclip, A., Grande, V., Cardinetti, D., Colombo, A., Canu, N., Benussi, L., Ghidoni, R., Forloni, G., and Borsello, T. (2011) JNK plays a key role in tau hyperphosphorylation in Alzheimer's disease models. J. Alzheimers Dis., 26 (2), 315–329.
- Chong, Y.H., Shin, Y.J., Lee, E.O., Kayed, R., Glabe, C.G., and Tenner, A.J. (2006) ERK1/2 activation mediates abeta oligomer-induced neurotoxicity via caspase-3 activation and tau cleavage in rat organotypic hippocampal slice cultures. J. Biol. Chem., 281 (29), 20315–20325.
- Morishima, Y., Gotoh, Y., Zieg, J., Barrett, T., Takano, H., Flavell, R., Davis, R.J., Shirasaki, Y., and Greenberg, M.E. (2001) Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-jun N-terminal kinase pathway and the induction of fas ligand. J. Neurosci., 21 (19), 7551–7560.
- Feld, M., Krawczyk, M.C., Sol Fustinana, M., Blake, M.G., Baratti, C.M., Romano, A., and Boccia, M.M. (2014) Decrease of ERK/MAPK overactivation in prefrontal cortex reverses early memory deficit in a mouse model of Alzheimer's disease. J. Alzheimers Dis., 40 (1), 69–82.
- Quiroz-Baez, R., Rojas, E., and Arias, C. (2009) Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of alpha-, beta- and gamma-secretase expression. Neurochem. Int., 55 (7), 662–670.
- Guglielmotto, M., Monteleone, D., Giliberto, L., Fornaro, M., Borghi, R., Tamagno, E., and Tabaton, M. (2011) Amyloid-beta(4)(2) activates the expression of BACE1 through the JNK pathway. J. Alzheimers Dis., 27 (4), 871–883.
- Mazzitelli, S., Xu, P., Ferrer, I., Davis, R.J., and Tournier, C. (2011) The loss of c-jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo. J. Neurosci., 31 (47), 16969–16976.
- Sclip, A., Tozzi, A., Abaza, A., Cardinetti, D., Colombo, I., Calabresi, P., Salmona, M., Welker, E., and Borsello, T. (2014) c-jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo. Cell Death Dis., 5, e1019.
- Hensley, K., Floyd, R.A., Zheng, N.Y., Nael, R., Robinson, K.A., Nguyen, X., Pye, Q.N., Stewart, C.A., Geddes, J., Markesbery, W.R., Patel, E., Johnson, G.V., and Bing, G. (1999) p38 kinase is activated in the Alzheimer's disease brain. J. Neurochem., 72 (5), 2053–2058.
- Sheng, J.G., Jones, R.A., Zhou, X.Q., McGinness, J.M., Van Eldik, L.J., Mrak, R.E., and Griffin, W.S. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem. Int., 39 (5–6), 341–348.
- Sun, A., Liu, M., Nguyen, X.V., and Bing, G. (2003) P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Exp. Neurol., 183 (2), 394–405.
- Swatton, J.E., Sellers, L.A., Faull, R.L., Holland, A., Iritani, S., and Bahn, S. (2004) Increased MAP kinase activity in Alzheimer's and down syndrome but not in schizophrenia human brain. Eur. J. Neurosci., 19 (10), 2711–2719.
- Giovannini, M.G., Scali, C., Prosperi, C., Bellucci, A., Vannucchi, M.G., Rosi, S., Pepeu, G., and Casamenti, F. (2002) Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol. Dis., 11 (2), 257–274.
- Giraldo, E., Lloret, A., Fuchsberger, T., and Vina, J. (2014) Abeta and tau toxicities in Alzheimer's are linked via oxidative stress-induced p38 activation: protective role of vitamin E. Redox Biol., 2, 873–877.
- Bach, J.P., Mengel, D., Wahle, T., Kautz, A., Balzer-Geldsetzer, M., Al-Abed, Y., Dodel, R., and Bacher, M. (2011) The role of CNI-1493 in the function of primary microglia with respect to amyloid-beta. J. Alzheimers Dis., 26 (1), 69–80.
- Roy, S.M., Grum-Tokars, V.L., Schavocky, J.P., Saeed, F., Staniszewski, A., Teich, A.F., Arancio, O., Bachstetter, A.D., Webster, S.J., Van Eldik, L.J., Minasov, G., Anderson, W.F., Pelletier, J.C., and Watterson, D.M. (2015) Targeting human central nervous system protein kinases: an isoform selective p38alpha MAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models. ACS Chem. Neurosci., 6 (4), 666–680.
- Pei, J.J., An, W.L., Zhou, X.W., Nishimura, T., Norberg, J., Benedikz, E., Gotz, J., and Winblad, B. (2006) P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS Lett., 580 (1), 107–114.
- Ma, T., Hoeffer, C.A., Capetillo-Zarate, E., Yu, F., Wong, H., Lin, M.T., Tampellini, D., Klann, E., Blitzer, R.D., and Gouras, G.K. (2010) Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS One, 5 (9). doi: 10.1371/journal.pone.0012845
- Avrahami, L., Farfara, D., Shaham-Kol, M., Vassar, R., Frenkel, D., and Eldar-Finkelman, H. (2013) Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. J. Biol. Chem., 288 (2), 1295–1306.
- Lafay-Chebassier, C., Perault-Pochat, M.C., Page, G., Rioux Bilan, A., Damjanac, M., Pain, S., Houeto, J.L., Gil, R., and Hugon, J. (2006) The immunosuppressant rapamycin exacerbates neurotoxicity of abeta peptide. J. Neurosci. Res., 84 (6), 1323–1334.
- Sun, M.K. and Alkon, D.L. (2014) The “memory kinases”: roles of PKC isoforms in signal processing and memory formation. Prog. Mol. Biol. Transl. Sci., 122, 31–59.
- Skovronsky, D.M., Moore, D.B., Milla, M.E., Doms, R.W., and Lee, V.M. (2000) Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network. J. Biol. Chem., 275 (4), 2568–2575.
- Etcheberrigaray, R., Tan, M., Dewachter, I., Kuiperi, C., Van der Auwera, I., Wera, S., Qiao, L., Bank, B., Nelson, T.J., Kozikowski, A.P., Van Leuven, F., and Alkon, D.L. (2004) Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc. Natl. Acad. Sci. U.S.A., 101 (30), 11141–11146.
- Lee, W., Boo, J.H., Jung, M.W., Park, S.D., Kim, Y.H., Kim, S.U., and Mook-Jung, I. (2004) Amyloid beta peptide directly inhibits PKC activation. Mol. Cell. Neurosci., 26 (2), 222–231.
- Pakaski, M., Balaspiri, L., Checler, F., and Kasa, P. (2002) Human amyloid-beta causes changes in the levels of endothelial protein kinase C and its alpha isoform in vitro. Neurochem. Int., 41 (6), 409–414.
- Kim, T., Hinton, D.J., and Choi, D.S. (2011) Protein kinase C-regulated abeta production and clearance. Int. J. Alzheimers Dis., 2011, 857368.
- Choi, D.S., Wang, D., Yu, G.Q., Zhu, G., Kharazia, V.N., Paredes, J.P., Chang, W.S., Deitchman, J.K., Mucke, L., and Messing, R.O. (2006) PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc. Natl. Acad. Sci. U.S.A., 103 (21), 8215–8220.
- Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of cancer: the next generation. Cell, 144 (5), 646–674.
- Carnero, A. and Paramio, J.M. (2014) The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front. Oncol., 4, 252.
- Kang, S., Bader, A.G., and Vogt, P.K. (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl. Acad. Sci. U.S.A., 102 (3), 802–807.
- Adams, J.R., Xu, K., Liu, J.C., Agamez, N.M., Loch, A.J., Wong, R.G., Wang, W., Wright, K.L., Lane, T.F., Zacksenhaus, E., and Egan, S.E. (2011) Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res., 71 (7), 2706–2717.
- Meyer, D.S., Brinkhaus, H., Muller, U., Muller, M., Cardiff, R.D., and Bentires-Alj, M. (2011) Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res., 71 (13), 4344–4351.
- Yuan, W., Stawiski, E., Janakiraman, V., Chan, E., Durinck, S., Edgar, K.A., Kljavin, N.M., Rivers, C.S., Gnad, F., Roose-Girma, M., Haverty, P.M., Fedorowicz, G., Heldens, S., Soriano, R.H., Zhang, Z., Wallin, J.J., Johnson, L., Merchant, M., Modrusan, Z., Stern, H.M., and Seshagiri, S. (2013) Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. Oncogene, 32 (3), 318–326.
- Meyer, D.S., Koren, S., Leroy, C., Brinkhaus, H., Muller, U., Klebba, I., Muller, M., Cardiff, R.D., and Bentires-Alj, M. (2013) Expression of PIK3CA mutant E545K in the mammary gland induces heterogeneous tumors but is less potent than mutant H1047R. Oncogenesis, 2, e74.
- Trejo, C.L., Green, S., Marsh, V., Collisson, E.A., Iezza, G., Phillips, W.A., and McMahon, M. (2013) Mutationally activated PIK3CA(H1047R) cooperates with BRAF(V600E) to promote lung cancer progression. Cancer Res., 73 (21), 6448–6461.
- Kinross, K.M., Montgomery, K.G., Kleinschmidt, M., Waring, P., Ivetac, I., Tikoo, A., Saad, M., Hare, L., Roh, V., Mantamadiotis, T., Sheppard, K.E., Ryland, G.L., Campbell, I.G., Gorringe, K.L., Christensen, J.G., Cullinane, C., Hicks, R.J., Pearson, R.B., Johnstone, R.W., McArthur, G.A., and Phillips, W.A. (2012) An activating Pik3ca mutation coupled with pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Invest., 122 (2), 553–557.
- Hare, L.M., Phesse, T.J., Waring, P.M., Montgomery, K.G., Kinross, K.M., Mills, K., Roh, V., Heath, J.K., Ramsay, R.G., Ernst, M., and Phillips, W.A. (2014) Physiological expression of the PI3K-activating mutation Pik3ca(H1047R) combines with apc loss to promote development of invasive intestinal adenocarcinomas in mice. Biochem. J., 458 (2), 251–258.
- Joshi, A., Miller, C. Jr. Baker, S.J., and Ellenson, L.H. (2015) Activated mutant p110alpha causes endometrial carcinoma in the setting of biallelic pten deletion. Am. J. Pathol., 185 (4), 1104–1113.
- Blanco-Aparicio, C., Renner, O., Leal, J.F., and Carnero, A. (2007) PTEN, more than the AKT pathway. Carcinogenesis, 28 (7), 1379–1386.
- Blanco-Aparicio, C., Canamero, M., Cecilia, Y., Pequeno, B., Renner, O., Ferrer, I., and Carnero, A. (2010) Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models. PLoS One, 5 (2), e9305.
- Hutchinson, J.N., Jin, J., Cardiff, R.D., Woodgett, J.R., and Muller, W.J. (2004) Activation of akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res., 64 (9), 3171–3178.
- Dillon, R.L., Marcotte, R., Hennessy, B.T., Woodgett, J.R., Mills, G.B., and Muller, W.J. (2009) Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Res., 69 (12), 5057–5064.
- Maroulakou, I.G., Oemler, W., Naber, S.P., and Tsichlis, P.N. (2007) Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res., 67 (1), 167–177.
- Martini, M., Ciraolo, E., Gulluni, F., and Hirsch, E. (2013) Targeting PI3K in cancer: any good news? Front. Oncol., 3, 108.
- Miller, B.W., Przepiorka, D., de Claro, R.A., Lee, K., Nie, L., Simpson, N., Gudi, R., Saber, H., Shord, S., Bullock, J., Marathe, D., Mehrotra, N., Hsieh, L.S., Ghosh, D., Brown, J., Kane, R.C., Justice, R., Kaminskas, E., Farrell, A.T., and Pazdur, R. (2015) FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin. Cancer Res., 21 (77), 1525–1529.
- Keating, G.M. (2015) Idelalisib: a review of its use in chronic lymphocytic leukaemia and indolent non-hodgkin's lymphoma. Target. Oncol., 10 (1), 141–151.
- Menon, S. and Manning, B.D. (2008) Common corruption of the mTOR signaling network in human tumors. Oncogene, 27 (Suppl. 2), S43–S51.
- Cargnello, M., Tcherkezian, J., and Roux, P.P. (2015) The expanding role of mTOR in cancer cell growth and proliferation. Mutagenesis, 30 (2), 169–176.
- Wander, S.A., Hennessy, B.T., and Slingerland, J.M. (2011) Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Invest., 121 (4), 1231–1241.
- Bauer, T.M., Patel, M.R., and Infante, J.R. (2015) Targeting PI3 kinase in cancer. Pharmacol. Ther., 146, 53–60.
- Owonikoko, T.K. and Khuri, F.R. (2013) Targeting the PI3K/AKT/mTOR pathway: biomarkers of success and tribulation. Am. Soc. Clin. Oncol. Educ. Book.
- O'Reilly, K.E., Rojo, F., She, Q.B., Solit, D., Mills, G.B., Smith, D., Lane, H., Hofmann, F., Hicklin, D.J., Ludwig, D.L., Baselga, J., and Rosen, N. (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates akt. Cancer Res., 66 (3), 1500–1508.
- Kim, J., Thorne, S.H., Sun, L., Huang, B., and Mochly-Rosen, D. (2011) Sustained inhibition of PKCalpha reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene, 30 (3), 323–333.
- Jr. Sledge, G.W. and Gokmen-Polar, Y. (2006) Protein kinase C-beta as a therapeutic target in breast cancer. Semin. Oncol., 33 (3, Suppl. 9), S15–S18.
- Grossoni, V.C., Todaro, L.B., Kazanietz, M.G., de Kier Joffe, E.D., and Urtreger, A.J. (2009) Opposite effects of protein kinase C beta1 (PKCbeta1) and PKCepsilon in the metastatic potential of a breast cancer murine model. Breast Cancer Res. Treat., 118 (3), 469–480.
- Mischak, H., Goodnight, J.A., Kolch, W., Martiny-Baron, G., Schaechtle, C., Kazanietz, M.G., Blumberg, P.M., Pierce, J.H., and Mushinski, J.F. (1993) Overexpression of protein kinase C-delta and -epsilon in NIH 3 T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J. Biol. Chem., 268 (9), 6090–6096.
- Gorin, M.A. and Pan, Q. (2009) Protein kinase C epsilon: an oncogene and emerging tumor biomarker. Mol. Cancer, 8, 9. doi: 10.1186/1476-4598-8-9
- Pan, Q., Bao, L.W., Kleer, C.G., Sabel, M.S., Griffith, K.A., Teknos, T.N., and Merajver, S.D. (2005) Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. Cancer Res., 65 (18), 8366–8371.
- Parker, P.J., Justilien, V., Riou, P., Linch, M., and Fields, A.P. (2014) Atypical protein kinase ciota as a human oncogene and therapeutic target. Biochem. Pharmacol., 88 (1), 1–11.
- Liu, S.G., Wang, B.S., Jiang, Y.Y., Zhang, T.T., Shi, Z.Z., Yang, Y., Yang, Y.L., Wang, X.C., Lin, D.C., Zhang, Y., Yang, H., Cai, Y., Zhan, Q.M., and Wang, M.R. (2011) Atypical protein kinase ciota (PKCiota) promotes metastasis of esophageal squamous cell carcinoma by enhancing resistance to anoikis via PKCiota-SKP2-AKT pathway. Mol. Cancer Res., 9 (4), 390–402.
- Martin-Liberal, J., Lagares-Tena, L., and Larkin, J. (2014) Prospects for MEK inhibitors for treating cancer. Expert Opin. Drug Saf., 13 (4), 483–495.
- Santarpia, L., Lippman, S.M., and El-Naggar, A.K. (2012) Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin. Ther. Targets, 16 (1), 103–119.
- Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroiakovski, D., Lichinitser, M., Dummer, R., Grange, F., Mortier, L., Chiarion-Sileni, V., Drucis, K., Krajsova, I., Hauschild, A., Lorigan, P., Wolter, P., Long, G.V., Flaherty, K., Nathan, P., Ribas, A., Martin, A.M., Sun, P., Crist, W., Legos, J., Rubin, S.D., Little, S.M., and Schadendorf, D. (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med., 372 (1), 30–39.
- Grossi, V., Peserico, A., Tezil, T., and Simone, C. (2014) p38alpha MAPK pathway: a key factor in colorectal cancer therapy and chemoresistance. World J. Gastroenterol., 20 (29), 9744–9758.
- Rudalska, R., Dauch, D., Longerich, T., McJunkin, K., Wuestefeld, T., Kang, T.W., Hohmeyer, A., Pesic, M., Leibold, J., von Thun, A., Schirmacher, P., Zuber, J., Weiss, K.H., Powers, S., Malek, N.P., Eilers, M., Sipos, B., Lowe, S.W., Geffers, R., Laufer, S., and Zender, L. (2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med., 20 (10), 1138–1146.
- Bubici, C. and Papa, S. (2014) JNK signalling in cancer: in need of new, smarter therapeutic targets. Br. J. Pharmacol., 171 (1), 24–37.
- Hui, L., Zatloukal, K., Scheuch, H., Stepniak, E., and Wagner, E.F. (2008) Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J. Clin. Invest., 118 (12), 3943–3953.
- Chen, N., Nomura, M., She, Q.B., Ma, W.Y., Bode, A.M., Wang, L., Flavell, R.A., and Dong, Z. (2001) Suppression of skin tumorigenesis in c-jun NH(2)-terminal kinase-2-deficient mice. Cancer Res., 61 (10), 3908–3912.
- Wang, H., Wang, H.S., Zhou, B.H., Li, C.L., Zhang, F., Wang, X.F., Zhang, G., Bu, X.Z., Cai, S.H., and Du, J. (2013) Epithelial-mesenchymal transition (EMT) induced by TNF-alpha requires AKT/GSK-3beta-mediated stabilization of snail in colorectal cancer. PLoS One, 8 (2), e56664.
- Zheng, H., Li, W., Wang, Y., Liu, Z., Cai, Y., Xie, T., Shi, M., Wang, Z., and Jiang, B. (2013) Glycogen synthase kinase-3 beta regulates snail and beta-catenin expression during fas-induced epithelial-mesenchymal transition in gastrointestinal cancer. Eur. J. Cancer, 49 (12), 2734–2746.
- Wen, W., Ding, J., Sun, W., Fu, J., Chen, Y., Wu, K., Ning, B., Han, T., Huang, L., Chen, C., Xie, D., Li, Z., Feng, G., Wu, M., Xie, W., and Wang, H. (2012) Cyclin G1-mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression. Hepatology, 55 (6), 1787–1798.
- McCubrey, J.A., Steelman, L.S., Bertrand, F.E., Davis, N.M., Sokolosky, M., Abrams, S.L., Montalto, G., D'Assoro, A.B., Libra, M., Nicoletti, F., Maestro, R., Basecke, J., Rakus, D., Gizak, A., Demidenko, Z.N., Cocco, L., Martelli, A.M., and Cervello, M. (2014) GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget, 5 (10), 2881–2911.
- Desbois-Mouthon, C., Blivet-Van Eggelpoel, M.J., Beurel, E., Boissan, M., Delelo, R., Cadoret, A., and Capeau, J. (2002) Dysregulation of glycogen synthase kinase-3beta signaling in hepatocellular carcinoma cells. Hepatology, 36 (6), 1528–1536.
- Farago, M., Dominguez, I., Landesman-Bollag, E., Xu, X., Rosner, A., Cardiff, R.D., and Seldin, D.C. (2005) Kinase-inactive glycogen synthase kinase 3beta promotes wnt signaling and mammary tumorigenesis. Cancer Res., 65 (13), 5792–5801.
- Zhou, W., Wang, L., Gou, S.M., Wang, T.L., Zhang, M., Liu, T., and Wang, C.Y. (2012) ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer. Cancer Lett., 316 (2), 178–186.
- Mann, K.M., Ward, J.M., Yew, C.C., Kovochich, A., Dawson, D.W., Black, M.A., Brett, B.T., Sheetz, T.E., Dupuy, A.J., Australian Pancreatic Cancer Genome Initiative, Chang, D.K., Biankin, A.V., Waddell, N., Kassahn, K.S., Grimmond, S.M., Rust, A.G., Adams, D.J., Jenkins, N.A., and Copeland, N.G. (2012) Sleeping beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc. Natl. Acad. Sci. U.S.A., 109 (16), 5934–5941.
- Rahrmann, E.P., Watson, A.L., Keng, V.W., Choi, K., Moriarity, B.S., Beckmann, D.A., Wolf, N.K., Sarver, A., Collins, M.H., Moertel, C.L., Wallace, M.R., Gel, B., Serra, E., Ratner, N., and Largaespada, D.A. (2013) Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nat. Genet., 45 (7), 756–766.
- Kean, M.J., Couzens, A.L., and Gingras, A.C. (2012) Mass spectrometry approaches to study mammalian kinase and phosphatase associated proteins. Methods, 57 (4), 400–408.
- Zhang, L., Holmes, I.P., Hochgrafe, F., Walker, S.R., Ali, N.A., Humphrey, E.S., Wu, J., de Silva, M., Kersten, W.J., Connor, T., Falk, H., Allan, L., Street, I.P., Bentley, J.D., Pilling, P.A., Monahan, B.J., Peat, T.S., and Daly, R.J. (2013) Characterization of the novel broad-spectrum kinase inhibitor CTx-0294885 as an affinity reagent for mass spectrometry-based kinome profiling. J. Proteome Res., 12 (7), 3104–3116.
- Dunham, W.H., Mullin, M., and Gingras, A.C. (2012) Affinity-purification coupled to mass spectrometry: basic principles and strategies. Proteomics, 12 (10), 1576–1590.
- Song, J., Hao, Y., Du, Z., Wang, Z., and Ewing, R.M. (2012) Identifying novel protein complexes in cancer cells using epitope-tagging of endogenous human genes and affinity-purification mass spectrometry. J. Proteome Res., 11 (12), 5630–5641.
- Dalgliesh, G.L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., Teague, J., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P.J., Forbes, S., Jia, M., Jones, D., Knott, H., Kok, C.Y., Lau, K.W., Leroy, C., Lin, M.L., McBride, D.J., Maddison, M., Maguire, S., McLay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., O'Meara, S., Pleasance, E., Rajasingham, A., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P.S., Turrell, K., Dykema, K.J., Khoo, S.K., Petillo, D., Wondergem, B., Anema, J., Kahnoski, R.J., Teh, B.T., Stratton, M.R., and Futreal, P.A. (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature, 463 (7279), 360–363.
- Song, X.M., Fiedler, M., Galuska, D., Ryder, J.W., Fernstrom, M., Chibalin, A.V., Wallberg-Henriksson, H., and Zierath, J.R. (2002) 5-aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia, 45 (1), 56–65.
- Liu, J., Bang, A.G., Kintner, C., Orth, A.P., Chanda, S.K., Ding, S., and Schultz, P.G. (2005) Identification of the wnt signaling activator leucine-rich repeat in flightless interaction protein 2 by a genome-wide functional analysis. Proc. Natl. Acad. Sci. U.S.A., 102 (6), 1927–1932.
- Kim, Y.H., Lee, E.K., Park, S.A., Kim, N.H., and Kim, C.W. (2012) Proteomic analysis of plasma from a tau transgenic mouse. Int. J. Dev. Neurosci., 30 (4), 277–283.
- Stuhlmiller, T.J., Earp, H.S., and Johnson, G.L. (2014) Adaptive reprogramming of the breast cancer kinome. Clin. Pharmacol. Ther., 95 (4), 413–415.
- Duncan, J.S., Whittle, M.C., Nakamura, K., Abell, A.N., Midland, A.A., Zawistowski, J.S., Johnson, N.L., Granger, D.A., Jordan, N.V., Darr, D.B., Usary, J., Kuan, P.F., Smalley, D.M., Major, B., He, X., Hoadley, K.A., Zhou, B., Sharpless, N.E., Perou, C.M., Kim, W.Y., Gomez, S.M., Chen, X., Jin, J., Frye, S.V., Earp, H.S., Graves, L.M., and Johnson, G.L. (2012) Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell, 149 (2), 307–321.
- Cooper, M.J., Cox, N.J., Zimmerman, E.I., Dewar, B.J., Duncan, J.S., Whittle, M.C., Nguyen, T.A., Jones, L.S., Ghose Roy, S., Smalley, D.M., Kuan, P.F., Richards, K.L., Christopherson, R.I., Jin, J., Frye, S.V., Johnson, G.L., Baldwin, A.S., and Graves, L.M. (2013) Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia. PLoS One, 8 (6), e66755.
- Roszik, J., Toth, G., Szollosi, J., and Vereb, G. (2013) Validating pharmacological disruption of protein-protein interactions by acceptor photobleaching FRET imaging. Methods Mol. Biol., 986, 165–178.
- Ng, T., Squire, A., Hansra, G., Bornancin, F., Prevostel, C., Hanby, A., Harris, W., Barnes, D., Schmidt, S., Mellor, H., Bastiaens, P.I., and Parker, P.J. (1999) Imaging protein kinase calpha activation in cells. Science, 283 (5410), 2085–2089.
- Yadav, R.B., Burgos, P., Parker, A.W., Iadevaia, V., Proud, C.G., Allen, R.A., O'Connell, J.P., Jeshtadi, A., Stubbs, C.D., and Botchway, S.W. (2013) mTOR direct interactions with rheb-GTPase and raptor: sub-cellular localization using fluorescence lifetime imaging. BMC Cell. Biol., 14, 3. doi: 10.1186/1471-2121-14-3
- Veeriah, S., Leboucher, P., de Naurois, J., Jethwa, N., Nye, E., Bunting, T., Stone, R., Stamp, G., Calleja, V., Jeffrey, S.S., Parker, P.J., and Larijani, B. (2014) High-throughput time-resolved FRET reveals Akt/PKB activation as a poor prognostic marker in breast cancer. Cancer Res., 74 (18), 4983–4995.
- Shea, K.F., Wells, C.M., Garner, A.P., and Jones, G.E. (2008) ROCK1 and LIMK2 interact in spread but not blebbing cancer cells. PLoS One, 3 (10), e3398.
- Fernandez-Duenas, V., Llorente, J., Gandia, J., Borroto-Escuela, D.O., Agnati, L.F., Tasca, C.I., Fuxe, K., and Ciruela, F. (2012) Fluorescence resonance energy transfer-based technologies in the study of protein-protein interactions at the cell surface. Methods, 57 (4), 467–472.
- Larbouret, C., Gaborit, N., Chardes, T., Coelho, M., Campigna, E., Bascoul-Mollevi, C., Mach, J.P., Azria, D., Robert, B., and Pelegrin, A. (2012) In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption. Neoplasia, 14 (2), 121–130.
- Mizutani, T., Kondo, T., Darmanin, S., Tsuda, M., Tanaka, S., Tobiume, M., Asaka, M., and Ohba, Y. (2010) A novel FRET-based biosensor for the measurement of BCR-ABL activity and its response to drugs in living cells. Clin. Cancer Res., 16 (15), 3964–3975.
- Morris, M.C. (2013) Fluorescent biosensors – probing protein kinase function in cancer and drug discovery. Biochim. Biophys. Acta, 1834 (7), 1387–1395.
- Fire, A., Xu, S., Montgomery, M.K., Kostas, S.A., Driver, S.E., and Mello, C.C. (1998) Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans. Nature, 391 (6669), 806–811.
- Dykxhoorn, D.M., Novina, C.D., and Sharp, P.A. (2003) Killing the messenger: short RNAs that silence gene expression. Nat. Rev. Mol. Cell Biol., 4 (6), 457–467.
- Breen, M.E. and Soellner, M.B. (2015) Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges. ACS Chem. Biol., 10 (1), 175–189.
- Schonherr, M., Bhattacharya, A., Kottek, T., Szymczak, S., Koberle, M., Wickenhauser, C., Siebolts, U., Saalbach, A., Koczan, D., Magin, T.M., Simon, J.C., and Kunz, M. (2014) Genomewide RNAi screen identifies protein kinase cb and new members of mitogen-activated protein kinase pathway as regulators of melanoma cell growth and metastasis. Pigm. Cell Melanoma Res., 27 (3), 418–430.
- Izrailit, J., Berman, H.K., Datti, A., Wrana, J.L., and Reedijk, M. (2013) High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFbeta pathways as fundamental notch regulators in breast cancer. Proc. Natl. Acad. Sci. U.S.A., 110 (5), 1714–1719.
- Banerji, V., Frumm, S.M., Ross, K.N., Li, L.S., Schinzel, A.C., Hahn, C.K., Kakoza, R.M., Chow, K.T., Ross, L., Alexe, G., Tolliday, N., Inguilizian, H., Galinsky, I., Stone, R.M., DeAngelo, D.J., Roti, G., Aster, J.C., Hahn, W.C., Kung, A.L., and Stegmaier, K. (2012) The intersection of genetic and chemical genomic screens identifies GSK-3alpha as a target in human acute myeloid leukemia. J. Clin. Invest., 122 (3), 935–947.
- Cronan, M.R., Nakamura, K., Johnson, N.L., Granger, D.A., Cuevas, B.D., Wang, J.G., Mackman, N., Scott, J.E., Dohlman, H.G., and Johnson, G.L. (2012) Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis. Oncogene, 31 (34), 3889–3900.
- Liu-Sullivan, N., Zhang, J., Bakleh, A., Marchica, J., Li, J., Siolas, D., Laquerre, S., Degenhardt, Y.Y., Wooster, R., Chang, K., Hannon, G.F., and Powers, S. (2011) Pooled shRNA screen for sensitizers to inhibition of the mitotic regulator polo-like kinase (PLK1). Oncotarget, 2 (12), 1254–1264.
- Iorns, E., Turner, N.C., Elliott, R., Syed, N., Garrone, O., Gasco, M., Tutt, A.N., Crook, T., Lord, C.J., and Ashworth, A. (2008) Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell, 13 (2), 91–104.
- Vora, S.R., Juric, D., Kim, N., Mino-Kenudson, M., Huynh, T., Costa, C., Lockerman, E.L., Pollack, S.F., Liu, M., Li, X., Lehar, J., Wiesmann, M., Wartmann, M., Chen, Y., Cao, Z.A., Pinzon-Ortiz, M., Kim, S., Schlegel, R., Huang, A., and Engelman, J.A. (2014) CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell, 26 (1), 136–149.
- Thorne, C.A., Wichaidit, C., Coster, A.D., Posner, B.A., Wu, L.F., and Altschuler, S.J. (2015) GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors. Nat. Chem. Biol., 11 (1), 58–63.
- Sauer, B. and Henderson, N. (1988) Site-specific DNA recombination in mammalian cells by the cre recombinase of bacteriophage P1. Proc. Natl. Acad. Sci. U.S.A., 85 (14), 5166–5170.
- Sternberg, N. and Hamilton, D. (1981) Bacteriophage P1 site-specific recombination. I. Recombination between loxP sites. J. Mol. Biol., 150 (4), 467–486.
-
Hall, B., Limaye, A., and Kulkarni, A.B. (2009) Overview: generation of gene knockout mice. Curr. Protoc. Cell Biol.,Chapter 19 Unit 19.12 19.12.1-17.
10.1002/0471143030.cb1912s44 Google Scholar
- Gu, H., Marth, J.D., Orban, P.C., Mossmann, H., and Rajewsky, K. (1994) Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science, 265 (5168), 103–106.
- Feil, R., Wagner, J., Metzger, D., and Chambon, P. (1997) Regulation of cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem. Biophys. Res. Commun., 237 (3), 752–757.
- Hayashi, S. and McMahon, A.P. (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev. Biol., 244 (2), 305–318.
- Utomo, A.R., Nikitin, A.Y., and Lee, W.H. (1999) Temporal, spatial, and cell type-specific control of cre-mediated DNA recombination in transgenic mice. Nat. Biotechnol., 17 (11), 1091–1096.
- Anton, M. and Graham, F.L. (1995) Site-specific recombination mediated by an adenovirus vector expressing the cre recombinase protein: a molecular switch for control of gene expression. J. Virol., 69 (8), 4600–4606.
- Patel, S., MacAulay, K., and Woodgett, J.R. (2011) Tissue-specific analysis of glycogen synthase kinase-3alpha (GSK-3alpha) in glucose metabolism: effect of strain variation. PLoS One, 6 (1), e15845.
- Bhattacharjee, R., Goswami, S., Dudiki, T., Popkie, A.P., Phiel, C.J., Kline, D., and Vijayaraghavan, S. (2015) Targeted disruption of glycogen synthase kinase 3a (gsk3a) in mice affects sperm motility resulting in male infertility. Biol. Reprod., 92 (3), 65.
- Lal, H., Zhou, J., Ahmad, F., Zaka, R., Vagnozzi, R.J., Decaul, M., Woodgett, J., Gao, E., and Force, T. (2012) Glycogen synthase kinase-3alpha limits ischemic injury, cardiac rupture, post-myocardial infarction remodeling and death. Circulation, 125 (1), 65–75.
- Zhou, J., Lal, H., Chen, X., Shang, X., Song, J., Li, Y., Kerkela, R., Doble, B.W., MacAulay, K., DeCaul, M., Koch, W.J., Farber, J., Woodgett, J., Gao, E., and Force, T. (2010) GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice. J. Clin. Invest., 120 (7), 2280–2291.
- Zhou, J., Freeman, T.A., Ahmad, F., Shang, X., Mangano, E., Gao, E., Farber, J., Wang, Y., Ma, X.L., Woodgett, J., Vagnozzi, R.J., Lal, H., and Force, T. (2013) GSK-3alpha is a central regulator of age-related pathologies in mice. J. Clin. Invest., 123 (4), 1821–1832.
- Kaidanovich-Beilin, O., Lipina, T.V., Takao, K., van Eede, M., Hattori, S., Laliberte, C., Khan, M., Okamoto, K., Chambers, J.W., Fletcher, P.J., MacAulay, K., Doble, B.W., Henkelman, M., Miyakawa, T., Roder, J., and Woodgett, J.R. (2009) Abnormalities in brain structure and behavior in GSK-3alpha mutant mice. Mol. Brain, 2, 35. doi: 10.1186/1756-6606-2-35
- Norregaard, R., Tao, S., Nilsson, L., Woodgett, J.R., Kakade, V., Yu, A.S., Howard, C., and Rao, R. (2015) Glycogen synthase kinase 3alpha regulates urine concentrating mechanism in mice. Am. J. Physiol. Renal. Physiol., 308 (6), F650–F660.
- Kimura, T., Yamashita, S., Nakao, S., Park, J.M., Murayama, M., Mizoroki, T., Yoshiike, Y., Sahara, N., and Takashima, A. (2008) GSK-3beta is required for memory reconsolidation in adult brain. PLoS One, 3 (10), e3540.
- Zhai, P., Sciarretta, S., Galeotti, J., Volpe, M., and Sadoshima, J. (2011) Differential roles of GSK-3beta during myocardial ischemia and ischemia/reperfusion. Circ. Res., 109 (5), 502–511.
- Woulfe, K.C., Gao, E., Lal, H., Harris, D., Fan, Q., Vagnozzi, R., DeCaul, M., Shang, X., Patel, S., Woodgett, J.R., Force, T., and Zhou, J. (2010) Glycogen synthase kinase-3beta regulates post-myocardial infarction remodeling and stress-induced cardiomyocyte proliferation in vivo. Circ. Res., 106 (10), 1635–1645.
- Ahmad, F., Lal, H., Zhou, J., Vagnozzi, R.J., Yu, J.E., Shang, X., Woodgett, J.R., Gao, E., and Force, T. (2014) Cardiomyocyte-specific deletion of Gsk3alpha mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J. Am. Coll. Cardiol., 64 (7), 696–706.
- Maurin, H., Lechat, B., Dewachter, I., Ris, L., Louis, J.V., Borghgraef, P., Devijver, H., Jaworski, T., and Van Leuven, F. (2013) Neurological characterization of mice deficient in GSK3alpha highlight pleiotropic physiological functions in cognition and pathological activity as tau kinase. Mol. Brain, 6, 27. doi: 10.1186/1756-6606-6-27
- Urs, N.M., Snyder, J.C., Jacobsen, J.P., Peterson, S.M., and Caron, M.G. (2012) Deletion of GSK3beta in D2R-expressing neurons reveals distinct roles for beta-arrestin signaling in antipsychotic and lithium action. Proc. Natl. Acad. Sci. U.S.A., 109 (50), 20732–20737.
- Zhou, W., Chen, L., Paul, J., Yang, S., Li, F., Sampson, K., Woodgett, J.R., Beaulieu, J.M., Gamble, K.L., and Li, X. (2012) The effects of glycogen synthase kinase-3beta in serotonin neurons. PLoS One, 7 (8), e43262.
- Patel, S., Doble, B.W., MacAulay, K., Sinclair, E.M., Drucker, D.J., and Woodgett, J.R. (2008) Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. Mol. Cell. Biol., 28 (20), 6314–6328.
- Pansters, N.A., Schols, A.M., Verhees, K.J., de Theije, C.C., Snepvangers, F.J., Kelders, M.C., Ubags, N.D., Haegens, A., and Langen, R.C. (2015) Muscle-specific GSK-3beta ablation accelerates regeneration of disuse-atrophied skeletal muscle. Biochim. Biophys. Acta, 1852 (3), 490–506.
- Liu, Y., Tanabe, K., Baronnier, D., Patel, S., Woodgett, J., Cras-Meneur, C., and Permutt, M.A. (2010) Conditional ablation of gsk-3beta in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice. Diabetologia, 53 (12), 2600–2610.
- Tanabe, K., Liu, Z., Patel, S., Doble, B.W., Li, L., Cras-Meneur, C., Martinez, S.C., Welling, C.M., White, M.F., Bernal-Mizrachi, E., Woodgett, J.R., and Permutt, M.A. (2008) Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol., 6 (2), e37.
- Kim, W.Y., Wang, X., Wu, Y., Doble, B.W., Patel, S., Woodgett, J.R., and Snider, W.D. (2009) GSK-3 is a master regulator of neural progenitor homeostasis. Nat. Neurosci., 12 (11), 1390–1397.
- Dembowy, J., Adissu, H.A., Liu, J.C., Zacksenhaus, E., and Woodgett, J.R. (2014) Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis. Oncogene, doi: 10.1038/onc.2014.279
- Kyriakis, J.M. and Avruch, J. (2012) Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol. Rev., 92 (2), 689–737.
- Wang, X., Destrument, A., and Tournier, C. (2007) Physiological roles of MKK4 and MKK7: insights from animal models. Biochim. Biophys. Acta, 1773 (8), 1349–1357.
- Lim, S. and Kaldis, P. (2013) Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development, 140 (15), 3079–3093.
- Moore, J.D. (2015) The impact of CRISPR-Cas9 on target identification and validation. Drug Discovery Today, 20 (4), 450–457.
- Hsu, P.D., Lander, E.S., and Zhang, F. (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell, 157 (6), 1262–1278.
- Mojica, F.J., Diez-Villasenor, C., Garcia-Martinez, J., and Soria, E. (2005) Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J. Mol. Evol., 60 (2), 174–182.
- Pourcel, C., Salvignol, G., and Vergnaud, G. (2005) CRISPR elements in yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies. Microbiology, 151(Pt. 3), 653–663.
- Hartenian, E. and Doench, J.G. (2015) Genetic screens and functional genomics using CRISPR/Cas9 technology. FEBS J., 282 (8), 1383–1393.
- Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J.A., and Charpentier, E. (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 337 (6096), 816–821.
- Cong, L., Ran, F.A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P.D., Wu, X., Jiang, W., Marraffini, L.A., and Zhang, F. (2013) Multiplex genome engineering using CRISPR/Cas systems. Science, 339 (6121), 819–823.
- Mali, P., Yang, L., Esvelt, K.M., Aach, J., Guell, M., DiCarlo, J.E., Norville, J.E., and Church, G.M. (2013) RNA-guided human genome engineering via Cas9. Science, 339 (6121), 823–826.
- Wang, T., Wei, J.J., Sabatini, D.M., and Lander, E.S. (2014) Genetic screens in human cells using the CRISPR-Cas9 system. Science, 343 (6166), 80–84.
- Chen, S., Sanjana, N.E., Zheng, K., Shalem, O., Lee, K., Shi, X., Scott, D.A., Song, J., Pan, J.Q., Weissleder, R., Lee, H., Zhang, F., and Sharp, P.A. (2015) Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis. Cell, 160 (6), 1246–1260.
- Shalem, O., Sanjana, N.E., Hartenian, E., Shi, X., Scott, D.A., Mikkelsen, T.S., Heckl, D., Ebert, B.L., Root, D.E., Doench, J.G., and Zhang, F. (2014) Genome-scale CRISPR-Cas9 knockout screening in human cells. Science, 343 (6166), 84–87.
- Matano, M., Date, S., Shimokawa, M., Takano, A., Fujii, M., Ohta, Y., Watanabe, T., Kanai, T., and Sato, T. (2015) Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat. Med., 21 (3), 256–262.
- Zhang, L.L., Cao, F.F., Wang, Y., Meng, F.L., Zhang, Y., Zhong, D.S., and Zhou, Q.H. (2014) The protein kinase C (PKC) inhibitors combined with chemotherapy in the treatment of advanced non-small cell lung cancer: meta-analysis of randomized controlled trials. Clin. Transl. Oncol., 17 (5), 371–377.
- Antal, C.E., Hudson, A.M., Kang, E., Zanca, C., Wirth, C., Stephenson, N.L., Trotter, E.W., Gallegos, L.L., Miller, C.J., Furnari, F.B., Hunter, T., Brognard, J., and Newton, A.C. (2015) Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor. Cell, 160 (3), 489–502.
- Xue, W., Chen, S., Yin, H., Tammela, T., Papagiannakopoulos, T., Joshi, N.S., Cai, W., Yang, G., Bronson, R., Crowley, D.G., Zhang, F., Anderson, D.G., Sharp, P.A., and Jacks, T. (2014) CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature, 514 (7522), 380–384.
- Platt, R.J., Chen, S., Zhou, Y., Yim, M.J., Swiech, L., Kempton, H.R., Dahlman, J.E., Parnas, O., Eisenhaure, T.M., Jovanovic, M., Graham, D.B., Jhunjhunwala, S., Heidenreich, M., Xavier, R.J., Langer, R., Anderson, D.G., Hacohen, N., Regev, A., Feng, G., Sharp, P.A., and Zhang, F. (2014) CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell, 159 (2), 440–455.
- Doudna, J.A. and Charpentier, E. (2014) Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science, 346 (6213), 1258096.
- Sander, J.D. and Joung, J.K. (2014) CRISPR-cas systems for editing, regulating and targeting genomes. Nat. Biotechnol., 32 (4), 347–355.
