Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets

Science Signaling

Volumn 6, Issue 294, 2013, Pages

  Miller, Martin L ^a   Molinelli, Evan J ^a   Nair, Jayasree S ^a   Sheikh, Tahir ^a   Samy, Rita ^a   Jing, Xiaohong ^a   He, Qin ^a   Korkut, Anil ^a   Crago, Aimee M ^a   Singer, Samuel ^a   Schwartz, Gary K ^a   Sander, Chris ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AG 538; ALPHA [AMINO(4 AMINOPHENYLTHIO)METHYLENE] 2 (TRIFLUOROMETHYL)PHENYLACETONITRILE; ANTINEOPLASTIC AGENT; CYCLIN DEPENDENT KINASE 4; FR 180204; GEFITINIB; HISTONE DEACETYLASE INHIBITOR; NVP AEW 541; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PLATELET DERIVED GROWTH FACTOR RECEPTOR INHIBITOR; PROTEIN KINASE B INHIBITOR; PROTEIN KINASE INHIBITOR; R 1507; RAPAMYCIN; ROTTLERIN; RYUVIDINE; SELUMETINIB; SOMATOMEDIN C RECEPTOR; STAT3 PROTEIN INHIBITOR; SU 11247; UNCLASSIFIED DRUG;

ARTICLE; CANCER CELL CULTURE; CELL ASSAY; CELL COUNT; CELL CYCLE ARREST; CELL PROLIFERATION; CELL SURVIVAL; CELL VIABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DEDIFFERENTIATED LIPOSARCOMA; DRUG POTENTIATION; DRUG TARGETING; ENZYME INHIBITION; FLOW CYTOMETRY; GENE DOSAGE; GENE EXPRESSION; HUMAN; HUMAN CELL; IMMUNOBLOTTING; IN VITRO STUDY; LIPOSARCOMA; PRIORITY JOURNAL; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; PROTEOMICS; RETINOBLASTOMA; SIGNAL TRANSDUCTION; WESTERN BLOTTING;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CELL LINE, TUMOR; COMPUTER SIMULATION; CYCLIN-DEPENDENT KINASE 4; DRUG DELIVERY SYSTEMS; DRUG SCREENING ASSAYS, ANTITUMOR; DRUG SYNERGISM; HUMANS; LIPOSARCOMA; MODELS, BIOLOGICAL; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTOR, IGF TYPE 1; SIGNAL TRANSDUCTION;

EID: 84885811004     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.2004014     Document Type: Article

References (96)

1. A. Dei Tos, Liposarcoma: New entities and evolving concepts. Ann. Diagn. Pathol. 4, 252-266 (2000).
2. R. L. Jones, C. Fisher, O. Al-Muderis, I. R. Judson, Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur. J. Cancer 41, 2853-2860 (2005).
3. A. M. Crago, S. Singer, Clinical and molecular approaches to well differentiated and dedifferentiated liposarcoma. Curr. Opin. Oncol. 23, 373-378 (2011).
4. P. Lorigan, J. Verweij, Z. Papai, S. Rodenhuis, A. Le Cesne, M. G. Leahy, J. A. Radford, M. M. Van Glabbeke, A. Kirkpatrick, P. C. W. Hogendoorn, P. C. Hogendoorn, J. Y. Blay; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study, Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J. Clin. Oncol. 25, 3144-3150 (2007).
5. R. G. Maki, D. R. D'Adamo, M. L. Keohan, M. Saulle, S. M. Schuetze, S. D. Undevia, M. B. Livingston, M. M. Cooney, M. L. Hensley, M. M. Mita, C. H. Takimoto, A. S. Kraft, A. D. Elias, B. Brockstein, N. E. Blachère, M. A. Edgar, L. H. Schwartz, L. X. Qin, C. R. Antonescu, G. K. Schwartz, Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J. Clin. Oncol. 27, 3133-3140 (2009).
6. R. Chugh, J. K. Wathen, R. G. Maki, R. S. Benjamin, S. R. Patel, P. A. Meyers, P. A. Myers, D. A. Priebat, D. K. Reinke, D. G. Thomas, M. L. Keohan, B. L. Samuels, L. H. Baker, Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a Bayesian hierarchical statistical model. J. Clin. Oncol. 27, 3148-3153 (2009).
7. J. Barretina, B. S. Taylor, S. Banerji, A. H. Ramos, M. Lagos-Quintana, P. L. DeCarolis, K. Shah, N. D. Socci, B. A. Weir, A. Ho, D. Y. Chiang, B. Reva, C. H. Mermel, G. Getz, Y. Antipin, R. Beroukhim, J. E. Major, C. Hatton, R. Nicoletti, M. Hanna, T. Sharpe, T. J. Fennell, K. Cibulskis, R. C. Onofrio, T. Saito, N. Shukla, C. Lau, S. Nelander, S. J. Silver, C. Sougnez, A. Viale, W. Winckler, R. G. Maki, L. A. Garraway, A. Lash, H. Greulich, D. E. Root, W. R. Sellers, G. K. Schwartz, C. R. Antonescu, E. S. Lander, H. E. Varmus, M. Ladanyi, C. Sander, M. Meyerson, S. Singer, Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat. Genet. 42, 715-721 (2010).
8. M. A. Dickson, W. D. Tap, M. L. Keohan, S. P. D'Angelo, M. M. Gounder, C. R. Antonescu, J. Landa, L. X. Qin, D. D. Rathbone, M. M. Condy, Y. Ustoyev, A. M. Crago, S. Singer, G. K. Schwartz, Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J. Clin. Oncol. 31, 2024-2028 (2013).
9. K. S. Saini, H. A. Azim Jr., O. Metzger-Filho, S. Loi, C. Sotiriou, E. de Azambuja, M. Piccart, Beyond trastuzumab: New treatment options for HER2-positive breast cancer. Breast 20, S20-S27 (2012).
10. P. R. Pohlmann, I. A. Mayer, R. Mernaugh, Resistance to trastuzumab in breast cancer. Clin. Cancer Res. 15, 7479-7491 (2009).
11. P. A. Jänne, N. Gray, J. Settleman, Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat. Rev. Drug Discov. 8, 709-723 (2009).
12. P. Csermely, V. Agoston, S. Pongor, The efficiency of multi-target drugs: The network approach might help drug design. Trends Pharmacol. Sci. 26, 178-182 (2005).
13. K. L. Blackwell, H. J. Burstein, A. M. Storniolo, H. Rugo, G. Sledge, M. Koehler, C. Ellis, M. Casey, S. Vukelja, J. Bischoff, J. Baselga, J. O'Shaughnessy, Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J. Clin. Oncol. 28, 1124-1130 (2010).
14. K. T. Flaherty, Dividing and conquering: Controlling advanced melanoma by targeting oncogene-defined subsets. Clin. Exp. Metastasis 29, 841-846 (2012).
15. J. B. Fitzgerald, B. Schoeberl, U. B. Nielsen, P. K. Sorger, Systems biology and combination therapy in the quest for clinical efficacy. Nat. Chem. Biol. 2, 458-466 (2006).
16. M. S. Glickman, C. L. Sawyers, Converting cancer therapies into cures: Lessons from infectious diseases. Cell 148, 1089-1098 (2012).
17. B. Al-Lazikani, U. Banerji, P. Workman, Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30, 679-692 (2012).
18. B. S. Taylor, J. Barretina, R. G. Maki, C. R. Antonescu, S. Singer, M. Ladanyi, Advances in sarcoma genomics and new therapeutic targets. Nat. Rev. Cancer 11, 541-557 (2011).
19. A. M. Crago, N. D. Socci, P. DeCarolis, R. O'Connor, B. S. Taylor, L. X. Qin, C. R. Antonescu, S. Singer, Copy number losses define subgroups of dedifferentiated liposarcoma with poor prognosis and genomic instability. Clin. Cancer Res. 18, 1334-1340 (2012).
20. J. Lehár, B. R. Stockwell, G. Giaever, C. Nislow, Combination chemical genetics. Nat. Chem. Biol. 4, 674-681 (2008).
21. M. Cokol, H. N. Chua, M. Tasan, B. Mutlu, Z. B. Weinstein, Y. Suzuki, M. E. Nergiz, M. Costanzo, A. Baryshnikova, G. Giaever, C. Nislow, C. L. Myers, B. J. Andrews, C. Boone, F. P. Roth, Systematic exploration of synergistic drug pairs. Mol. Syst. Biol. 7, 544 (2011).
22. P. J. Yeh, M. J. Hegreness, A. P. Aiden, R. Kishony, Drug interactions and the evolution of antibiotic resistance. Nat. Rev. Microbiol. 7, 460-466 (2009).
23. A. S. Azmi, Z. Wang, P. A. Philip, R. M. Mohammad, F. H. Sarkar, Proof of concept: Network and systems biology approaches aid in the discovery of potent anticancer drug combinations. Mol. Cancer Ther. 9, 3137-3144 (2010).
24. W. R. Greco, G. Bravo, J. C. Parsons, The search for synergy: A critical review from a response surface perspective. Pharmacol. Rev. 47, 331-385 (1995).
25. M. A. Shah, G. K. Schwartz, Cell cycle-mediated drug resistance: An emerging concept in cancer therapy. Clin. Cancer Res. 7, 2168-2181 (2001).
26. M. Motwani, T. M. Delohery, G. K. Schwartz, Sequential dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxel-treated human gastric and breast cancer cells. Clin. Cancer Res. 5, 1876-1883 (1999).
27. M. Motwani, X. Li, G. K. Schwartz, Flavopiridol, a cyclin-dependent kinase inhibitor, prevents spindle inhibitor-induced endoreduplication in human cancer cells. Clin. Cancer Res. 6, 924-932 (2000).
28. A. K. McClendon, J. L. Dean, D. B. Rivadeneira, J. E. Yu, C. A. Reed, E. Gao, J. L. Farber, T. Force, W. J. Koch, E. S. Knudsen, CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle 11, 2747-2755 (2012).
29. S. Nelander, W. Wang, B. Nilsson, Q. B. She, C. Pratilas, N. Rosen, P. Gennemark, C. Sander, Models from experiments: Combinatorial drug perturbations of cancer cells. Mol. Syst. Biol. 4, 216 (2008).
30. E. J. Molinelli, A. Korkut, W. Wang, M. L. Miller, N. P. Gauthier, X. Jing, P. Kaushik, Q. He, G. B. Mills, D. B. Solit, C. A. Pratilas, M. Weigt, A. Braunstein, A. Pagnani, R. Zecchina, C. Sander, Perturbation biology: Inferring signaling networks in cellular systems. PLoS Comp. Biol., in press (2013).
31. D. Hanahan, R. A. Weinberg, Hallmarks of cancer: The next generation. Cell 144, 646-674 (2011).
32. D. Olmos, A. S. Martins, R. L. Jones, S. Alam, M. Scurr, I. R. Judson, Targeting the insulin-like growth factor 1 receptor in Ewing' s sarcoma: Reality and expectations. Sarcoma 2011, 402508 (2011).
33. T. C. Chou, P. Talalay, Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27-55 (1984).
34. L. Zhang, K. Yan, Y. Zhang, R. Huang, J. Bian, C. Zheng, H. Sun, Z. Chen, N. Sun, R. An, F. Min, W. Zhao, Y. Zhuo, J. You, Y. Song, Z. Yu, Z. Liu, K. Yang, H. Gao, H. Dai, X. Zhang, J. Wang, C. Fu, G. Pei, J. Liu, S. Zhang, M. Goodfellow, Y. Jiang, J. Kuai, G. Zhou, X. Chen, High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. Proc. Natl. Acad. Sci. U.S.A. 104, 4606-4611 (2007).
35. M. A. Farha, E. D. Brown, Chemical probes of Escherichia coli uncovered through chemical-chemical interaction profiling with compounds of known biological activity. Chem. Biol. 17, 852-862 (2010).
36. P. Yeh, A. I. Tschumi, R. Kishony, Functional classification of drugs by properties of their pairwise interactions. Nat. Genet. 38, 489-494 (2006).
37. A. A. Borisy, P. J. Elliott, N. W. Hurst, M. S. Lee, J. Lehár, E. R. Price, G. Serbedzija, G. R. Zimmermann, M. A. Foley, B. R. Stockwell, C. T. Keith, Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci. U.S.A. 100, 7977-7982 (2003).
38. T. C. Chou, Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621-681 (2006).
39. R. Tibes, Y. Qiu, Y. Lu, B. Hennessy, M. Andreeff, G. B. Mills, S. M. Kornblau, Reverse phase protein array: Validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells. Mol. Cancer Ther. 5, 2512-2521 (2006).
40. E. G. Cerami, B. E. Gross, E. Demir, I. Rodchenkov, O. Babur, N. Anwar, N. Schultz, G. D. Bader, C. Sander, Pathway Commons, a web resource for biological pathway data. Nucleic Acids Res. 39, D685-D690 (2011).
41. H. Ogata, S. Goto, K. Sato, W. Fujibuchi, H. Bono, M. Kanehisa, KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 27, 29-34 (1999).
42. C. F. Schaefer, K. Anthony, S. Krupa, J. Buchoff, M. Day, T. Hannay, K. H. Buetow, PID: The Pathway Interaction Database. Nucleic Acids Res. 37, D674-D679 (2009).
43. J. Lehár, A. S. Krueger, W. Avery, A. M. Heilbut, L. M. Johansen, E. R. Price, R. J. Rickles, G. F. Short III, J. E. Staunton, X. Jin, M. S. Lee, G. R. Zimmermann, A. A. Borisy, Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol. 27, 659-666 (2009).
44. F. Chang, J. T. Lee, P. M. Navolanic, L. S. Steelman, J. G. Shelton, W. L. Blalock, R. A. Franklin, J. A. McCubrey, Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia 17, 590-603 (2003).
45. I. Vivanco, C. L. Sawyers, The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501 (2002).
46. J. Schlessinger, Cell signaling by receptor tyrosine kinases. Cell 103, 211-225 (2000).
47. T. Shimura, Acquired radioresistance of cancer and the AKT/GSK3β/cyclin D1 overexpression cycle. J. Radiat. Res. 52, 539-544 (2011).
48. D. Pe'er, N. Hacohen, Principles and strategies for developing network models in cancer. Cell 144, 864-873 (2011).
49. T. Nakakuki, M. R. Birtwistle, Y. Saeki, N. Yumoto, K. Ide, T. Nagashima, L. Brusch, B. A. Ogunnaike, M. Okada-Hatakeyama, B. N. Kholodenko, Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics. Cell 141, 884-896 (2010).
50. B. B. Aldridge, J. M. Burke, D. A. Lauffenburger, P. K. Sorger, Physicochemical modelling of cell signalling pathways. Nat. Cell Biol. 8, 1195-1203 (2006).
51. M. S. Chatterjee, J. E. Purvis, L. F. Brass, S. L. Diamond, Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli. Nat. Biotechnol. 28, 727-732 (2010).
52. S. Singer, N. D. Socci, G. Ambrosini, E. Sambol, P. Decarolis, Y. Wu, R. O'Connor, R. Maki, A. Viale, C. Sander, G. K. Schwartz, C. R. Antonescu, Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma. Cancer Res. 67, 6626-6636 (2007).
53. B. S. Taylor, J. Barretina, N. D. Socci, P. Decarolis, M. Ladanyi, M. Meyerson, S. Singer, C. Sander, Functional copy-number alterations in cancer. PLoS One 3, e3179 (2008).
54. E. M. Czekanska, Assessment of cell proliferation with resazurin-based fluorescent dye. Methods Mol. Biol. 740, 27-32 (2011).
55. P. Kaushik, E. J. Molinelli, M. L. Miller, W. Liu, W. Wang, A. Korkut, W. Liu, Z. Ju, Y. Lu, G. B. Mills, C. Sander, Spatial normalization of reverse phase protein array data PLoS One, in press (2013).
56. J. Hu, X. He, K. A. Baggerly, K. R. Coombes, B. T. J. Hennessy, G. B. Mills, Non-parametric quantification of protein lysate arrays. Bioinformatics 23, 1986-1994 (2007).
57. F. Pineda, Generalization of back-propagation to recurrent neural networks. Phys. Rev. Lett. 59, 2229-2232 (1987).
58. D. Pe'er, Bayesian network analysis of signaling networks: A primer. Sci. STKE 2005, pl4 (2005).
59. K. Sachs, O. Perez, D. Pe'er, D. A. Lauffenburger, G. P. Nolan, Causal protein-signaling networks derived from multiparameter single-cell data. Science 308, 523-529 (2005).
60. T. Schneider, T. Kruse, R. Wimmer, I. Wiedemann, V. Sass, U. Pag, A. Jansen, A. K. Nielsen, P. H. Mygind, D. S. Raventós, S. Neve, B. Ravn, A. M. J. J. Bonvin, L. De Maria, A. S. Andersen, L. K. Gammelgaard, H. G. Sahl, H. H. Kristensen, Plectasin, a fungal defensin, targets the bacterial cell wall precursor Lipid II. Science 328, 1168-1172 (2010).
61. S. Persad, S. Attwell, V. Gray, N. Mawji, J. T. Deng, D. Leung, J. Yan, J. Sanghera, M. P. Walsh, S. Dedhar, Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: Critical roles for kinase activity and amino acids arginine 211 and serine 343. J. Biol. Chem. 276, 27462-27469 (2001).
62. A. C. Gingras, S. G. Kennedy, M. A. O'Leary, N. Sonenberg, N. Hay, 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 12, 502-513 (1998).
63. X. Fang, S. X. Yu, Y. Lu, R. C. Bast, J. R. Woodgett, G. B. Mills, Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc. Natl. Acad. Sci. U.S.A. 97, 11960-11965 (2000).
64. L. C. Cantley, B. G. Neel, New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. U.S.A. 96, 4240-4245 (1999).
65. J. Chung, E. Uchida, T. C. Grammer, J. Blenis, STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol. Cell. Biol. 17, 6508-6516 (1997).
66. A. Dufner, M. Andjelkovic, B. M. T. Burgering, B. A. Hemmings, G. Thomas, Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation. Mol. Cell. Biol. 19, 4525-4534 (1999).
67. L. Connell-Crowley, J. W. Harper, D. W. Goodrich, Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol. Biol. Cell 8, 287-301 (1997).
68. R. N. Jorissen, F. Walker, N. Pouliot, T. P. J. Garrett, C. W. Ward, A. W. Burgess, Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp. Cell Res. 284, 31-53 (2003).
69. A. Yogi, G. E. Callera, A. C. I. Montezano, A. B. Aranha, R. C. Tostes, E. L. Schiffrin, R. M. Touyz, Endothelin-1, but not Ang II, activates MAP kinases through c-Src-independent Ras-Raf-dependent pathways in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 27, 1960-1967 (2007).
70. A. Beeser, Z. M. Jaffer, C. Hofmann, J. Chernoff, Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors. J. Biol. Chem. 280, 36609-36615 (2005).
71. C. Rommel, B. A. Clarke, S. Zimmermann, L. Nuñez, R. Rossman, K. Reid, K. Moelling, G. D. Yancopoulos, D. J. Glass, Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 286, 1738-1741 (1999).
72. R. Gosens, G. Dueck, E. Rector, R. O. Nunes, W. T. Gerthoffer, H. Unruh, J. Zaagsma, H. Meurs, A. J. Halayko, Cooperative regulation of GSK-3 by muscarinic and PDGF receptors is associated with airway myocyte proliferation. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L1348-L1358 (2007).
73. M. Fedele, R. Visone, I. De Martino, G. Troncone, D. Palmieri, S. Battista, A. Ciarmiello, P. Pallante, C. Arra, R. M. Melillo, K. Helin, C. M. Croce, A. Fusco, HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell 9, 459-471 (2006).
74. S. Mohan, D. Baylink, IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J. Endocrinol. 175, 19-31 (2002).
75. C. Mur, M. Arribas, M. Benito, A. M. Valverde, Essential role of insulin-like growth factor i receptor in insulin-induced fetal brown adipocyte differentiation. Endocrinology 144, 581-593 (2003).
76. 3- integrin by endogenous ligands modulates IGF-I receptor activation and proliferation of human intestinal smooth muscle. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1194-G1202 (2006).
77. W. Zhang, H. T. Liu, MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12, 9-18 (2002).
78. J. A. Lehman, J. Gomez-Cambronero, Molecular crosstalk between p70S6k and MAPK cell signaling pathways. Biochem. Biophys. Res. Commun. 293, 463-469 (2002).
79. C. F. Zheng, K. L. Guan, Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. EMBO J. 13, 1123-1131 (1994).
80. C. F. Zheng, K. L. Guan, Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J. Biol. Chem. 268, 11435-11439 (1993).
81. G. Dong, Z. Chen, Z. Y. Li, N. T. Yeh, C. C. Bancroft, C. Van Waes, Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res. 61, 5911-5918 (2001).
82. S. Coughlin, J. Escobedo, L. Williams, Role of phosphatidylinositol kinase in PDGF receptor signal transduction. Science 243, 1191-1194 (1989).
83. M. P. Scheid, P. A. Marignani, J. R. Woodgett, Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol. Cell. Biol. 22, 6247-6260 (2002).
84. F. Bornancin, P. J. Parker, Phosphorylation of protein kinase C-a on serine 657 controls the accumulation of active enzyme and contributes to its phosphatase-resistant state. J. Biol. Chem. 272, 3544-3549 (1997).
85. T. Valovka, F. Verdier, R. Cramer, A. Zhyvoloup, T. Fenton, H. Rebholz, M. L. Wang, M. Gzhegotsky, A. Lutsyk, G. Matsuka, V. Filonenko, L. Wang, C. G. Proud, P. J. Parker, I. T. Gout, Protein kinase C phosphorylates ribosomal protein S6 kinase βII and regulates its subcellular localization. Mol. Cell. Biol. 23, 852-863 (2003).
86. P. D. Adams, X. Li, W. R. Sellers, K. B. Baker, X. Leng, J. W. Harper, Y. Taya, W. G. Kaelin, Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol. Cell. Biol. 19, 1068-1080 (1999).
87. S. Volarevic, M. J. Stewart, B. Ledermann, F. Zilberman, L. Terracciano, E. Montini, M. Grompe, S. C. Kozma, G. Thomas, Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science 288, 2045-2047 (2000).
88. D. R. Stover, P. Furet, N. B. Lydon, Modulation of the SH2 binding specificity and kinase activity of Src by tyrosine phosphorylation within its SH2 domain. J. Biol. Chem. 271, 12481-12487 (1996).
89. W. Xu, X. Yuan, K. Beebe, Z. Xiang, L. Neckers, Loss of Hsp90 association up-regulates Src-dependent ErbB2 activity. Mol. Cell. Biol. 27, 220-228 (2007).
90. M. P. Haynes, L. Li, D. Sinha, K. S. Russell, K. Hisamoto, R. Baron, M. Collinge, W. C. Sessa, J. R. Bender, Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J. Biol. Chem. 278, 2118-2123 (2003).
91. J. K. Westwick, A. E. Bielawska, G. Dbaibo, Y. A. Hannun, D. A. Brenner, Ceramide activates the stress-activated protein kinases. J. Biol. Chem. 270, 22689-22692 (1995).
92. Shc to activate MAPK/ERK and promote chemotaxis. J. Cell Biol. 162, 661-671 (2003).
93. M. Paulson, S. Pisharody, L. Pan, S. Guadagno, A. L. Mui, D. E. Levy, Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J. Biol. Chem. 274, 25343-25349 (1999).
94. H. Toshio, I. Katsuhiko, H. Masahiko, Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19, 2548-2556 (2000).
95. K. Hara, Y. Maruki, X. Long, K. i. Yoshino, N. Oshiro, S. Hidayat, C. Tokunaga, J. Avruch, K. Yonezawa, Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177-189 (2002).
96. S. M. Ali, D. M. Sabatini, Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site. J. Biol. Chem. 280, 19445-19448 (2005).