aacr final.pdf 1 4/2/15 10:40 am signaling pathways in cancer · 2015. 4. 16. · ras signaling and...

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FURTHER RECENT READING FROM CELL REPORTS RAS SIGNALING AND CANCER Dadi Jiang, Edward L. LaGory, Daniela Kenzelmann Brož, Kathryn T. Bieging, Colleen A. Brady, Nichole Link, John M. Abrams, Amato J. Giaccia, and Laura D. Attardi (2015). Analysis of p53 Transactivation Domain Mutants Reveals Acad11 as a Metabolic Target Important for p53 Pro-Survival Function. Cell Rep. 10, 1096–1109 Edward C. Stites, Paul C. Trampont, Lisa B. Haney, Scott F. Walk, Kodi S. Ravichandran (2015) Cooperation between Noncanonical Ras Network Mutations. Cell Rep. 10, 840 Bo-Kuan Wu, Charles Brenner (2014) Suppression of TET1-Dependent DNA Demethylation Is Essential for KRAS-Mediated Transformation. Cell Rep. 9, 1827–1840 Simona Lamba, Mariangela Russo, Chong Sun, Luca Lazzari, Carlotta Cancelliere, Wipawadee Grernrum, Cor Lieftink, Rene Bernards, Federica Di Nicolantonio, Alberto Bardelli (2014) RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells. Cell Rep. 8, 1475–1483 WNT/ β -CATENIN SIGNALING AND CANCER Victoria Llado, Yuki Nakanishi, Angeles Duran, Miguel Reina-Campos, Phillip M. Shelton, Juan F. Linares, Tomoko Yajima, Alex Campos, Pedro Aza-Blanc, Michael Leitges, Maria T Diaz-Meco, Jorge Moscat (2015)Re- pression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ. Cell Rep. 10, 740–754 Ekaterina Posokhova, Animesh Shukla, Steven Seaman, Suresh Volate, Mary Beth Hilton, Bofan Wu, Holly Morris, Deborah A. Swing, Ming Zhou, Enrique Zudaire, Jeffrey S. Rubin, Brad St. Croix (2015) GPR124 Functions as a WNT7-Specific Coactivator of Canonical β-Catenin Signaling. Cell Rep. 10, 123–130 Hadrien Demagny, Tatsuya Araki, Edward M. De Robertis (2014) The Tumor Suppressor Smad4/DPC4 Is Regulated by Phosphorylations that Integrate FGF, Wnt, and TGF-β Signaling. Cell Rep. 9, 688–700 Je-Hoon Song, David J. Huels, Rachel A. Ridgway, Owen J. Sansom, Boris N. Kholodenko, Walter Kolch, Kwang-Hyun Cho (2014) The APC Network Regulates the Removal of Mutated Cells from Colonic Crypts. Cell Rep. 7, 94–103 mTOR IN CANCER Xin Zhou, Terri L. Clister, Pamela R. Lowry, Marcus M. Seldin, G. William Wong, Jin Zhang (2015) Dynamic Visualization of mTORC1 Activity in Living Cells. Cell Rep. 10, 1767–1777 Shigeru Kawabata, José R. Mercado-Matos, M. Christine Hollander, Danielle Donahue, Willie Wilson, Lucia Regales, Mohit Butaney, William Pao, Kwok-Kin Wong, Pasi A. Jänne, Phillip A. Dennis (2014)Rapamycin Prevents the Development and Progression of Mutant Epidermal Growth Factor Receptor Lung Tumors with the Acquired Resistance Mutation T790M. Cell Rep. 7, 1824–1832 Valentina Pirazzoli, Caroline Nebhan, Xiaoling Song, Anna Wurtz, Zenta Walther, Guoping Cai, Zhongming Zhao, Peilin Jia, Elisa de Stanchina, Erik M. Shapiro, Molly Gale, Ruonan Yin, Leora Horn, David P. Carbone, Philip J. Stephens, Vincent Miller, Scott Gettinger, William Pao, Katerina Politi (2014) Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1 Cell Rep. 7, 999–1008 Filip Janku, David S. Hong, Siqing Fu, Sarina A. Piha-Paul, Aung Naing, Gerald S. Falchook, Apostolia M. Tsimberidou, Vanda M. Stepanek, Stacy L. Moulder, J. Jack Lee, Rajyalakshmi Luthra, Ralph G. Zinner, Russell R. Broaddus, Jennifer J. Wheler, Razelle Kurzrock (2014) Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors Cell Rep. 6, 377–387 www.cell.com/cell-reports/collections/pathways CyclinA1 Survivin CyclinD1 Telomerase Akt Glycogen synthesis Glycogen synthesis G1/S cell-cycle progression G1/S cell-cycle progression Chromatin remodeling Chromatin remodeling Survival Survival Amino acids Amino acids Rapamycin Rapamycin Insulin/IGF Growth factor Insulin/IGF Growth factor Growth factor e.g., EGF Growth factor e.g., EGF Autophagy Autophagy Cell survival Apoptosis Cell survival Apoptosis Metabolism Metabolism Inactive complex Inactive complex Non-TCF β-cat targets Non-TCF β-cat targets TCF/LEF target genes TCF/LEF target genes Hypoxia Hypoxia Ribosome biogenesis Translation Ribosome biogenesis Translation Bad Mdm2 Msk Rsk2 Ets1 Fos Jun MnSOD Bim Gadd45 p27 FasL CyclinD1 Fos Spry Myc CyclinD1 p27 p21 Ras Ras GDP GTP Raf Mek KSR Sos Grb2 Gab1 Srf Elk1 FoxO NF1 p120GAP Myc Erk RSK Adipose- specific genes p21 CIP1 , FAS PTEN, TSC2 rRNA Fas-L, p27 KIP1 p27 p16 p53 Rb Cyclin D1 CDK4 PPARγ mTORC1 PML Crm1 TIF-1A Pol I UBF SL1 eEF2K S6 PDCD4 elF4A elF4E eEF2 elF3 elF4B LKB1 AMPK AMPK AKT PDK1 PTEN PI3K PI3K PIP3 PIP2 S6K 4E-BP TSC1 RagA RagC Rheb PP2A PP2A PP2A Rheb TSC2 REDD1/2 PRAS40 GDP GTP BAD FOXO3a FOXO3a mTORC1 mTORC2 AKT Receptor Tyrosine Kinase Receptor Tyrosine Kinase, EGFR FKBP IRS-1 GRB2 14-3-3 Brm PAF1 MED CBP β-cat Lgs Pygo Pitx2/Prop1 DvI PR55 GSK3 CKI CKIγ β-arr p68 GBP/Frat Axin Cav Frizzled LRP5/6 Wnt Axin CKI MACF1 G TCF β-cat GSK3 GSK3 β-cat T hermo Scientific™ Pierce™ Antibodies are developed for a wide variety of application needs. We offer more than 40,000 antibodies in 50 research areas, including cancer, epigenetics, and stem cell research. All of our antibodies are validated and guaranteed to perform in the stated application and species. Also, our Innovator’s Program rewards researchers for sharing data on qualified antibodies. To learn more, go to lifetechnologies.com/antibodies Illustrated are some of the known components of three signaling pathways that have been linked to cancer: Ras, mTOR, and Wnt/β-catenin. Although these are not the only signaling pathways linked to cancer, and the chart is not comprehensive, they serve to illustrate the connectedness of these pathways and to provide an entryway into exploring functional studies, as outlined by the tables provided by Thermo Fisher Scientific. Brown, E.J., Albers, M.W., Shin, T.B., Ichikawa, K., Keith, C.T., Lane, W.S., and Schreiber, S.L. (1994). A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758. Cafferkey, R., Young, P.R., McLaughlin, M.M., Bergsma, D.J., Koltin, Y., Sathe, G.M., Faucette, L., Eng, W.K., Johnson, R.K., and Livi, G.P. (1993). Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol. Cell. Biol. 13, 6012–6023. Clevers. H., and Nusse, R. (2012). Wnt/β-Catenin Signaling and Disease. Cell 149, 1192-1205 Cully M., and Downward, J. (2008). Snapshot: Ras Signaling. Cell 133, 1292 MacDonald, B.T., Semenov N.V., and He, X. (2007). Snapshot: Wnt/β-Catenin Signaling Cell 131, 1204 Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., and Hedge, P. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665–669 Nusse, R., and Varmus, H.E. (1982). Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99–109 Kinzler, K.W., and Vogelstein, B. (1996). Lessons from hereditary colorectal cancer. Cell 87, 159–170 Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N.R., and Hall, M.N. (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585–596 Laplante, M. and Sabatini, D.M. (2012) mTOR signaling in growth control and disease. Cell 149, 274-293 Prior, I.A. et al. (2012) A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P., and Snyder, S.H. (1994). RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin- dependent fashion and is homologous to yeast TORs. Cell 78, 35–43. Sabers, C.J., Martin, M.M., Brunn, G.J., Williams, J.M., Dumont, F.J., Wiederrecht, G., and Abraham, R.T. (1995). Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815–822 Schmick, M., Kraemer, A., Bastiaens, P.I.H. (2015) Ras moves to stay in place. Trends in Cell Biol. http://dx.doi.org/10.1016/j.tcb.2015.02.004 Soulard A. and Hall, M.N. (2007) Snapshot: mTOR signaling. Cell 129, 434 The above touches only the surface of the rich information available about these pathways and the many unknowns that remain. Some further reading, as well as recent insights into these pathways and cancer that have been published in Cell Reports, can be found on the left. Points of potential path- way crosstalk are highlighted in red in the diagrams above. REFERENCES Signaling Pathways in Cancer β-cat GSK3 β-cat β-cat β-cat β-cat β-cat β-cat β-cat β-cat β-cat β-cat β-cat APC PR61 Axin WTX PP1 CKI Target List Rank GeneID Target Host Reactivity Applications Catalog Number ERK/RAS/RAF/MEK 1 801 Calmodulin Mouse Ba, Bv, Ck, Hu, Ms, Rt WB, IF, ICC, IHC, FACS, ELISA MA3-917 ERK/RAS/RAF/MEK 2 1956 EGFR Mouse Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-13070 ERK/RAS/RAF/MEK 3 3480 IGF-IR / IGF1 Receptor alpha Mouse Hu IF, ICC, IHC (P), IP, ELISA MA5-13799 ERK/RAS/RAF/MEK 4 598 BCL-XL Mouse Hu, Ms IF, ICC, IHC (P), FACS, IP MA5-11950 ERK/RAS/RAF/MEK 5 25 c-Abl Mouse Hu, Ms WB, IF, ICC, IHC (P), IP MA5-14398 ERK/RAS/RAF/MEK 6 207 AKT Rabbit Hu, Ms WB, IF, ICC, IHC (P), FACS 710005 ERK/RAS/RAF/MEK 7 2902 NMDA Receptor 1 Rabbit Hu, Ms, Rt WB, IF, ICC, IHC, IP, ELISA PA3-102 ERK/RAS/RAF/MEK 8 2904 NMDA Receptor 2B Rabbit Hu, Ms, Rt WB, IF, ICC, IHC, IP, ELISA PA3-104 ERK/RAS/RAF/MEK 9 3643 INSR / Insulin Receptor alpha Mouse Bv, Hu, Ov, Po, Rb, Rt IF, ICC, IHC (P), FACS, ELISA MA5-13767 ERK/RAS/RAF/MEK 10 3815 c-Kit / CD117 Rabbit Ca, Hu, Rt WB, IF, ICC, IHC (P), FACS PA5-16770 ERK/RAS/RAF/MEK 11 5921 GTPase Activating Protein Mouse Bv, Hu, Ms, Nhp, Rt WB, IF, IP MA4-001 ERK/RAS/RAF/MEK 12 7422 VEGF Mouse Hu WB, IHC (P) MA5-12184 ERK/RAS/RAF/MEK 13 4804 NGFR / p75 NGF Receptor Mouse Fe, Ft, Hu, Nhp, Rb, Rt WB, IF, ICC, FACS MA5-13311 ERK/RAS/RAF/MEK 14 208 AKT2 Mouse Hu, Ms, Nhp, Rt WB, IF, ICC, IHC, IP, ChIP MA1-034 ERK/RAS/RAF/MEK 15 998 cdc42 Rabbit Hu, Ms, Nhp, Rt WB, IF, IHC (P) PA1-092 ERK/RAS/RAF/MEK 16 2002 ELK1 Mouse Bv, Hu, Ms, Nhp, Rt WB, IF, IP 45-8700 ERK/RAS/RAF/MEK 17 2260 FGFR1 / CD331 Mouse Hu, Rt WB, IHC, IP, ELISA 37-9200 ERK/RAS/RAF/MEK 18 2324 Flt-4 Rabbit Hu, Ms, Rt WB, IHC (P), IP PA5-16871 ERK/RAS/RAF/MEK 19 3082 Hepatocyte Growth Factor Mouse Hu, Ms WB, IF, ICC MA5-14160 ERK/RAS/RAF/MEK 20 3265 v-H-Ras Rat Hu, Ms, Rt WB, IF, IHC, IP 33-7200 ERK/RAS/RAF/MEK 21 4233 c-Met Mouse Hu WB, IHC, IP, ELISA 37-0100 ERK/RAS/RAF/MEK 22 5156 PDGF-RA / CD140a Rabbit Hu WB, IF, ICC, ChIP 701142 ERK/RAS/RAF/MEK 23 5159 PDGF-RB / CD140b Rabbit Hu, Ms, Rt WB, IF, ICC, IHC (F), IHC (P), IP MA5-15143 ERK/RAS/RAF/MEK 24 5594 p42 MAP Kinase / ERK2 / MAPK1 Mouse Ca, Hu, Ms, Nhp, Rt WB, IF, IHC (P), IP, ChIP MA1-099 ERK/RAS/RAF/MEK 25 5595 p44 MAP Kinase / ERK1 Mouse Hu, Ms, Nhp WB, IF, IHC, ChIP MA1-13041 ERK/RAS/RAF/MEK 26 5879 Rac1 Rabbit Hu, Ms WB, IF, IHC (P) PA1-091 ERK/RAS/RAF/MEK 27 7535 Phospho-Zap-70 pTyr315+319 Rabbit Hu WB, IF, ICC, FACS 700177 ERK/RAS/RAF/MEK 28 1942 Ephrin-A1 Rabbit Hu, Ms WB, IHC, IP 34-3300 ERK/RAS/RAF/MEK 29 1945 Ephrin-A4 Rabbit Hu, Ms WB, IHC, IP 34-3700 ERK/RAS/RAF/MEK 30 2263 FGFR2 / CD332 Rabbit Hu, Ms, Nhp, Rt WB, IF, IHC, FACS PA5-14651 ERK/RAS/RAF/MEK 31 3630 Insulin Mouse Hu IHC (P) MA5-12029 ERK/RAS/RAF/MEK 32 5578 PKC alpha Mouse Bv, Ca, Hu, Ms, Nhp, Rb, Rt WB, IF, IHC (P), IP MA1-157 ERK/RAS/RAF/MEK 33 5906 Rap1 Mouse Hu, Ms WB, IF, ICC, IHC (P), IP MA1-013 ERK/RAS/RAF/MEK 34 382 Arf6 Rabbit Hu, Ms, Nhp WB, IF, IHC (P) PA1-093 ERK/RAS/RAF/MEK 35 1950 EGF Mouse Hu WB, IF, ELISA M806 ERK/RAS/RAF/MEK 36 2113 ETS1 Mouse Hu, Ms WB, IF, ICC, IHC, FACS MA5-15609 ERK/RAS/RAF/MEK 37 2247 FGF-2 Rabbit Hu WB 710148 ERK/RAS/RAF/MEK 38 2261 FGFR3 / CD333 Rabbit Hu WB, IF, ICC, IHC (P), IP MA5-14843 ERK/RAS/RAF/MEK 39 2321 Flt-1 Rabbit Hu, Ms, Rt WB PA5-16493 ERK/RAS/RAF/MEK 40 2903 NMDA Recep- tor Subunit 2A / NMDAR2A Rabbit Hu, Ms, Rt WB, IHC A-6473 Ras is at the core of the cell signaling network in response to growth factors, and mutations that lead to its activation are strongly linked to cancer, being found in 20–30% of tumors. A small membrane-lo - calized GTPase, Ras, cycles between a GTP-bound active state, which is promoted by guanine nucle - otide exchange factors, and a GDP-bound form. The GTPase activity is stimulated by GTPase-activat - ing proteins. The Ras pathway signals through a phosphorylation cascade that runs through Raf/ME - K/ERK, as highlighted here. RAS The Wnt signaling pathway has been tied to tumorigenesis since the discovery of the first Wnt family member as the site of MMTV integration in a mouse breast tumor model. As further components of the pathway were uncovered, mutations in a downstream component of the pathway, APC, were linked to familial adenomatous polyposis. Many intriguing questions surrounding this pathway (a core version of which is shown here) remain, regarding the mechanisms involved in modification of Wnt family mem - bers, as well as the receptor and co-receptor families (Frizzled and LRPs) and the regulation of a key downstream component, β -catenin. WNT Initially uncovered as genetic and biochemical targets of rapamycin, mTOR1 and mTOR2 form complexes that respond to a range of environmental and nutritional triggers. Stimulated by the Ras-like protein Rheb, as well as the kinases Akt/PKB, ERK1/2, and RSK1, the mTOR complexes lie at the heart of a network of signaling pathways that are wired into both Ras/ERK and Wnt pathway components. Some examples of the affected pathways, which include links to protein synthesis and energy consumption, are illustrated. These central roles in cellular proliferation and metabolism indicate why mutations in mTOR signaling components (such as TSC1/2) have been linked to familial cancer and why mTORC1 itself, as well as downstream components, can be dysregulated in cancer. mTOR Target List Rank GeneID Target Host Reactivity Applications Catalog Number mTOR-PI3K 1 596 BCL-2 Mouse Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-11757 mTOR-PI3K 2 898 Cyclin E Mouse Hu, Ms WB, IF, IHC (P), FACS MA5-14336 mTOR-PI3K 3 1956 EGFR Mouse Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-13070 mTOR-PI3K 4 3091 HIF-1 alpha Mouse Bv, Hu, Ms, Nhp, Po WB, IF, ICC, IHC (P), IP, GS, IE MA1-516 mTOR-PI3K 5 3320 HSP90 / Heat Shock Protein 90 alpha Mouse Ck, Fs, Hu, Ms, Nhp, Rt WB, IF, IHC, IP MA3-011 mTOR-PI3K 6 4609 c-Myc Mouse Hu WB, IF, ICC, IHC (P, F), FACS, IP, ChIP, ELISA MA1-980 mTOR-PI3K 7 7057 Thrombospondin Mouse Bv, Ca, Eq, Hu, Ms, Ov, Po, Rt WB, IF, ICC, IHC (P), FACS, IP, IM MA5-13398 mTOR-PI3K 8 7157 p53 Mouse Bv, Hu WB, IF, ICC, IHC (P), FACS, IP MA5-12557 mTOR-PI3K 9 7184 GRP94 / HSP90B1 Rat Bv, Ck, Hm, Hu, Ms, Rt WB, IF, ICC, IHC (P), IP MA3-016 mTOR-PI3K 10 11140 Cdc37 Mouse Hm, Hu, Ms, Rt WB, IF, ICC, IHC (P), FACS, IP MA3-029 mTOR-PI3K 11 595 Cyclin D1 / Bcl-1 Rabbit Hu, Ms WB, IF, ICC, IHC (P) MA5-14512 mTOR-PI3K 12 896 Cyclin D3 Mouse Hu, Ms, Nhp, Rt WB, IF, IHC (P), FACS, IP MA5-12717 mTOR-PI3K 13 1019 Cdk4 Mouse Hu, Ms, Rt WB, IF, FACS, IP MA5-13498 mTOR-PI3K 14 1021 Cdk6 Mouse Hu, Ms, Rt WB, IF, ICC, IHC (F), IHC (P), IP MA5-13333 mTOR-PI3K 15 1027 p27Kip1 Mouse Ca, Hu, Ms, Rt WB, IF, FACS, IP MA5-12835 mTOR-PI3K 16 1129 Muscarinic Acetylcholine Receptor M2 Mouse Hu, Ms, Po, Rt WB, IF, IHC (P), FACS, IP MA3-044 mTOR-PI3K 17 1280 Collagen II Mouse Bv, Ck, Hu, Ms, Rt WB, IF, IHC (P), FACS MA1-37493 mTOR-PI3K 18 3480 IGF-IR / IGF1 Receptor alpha Mouse Hu IF, ICC, IHC (P), IP, ELISA MA5-13799 mTOR-PI3K 19 598 BCL-XL Mouse Hu, Ms IF, ICC, IHC (P), FACS, IP MA5-11950 mTOR-PI3K 20 3676 Integrin alpha 4 / CD49d Mouse Hu, Rt IHC, FACS, Neu MA49D7 mTOR-PI3K 21 5618 Prolactin Receptor Mouse Eq, Hu, Po, Rb, Rt WB, IF, ICC, IHC (F), IHC (P), FACS, IP MA1-610 mTOR-PI3K 22 207 AKT Rabbit Hu, Ms WB, IF, ICC, IHC (P), FACS 710005 mTOR-PI3K 23 894 Cyclin D2 Mouse Hu, Ms, Rt WB, IF, FACS, IP MA5-12712 mTOR-PI3K 24 1385 CREB Mouse Hu, Ms, Nhp, Rt WB, IF, IHC, IP, ELISA MA1-083 mTOR-PI3K 25 2335 Fibronectin Mouse Hu, Ms, Rt WB, IF, IHC (P) MA5-11981 mTOR-PI3K 26 3559 IL-2R alpha / CD25 Mouse Hu WB, IF, ICC, IHC, FACS, IP M10AR mTOR-PI3K 27 3643 INSR / Insulin Receptor alpha Mouse Bv, Hu, Ov, Po, Rb, Rt IF, ICC, IHC (P), FACS, ELISA MA5-13767 mTOR-PI3K 28 3815 c-Kit / CD117 Rabbit Ca, Hu, Rt WB, IF, ICC, IHC (P), FACS PA5-16770 mTOR-PI3K 29 5728 PTEN Mouse Hu WB, IF, ICC, IHC (P) MA5-12278 mTOR-PI3K 30 6198 Phospho-p70 S6 Kinase pThr389 Rabbit Hu, Rt WB, IF, ICC, FACS, ChIP 710095 mTOR-PI3K 31 7422 VEGF Mouse Hu WB, IHC (P) MA5-12184 mTOR-PI3K 32 3672 Integrin alpha-1 / CD49a Mouse Hu WB, IHC (F), FACS, IP MA49A0 mTOR-PI3K 33 3688 Integrin beta-1 / CD29 Mouse Hu FACS MA2910 mTOR-PI3K 34 4804 NGFR / p75 NGF Re- ceptor Mouse Fe, Ft, Hu, Nhp, Rb, Rt WB, IF, ICC, FACS MA5-13311 mTOR-PI3K 35 4846 eNOS Rabbit Bv, Ca, Hu, Ms, Rt WB, IF, ICC, IHC, IHC (P) PA3-031A mTOR-PI3K 36 208 AKT2 Mouse Hu, Ms, Nhp, Rt WB, IF, ICC, IHC, IP, ChIP MA1-034 mTOR-PI3K 37 842 Caspase 9 Rabbit Bv, Hu, Ms, Ov, Rt WB, IHC (P), IP PA5-16358 mTOR-PI3K 38 1017 Cdk2 Mouse Hu, Ms, Rt WB, IF, IHC (P) MA5-13479 mTOR-PI3K 39 1026 p21 Waf1/Cip1 Rabbit Ca, Hu, Nhp WB, IF, ICC, IHC (P), FACS, IP MA5-14949 mTOR-PI3K 40 1977 eIF4E Mouse Hu, Ms WB, IF, ICC, IP MA1-089 Target List Rank GeneID Target Host Reactivity Applications Catalog Number WNT/ β-Catenin 1 1387 CREB Binding Protein Rabbit Hu, Ms WB, IF, ICC, IHC (P), ChIP PA1-847 WNT/ β-Catenin 2 4609 c-Myc Mouse Hu WB, IF, ICC, IHC (P, F), FACS, IP, ChIP, ELISA MA1-980 WNT/ β-Catenin 3 4772 NFATc1 Mouse Hu, Ms, Nhp, Rt WB, IF, ICC, IHC, IHC (P), IHC (PFA), IP, ChIP, GS MA3-024 WNT/ β-Catenin 4 4773 NFATc2 Mouse Hu, Ms, Rt WB, IF, ICC, IHC (P, F), IP, ChIP, GS MA1-025 WNT/ β-Catenin 5 4776 NFAT3 Rabbit Hu WB, IF, IHC, IP PA1-021 WNT/ β-Catenin 6 7157 p53 Mouse Bv, Hu WB, IF, ICC, IHC (P), FACS, IP MA5-12557 WNT/ β-Catenin 7 595 Cyclin D1 / Bcl-1 Rabbit Hu, Ms WB, IF, ICC, IHC (P) MA5-14512 WNT/ β-Catenin 8 896 Cyclin D3 Mouse Hu, Ms, Nhp, Rt WB, IF, IHC (P), FACS, IP MA5-12717 WNT/ β-Catenin 9 5663 Presenilin 1 Mouse Hu, Ms, Nhp, Rt WB, IF, ICC, IHC, ELISA MA1-752 WNT/ β-Catenin 10 815 Phospho-CaM Kinase II pThr286 Mouse Hu, Ms, Rt WB, IF, ICC, IHC, FACS, IP, ELISA MA1-047 WNT/ β-Catenin 11 894 Cyclin D2 Mouse Hu, Ms, Rt WB, IF, FACS, IP MA5-12712 WNT/ β-Catenin 12 1499 beta Catenin Mouse Hu, Ms WB, IF, IP MA1-2001 WNT/ β-Catenin 13 5467 PPAR delta Rabbit Hu, Ms, Rt WB, IF, IHC (F) PA1-823A WNT/ β-Catenin 14 816 CaM Kinase II beta Mouse Fs, Hu, Ms, Ov, Rt, Su WB, IHC, IP, ELISA 13-9800 WNT/ β-Catenin 15 2033 EP300 Mouse Hu WB, IF, IHC, IP 33-7600 WNT/ β-Catenin 16 4316 MMP-7 (Matrilysin) Mouse Hu IF MA5-14215 WNT/ β-Catenin 17 5879 Rac1 Rabbit Hu, Ms WB, IF, IHC (P) PA1-091 WNT/ β-Catenin 18 6885 TAK1 / MAP3K7 Rabbit Hu WB, IF, ICC, FACS 700113 WNT/ β-Catenin 19 8312 Axin Rabbit Hu WB, IF, IP 34-5900 WNT/ β-Catenin 20 5578 PKC alpha Mouse Bv, Ca, Hu, Ms, Nhp, Rb, Rt WB, IF, IHC (P), IP MA1-157 WNT/ β-Catenin 21 2535 Frizzled-2 / FZD2 Rabbit Hu WB, IP 38-4700 WNT/ β-Catenin 22 2932 GSK3 Rabbit Hu WB, IF, ICC 701102 WNT/ β-Catenin 23 3725 c-Jun Mouse Hu, Ms, Nhp WB, IF, ICC, IHC, FACS MA5-15881 WNT/ β-Catenin 24 4041 LRP-5 Rabbit Hu, Ms WB, IF 36-5400 WNT/ β-Catenin 25 4088 SMAD3 Rabbit Hu WB, IF, IHC, ELISA 51-1500 WNT/ β-Catenin 26 4089 Smad4 Rabbit Hu, Ms, Nhp, Rt WB, IF, ChIP PA5-16191 WNT/β-Catenin 27 6932 TCF1 Rabbit Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-14965 WNT/β-Catenin 28 7471 WNT1 Mouse Hu, Ms WB, IF, ICC, IHC, FACS MA5-15544 WNT/β-Catenin 29 8945 BTRC Mouse Hu WB, IP, ELISA 37-3400 WNT/β-Catenin 30 51176 LEF1 Rabbit Hu, Ms, Rt WB, IF, ICC, FACS MA5-14966 WNT/β-Catenin 31 1460 Casein Kinase 2 beta Rabbit Hu, Ms WB, IF, ICC, IHC (P), ChIP PA5-27416 WNT/β-Catenin 32 5582 PKC-gamma Mouse Hu, Ms, Rt WB, IHC 13-3800 WNT/β-Catenin 33 8454 CUL-1 Rabbit Hu WB, IP, ELISA 71-8700 WNT/β-Catenin 34 9978 ROC1C Rabbit Hu, Ms WB, IP 34-2500 WNT/β-Catenin 35 817 CaMKII delta Rabbit Hu, Ms, Rb, Rt WB, IF, ICC PA5-22168 WNT/β-Catenin 36 5566 PKA C-alpha Rabbit Hu, Ms, Rt WB, IF, ICC, FACS, IP PA5-17626 WNT/β-Catenin 37 5599 JNK1 Rabbit Hu, Ms, Rt WB 44-690G WNT/β-Catenin 38 5881 Rac1, 2, 3 Rabbit Bv, Hu, Ms, Nhp, Rt, Xl WB, FACS PA5-17519 WNT/β-Catenin 39 6934 TCF4 Rabbit Hu, Ms, Rt WB, IP, ChIP MA5-14975 WNT/β-Catenin 40 7473 WNT3 Mouse Hu, Ms, Rt WB, ELISA 39-0300 C M Y CM MY CY CMY K AACR_final.pdf 1 4/2/15 10:40 AM

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Page 1: AACR final.pdf 1 4/2/15 10:40 AM Signaling Pathways in Cancer · 2015. 4. 16. · RAS SIGNALING AND CANCER Dadi Jiang, Edward L. LaGory, Daniela Kenzelmann Brož, Kathryn T. Bieging,

FURTHER RECENT READING FROM CELL REPORTS

R A S S I G N A L I N G A N D C A N C E R

Dadi Jiang, Edward L. LaGory, Daniela Kenzelmann Brož, Kathryn T. Bieging, Colleen A. Brady, Nichole Link, John M. Abrams, Amato J. Giaccia, and Laura D. Attardi (2015). Analysis of p53 Transactivation Domain Mutants Reveals Acad11 as a Metabolic Target Important for p53 Pro-Survival Function. Cell Rep. 10, 1096–1109

Edward C. Stites, Paul C. Trampont, Lisa B. Haney, Scott F. Walk, Kodi S. Ravichandran (2015) Cooperation between Noncanonical Ras Network Mutations. Cell Rep. 10, 840

Bo-Kuan Wu, Charles Brenner (2014) Suppression of TET1-Dependent DNA Demethylation Is Essential for KRAS-Mediated Transformation. Cell Rep. 9, 1827–1840

Simona Lamba, Mariangela Russo, Chong Sun, Luca Lazzari, Carlotta Cancelliere, Wipawadee Grernrum, Cor Lieftink, Rene Bernards, Federica Di Nicolantonio, Alberto Bardelli (2014) RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells. Cell Rep. 8, 1475–1483

W N T /β - C AT E N I N S I G N A L I N G A N D C A N C E R

Victoria Llado, Yuki Nakanishi, Angeles Duran, Miguel Reina-Campos, Phillip M. Shelton, Juan F. Linares, Tomoko Yajima, Alex Campos, Pedro Aza-Blanc, Michael Leitges, Maria T Diaz-Meco, Jorge Moscat (2015)Re-pression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ. Cell Rep. 10, 740–754

Ekaterina Posokhova, Animesh Shukla, Steven Seaman, Suresh Volate, Mary Beth Hilton, Bofan Wu, Holly Morris, Deborah A. Swing, Ming Zhou, Enrique Zudaire, Jeffrey S. Rubin, Brad St. Croix (2015) GPR124 Functions as a WNT7-Specific Coactivator of Canonical β-Catenin Signaling. Cell Rep. 10, 123–130

Hadrien Demagny, Tatsuya Araki, Edward M. De Robertis (2014) The Tumor Suppressor Smad4/DPC4 Is Regulated by Phosphorylations that Integrate FGF, Wnt, and TGF-β Signaling. Cell Rep. 9, 688–700

Je-Hoon Song, David J. Huels, Rachel A. Ridgway, Owen J. Sansom, Boris N. Kholodenko, Walter Kolch, Kwang-Hyun Cho (2014) The APC Network Regulates the Removal of Mutated Cells from Colonic Crypts. Cell Rep. 7, 94–103

m T O R I N C A N C E R

Xin Zhou, Terri L. Clister, Pamela R. Lowry, Marcus M. Seldin, G. William Wong, Jin Zhang (2015) Dynamic Visualization of mTORC1 Activity in Living Cells. Cell Rep. 10, 1767–1777

Shigeru Kawabata, José R. Mercado-Matos, M. Christine Hollander, Danielle Donahue, Willie Wilson, Lucia Regales, Mohit Butaney, William Pao, Kwok-Kin Wong, Pasi A. Jänne, Phillip A. Dennis (2014)Rapamycin Prevents the Development and Progression of Mutant Epidermal Growth Factor Receptor Lung Tumors with the Acquired Resistance Mutation T790M. Cell Rep. 7, 1824–1832

Valentina Pirazzoli, Caroline Nebhan, Xiaoling Song, Anna Wurtz, Zenta Walther, Guoping Cai, Zhongming Zhao, Peilin Jia, Elisa de Stanchina, Erik M. Shapiro, Molly Gale, Ruonan Yin, Leora Horn, David P. Carbone, Philip J. Stephens, Vincent Miller, Scott Gettinger, William Pao, Katerina Politi (2014) Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1 Cell Rep. 7, 999–1008

Filip Janku, David S. Hong, Siqing Fu, Sarina A. Piha-Paul, Aung Naing, Gerald S. Falchook, Apostolia M. Tsimberidou, Vanda M. Stepanek, Stacy L. Moulder, J. Jack Lee, Rajyalakshmi Luthra, Ralph G. Zinner, Russell R. Broaddus, Jennifer J. Wheler, Razelle Kurzrock (2014) Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors Cell Rep. 6, 377–387

www.cell.com/cell-reports/collections/pathways

CyclinA1

SurvivinCyclinD1Telomerase

Akt

GlycogensynthesisGlycogensynthesis

G1/S cell-cycleprogression

G1/S cell-cycleprogression

ChromatinremodelingChromatinremodeling

SurvivalSurvival

AminoacidsAminoacids

RapamycinRapamycin

Insulin/IGFGrowth factorInsulin/IGFGrowth factor

Growth factore.g., EGFGrowth factore.g., EGF

AutophagyAutophagy

Cell survivalApoptosis

Cell survivalApoptosis

MetabolismMetabolism

Inactive complexInactive complex

Non-TCF β-cat targetsNon-TCF β-cat targets TCF/LEF target genesTCF/LEF target genes

HypoxiaHypoxiaRibosome biogenesis

TranslationRibosome biogenesis

Translation

Bad

Mdm2

Msk Rsk2 Ets1

Fos Jun

MnSODBimGadd45p27FasL

CyclinD1Fos

Spry

MycCyclinD1

p27

p21

RasRasGDP GTP

Raf

Mek

KSR

SosGrb2

Gab1

SrfElk1

FoxO

NF1 p120GAP

Myc

Erk RSK

Adipose-specific genes

p21CIP1, FASPTEN, TSC2

rRNA

Fas-L, p27KIP1p27

p16

p53

Rb

Cyclin D1CDK4

PPARγ

mTORC1PML

Crm1

TIF-1APol I

UBFSL1

eEF2KS6PDCD4

elF4AelF4E eEF2

elF3

elF4B

LKB1

AMPK

AMPK

AKT

PDK1PTEN

PI3K

PI3K

PIP3PIP2

S6K

4E-BP

TSC1

RagARagC

Rheb

PP2A

PP2A

PP2A

RhebTSC2

REDD1/2

PRAS40

GDP

GTP

BADFOXO3a

FOXO3a

mTORC1 mTORC2

AKT

Receptor TyrosineKinase

Receptor Tyrosine Kinase, EGFR

FKBP

IRS-1 GRB2

14-3-3

Brm

PAF1

MEDCBP

β-catLgsPygo

Pitx2/Prop1

DvI

PR55

GSK3CKI

CKIγ

β-arr

p68

GBP/Frat

AxinCav

FrizzledLRP5/6

Wnt

Axin CKIMACF1

G

TCF

β-catGSK3

GSK3

β-cat

Thermo Scientific™ Pierce™ Antibodies are developed for a wide variety of application needs. We offer more than 40,000 antibodies in 50 research areas, including cancer, epigenetics, and stem cell research. All of our antibodies are validated and guaranteed to perform in the stated application and species. Also, our Innovator’s Program rewards researchers for sharing data on qualified antibodies.To learn more, go to lifetechnologies.com/antibodies

Illustrated are some of the known components of three signaling pathways that have been linked to cancer: Ras, mTOR, and Wnt/β-catenin. Although these are not the only signaling pathways linked to cancer, and the chart is not comprehensive, they serve to illustrate the connectedness of these pathways and to provide an entryway into exploring functional studies, as outlined by the tables provided by Thermo Fisher Scienti�c.

Brown, E.J., Albers, M.W., Shin, T.B., Ichikawa, K., Keith, C.T., Lane, W.S., and Schreiber, S.L. (1994). A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758.

Cafferkey, R., Young, P.R., McLaughlin, M.M., Bergsma, D.J., Koltin, Y., Sathe, G.M., Faucette, L., Eng, W.K., Johnson, R.K., and Livi, G.P. (1993). Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol. Cell. Biol. 13, 6012–6023.

Clevers. H., and Nusse, R. (2012). Wnt/β-Catenin Signaling and Disease. Cell 149, 1192-1205

Cully M., and Downward, J. (2008). Snapshot: Ras Signaling. Cell 133, 1292

MacDonald, B.T., Semenov N.V., and He, X. (2007). Snapshot: Wnt/β-Catenin Signaling Cell 131, 1204

Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., and Hedge, P. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665–669

Nusse, R., and Varmus, H.E. (1982). Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99–109

Kinzler, K.W., and Vogelstein, B. (1996). Lessons from hereditary colorectal cancer. Cell 87, 159–170

Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N.R., and Hall, M.N. (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585–596

Laplante, M. and Sabatini, D.M. (2012) mTOR signaling in growth control and disease. Cell 149, 274-293

Prior, I.A. et al. (2012) A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467

Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P., and Snyder, S.H. (1994). RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43.

Sabers, C.J., Martin, M.M., Brunn, G.J., Williams, J.M., Dumont, F.J., Wiederrecht, G., and Abraham, R.T. (1995). Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815–822

Schmick, M., Kraemer, A., Bastiaens, P.I.H. (2015) Ras moves to stay in place. Trends in Cell Biol. http://dx.doi.org/10.1016/j.tcb.2015.02.004

Soulard A. and Hall, M.N. (2007) Snapshot: mTOR signaling. Cell 129, 434

The above touches only the surface of the rich information available about these pathways and the many unknowns that remain. Some further reading, as well as recent insights into these pathways and cancer that have been published in Cell Reports, can be found on the left. Points of potential path-way crosstalk are highlighted in red in the diagrams above.

R E F E R E N C E S

Signaling Pathways in Cancer

β-catGSK3

β-cat

β-cat

β-cat

β-cat

β-cat

β-cat

β-cat

β-cat

β-cat

β-cat

β-cat

APCPR61

AxinWTX

PP1

CKI

Target List Rank GeneID Target Host Reactivity Applications Catalog Number

ERK/RAS/RAF/MEK 1 801 Calmodulin Mouse Ba, Bv, Ck, Hu, Ms, Rt

WB, IF, ICC, IHC, FACS, ELISA MA3-917

ERK/RAS/RAF/MEK 2 1956 EGFR Mouse Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-13070

ERK/RAS/RAF/MEK 3 3480 IGF-IR / IGF1 Receptor alpha Mouse Hu IF, ICC, IHC (P), IP, ELISA MA5-13799

ERK/RAS/RAF/MEK 4 598 BCL-XL Mouse Hu, Ms IF, ICC, IHC (P), FACS, IP MA5-11950

ERK/RAS/RAF/MEK 5 25 c-Abl Mouse Hu, Ms WB, IF, ICC, IHC (P), IP MA5-14398

ERK/RAS/RAF/MEK 6 207 AKT Rabbit Hu, Ms WB, IF, ICC, IHC (P), FACS 710005

ERK/RAS/RAF/MEK 7 2902 NMDA Receptor 1 Rabbit Hu, Ms, Rt WB, IF, ICC, IHC, IP, ELISA PA3-102

ERK/RAS/RAF/MEK 8 2904 NMDA Receptor 2B Rabbit Hu, Ms, Rt WB, IF, ICC, IHC, IP,

ELISA PA3-104

ERK/RAS/RAF/MEK 9 3643 INSR / Insulin Receptor alpha Mouse Bv, Hu, Ov, Po,

Rb, RtIF, ICC, IHC (P), FACS, ELISA MA5-13767

ERK/RAS/RAF/MEK 10 3815 c-Kit / CD117 Rabbit Ca, Hu, Rt WB, IF, ICC, IHC (P), FACS PA5-16770

ERK/RAS/RAF/MEK 11 5921 GTPase Activating Protein Mouse Bv, Hu, Ms, Nhp, Rt WB, IF, IP MA4-001

ERK/RAS/RAF/MEK 12 7422 VEGF Mouse Hu WB, IHC (P) MA5-12184

ERK/RAS/RAF/MEK 13 4804 NGFR / p75 NGF Receptor Mouse Fe, Ft, Hu, Nhp,

Rb, Rt WB, IF, ICC, FACS MA5-13311

ERK/RAS/RAF/MEK 14 208 AKT2 Mouse Hu, Ms, Nhp, Rt WB, IF, ICC, IHC, IP, ChIP MA1-034

ERK/RAS/RAF/MEK 15 998 cdc42 Rabbit Hu, Ms, Nhp, Rt WB, IF, IHC (P) PA1-092

ERK/RAS/RAF/MEK 16 2002 ELK1 Mouse Bv, Hu, Ms, Nhp, Rt WB, IF, IP 45-8700

ERK/RAS/RAF/MEK 17 2260 FGFR1 / CD331 Mouse Hu, Rt WB, IHC, IP, ELISA 37-9200

ERK/RAS/RAF/MEK 18 2324 Flt-4 Rabbit Hu, Ms, Rt WB, IHC (P), IP PA5-16871

ERK/RAS/RAF/MEK 19 3082 Hepatocyte Growth Factor Mouse Hu, Ms WB, IF, ICC MA5-14160

ERK/RAS/RAF/MEK 20 3265 v-H-Ras Rat Hu, Ms, Rt WB, IF, IHC, IP 33-7200

ERK/RAS/RAF/MEK 21 4233 c-Met Mouse Hu WB, IHC, IP, ELISA 37-0100

ERK/RAS/RAF/MEK 22 5156 PDGF-RA / CD140a Rabbit Hu WB, IF, ICC, ChIP 701142

ERK/RAS/RAF/MEK 23 5159 PDGF-RB / CD140b Rabbit Hu, Ms, Rt WB, IF, ICC, IHC (F), IHC

(P), IP MA5-15143

ERK/RAS/RAF/MEK 24 5594 p42 MAP Kinase / ERK2 / MAPK1 Mouse Ca, Hu, Ms, Nhp, Rt WB, IF, IHC (P), IP, ChIP MA1-099

ERK/RAS/RAF/MEK 25 5595 p44 MAP Kinase / ERK1 Mouse Hu, Ms, Nhp WB, IF, IHC, ChIP MA1-13041

ERK/RAS/RAF/MEK 26 5879 Rac1 Rabbit Hu, Ms WB, IF, IHC (P) PA1-091

ERK/RAS/RAF/MEK 27 7535 Phospho-Zap-70 pTyr315+319 Rabbit Hu WB, IF, ICC, FACS 700177

ERK/RAS/RAF/MEK 28 1942 Ephrin-A1 Rabbit Hu, Ms WB, IHC, IP 34-3300

ERK/RAS/RAF/MEK 29 1945 Ephrin-A4 Rabbit Hu, Ms WB, IHC, IP 34-3700

ERK/RAS/RAF/MEK 30 2263 FGFR2 / CD332 Rabbit Hu, Ms, Nhp, Rt WB, IF, IHC, FACS PA5-14651

ERK/RAS/RAF/MEK 31 3630 Insulin Mouse Hu IHC (P) MA5-12029

ERK/RAS/RAF/MEK 32 5578 PKC alpha Mouse Bv, Ca, Hu, Ms, Nhp, Rb, Rt WB, IF, IHC (P), IP MA1-157

ERK/RAS/RAF/MEK 33 5906 Rap1 Mouse Hu, Ms WB, IF, ICC, IHC (P), IP MA1-013

ERK/RAS/RAF/MEK 34 382 Arf6 Rabbit Hu, Ms, Nhp WB, IF, IHC (P) PA1-093

ERK/RAS/RAF/MEK 35 1950 EGF Mouse Hu WB, IF, ELISA M806

ERK/RAS/RAF/MEK 36 2113 ETS1 Mouse Hu, Ms WB, IF, ICC, IHC, FACS MA5-15609

ERK/RAS/RAF/MEK 37 2247 FGF-2 Rabbit Hu WB 710148

ERK/RAS/RAF/MEK 38 2261 FGFR3 / CD333 Rabbit Hu WB, IF, ICC, IHC (P), IP MA5-14843

ERK/RAS/RAF/MEK 39 2321 Flt-1 Rabbit Hu, Ms, Rt WB PA5-16493

ERK/RAS/RAF/MEK 40 2903NMDA Recep-tor Subunit 2A / NMDAR2A

Rabbit Hu, Ms, Rt WB, IHC A-6473

Ras is at the core of the cell signaling network in response to growth factors, and mutations that lead to its activation are strongly linked to cancer, being found in 20–30% of tumors. A small membrane-lo-calized GTPase, Ras, cycles between a GTP-bound active state, which is promoted by guanine nucle-otide exchange factors, and a GDP-bound form. The GTPase activity is stimulated by GTPase-activat-ing proteins. The Ras pathway signals through a phosphorylation cascade that runs through Raf/ME-K/ERK, as highlighted here.

RASThe Wnt signaling pathway has been tied to tumorigenesis since the discovery of the �rst Wnt family member as the site of MMTV integration in a mouse breast tumor model. As further components of the pathway were uncovered, mutations in a downstream component of the pathway, APC, were linked to familial adenomatous polyposis. Many intriguing questions surrounding this pathway (a core version of which is shown here) remain, regarding the mechanisms involved in modi�cation of Wnt family mem-bers, as well as the receptor and co-receptor families (Frizzled and LRPs) and the regulation of a key downstream component, β-catenin.

WNTInitially uncovered as genetic and biochemical targets of rapamycin, mTOR1 and mTOR2 form complexes that respond to a range of environmental and nutritional triggers. Stimulated by the Ras-like protein Rheb, as well as the kinases Akt/PKB, ERK1/2, and RSK1, the mTOR complexes lie at the heart of a network of signaling pathways that are wired into both Ras/ERK and Wnt pathway components. Some examples of the affected pathways, which include links to protein synthesis and energy consumption, are illustrated. These central roles in cellular proliferation and metabolism indicate why mutations in mTOR signaling components (such as TSC1/2) have been linked to familial cancer and why mTORC1 itself, as well as downstream components, can be dysregulated in cancer.

mTOR

Target List Rank GeneID Target Host Reactivity Applications Catalog Number

mTOR-PI3K 1 596 BCL-2 Mouse Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-11757

mTOR-PI3K 2 898 Cyclin E Mouse Hu, Ms WB, IF, IHC (P), FACS MA5-14336

mTOR-PI3K 3 1956 EGFR Mouse Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-13070

mTOR-PI3K 4 3091 HIF-1 alpha Mouse Bv, Hu, Ms, Nhp, Po WB, IF, ICC, IHC (P), IP, GS, IE MA1-516

mTOR-PI3K 5 3320 HSP90 / Heat Shock Protein 90 alpha Mouse Ck, Fs, Hu, Ms,

Nhp, Rt WB, IF, IHC, IP MA3-011

mTOR-PI3K 6 4609 c-Myc Mouse Hu WB, IF, ICC, IHC (P, F), FACS, IP, ChIP, ELISA MA1-980

mTOR-PI3K 7 7057 Thrombospondin Mouse Bv, Ca, Eq, Hu, Ms, Ov, Po, Rt

WB, IF, ICC, IHC (P), FACS, IP, IM MA5-13398

mTOR-PI3K 8 7157 p53 Mouse Bv, Hu WB, IF, ICC, IHC (P), FACS, IP MA5-12557

mTOR-PI3K 9 7184 GRP94 / HSP90B1 Rat Bv, Ck, Hm, Hu, Ms, Rt WB, IF, ICC, IHC (P), IP MA3-016

mTOR-PI3K 10 11140 Cdc37 Mouse Hm, Hu, Ms, Rt WB, IF, ICC, IHC (P), FACS, IP MA3-029

mTOR-PI3K 11 595 Cyclin D1 / Bcl-1 Rabbit Hu, Ms WB, IF, ICC, IHC (P) MA5-14512

mTOR-PI3K 12 896 Cyclin D3 Mouse Hu, Ms, Nhp, Rt WB, IF, IHC (P), FACS, IP MA5-12717

mTOR-PI3K 13 1019 Cdk4 Mouse Hu, Ms, Rt WB, IF, FACS, IP MA5-13498

mTOR-PI3K 14 1021 Cdk6 Mouse Hu, Ms, Rt WB, IF, ICC, IHC (F), IHC (P), IP MA5-13333

mTOR-PI3K 15 1027 p27Kip1 Mouse Ca, Hu, Ms, Rt WB, IF, FACS, IP MA5-12835

mTOR-PI3K 16 1129 Muscarinic Acetylcholine Receptor M2 Mouse Hu, Ms, Po, Rt WB, IF, IHC (P), FACS, IP MA3-044

mTOR-PI3K 17 1280 Collagen II Mouse Bv, Ck, Hu, Ms, Rt WB, IF, IHC (P), FACS MA1-37493

mTOR-PI3K 18 3480 IGF-IR / IGF1 Receptor alpha Mouse Hu IF, ICC, IHC (P), IP, ELISA MA5-13799

mTOR-PI3K 19 598 BCL-XL Mouse Hu, Ms IF, ICC, IHC (P), FACS, IP MA5-11950

mTOR-PI3K 20 3676 Integrin alpha 4 / CD49d Mouse Hu, Rt IHC, FACS, Neu MA49D7

mTOR-PI3K 21 5618 Prolactin Receptor Mouse Eq, Hu, Po, Rb, Rt WB, IF, ICC, IHC (F), IHC (P), FACS, IP MA1-610

mTOR-PI3K 22 207 AKT Rabbit Hu, Ms WB, IF, ICC, IHC (P), FACS 710005

mTOR-PI3K 23 894 Cyclin D2 Mouse Hu, Ms, Rt WB, IF, FACS, IP MA5-12712

mTOR-PI3K 24 1385 CREB Mouse Hu, Ms, Nhp, Rt WB, IF, IHC, IP, ELISA MA1-083

mTOR-PI3K 25 2335 Fibronectin Mouse Hu, Ms, Rt WB, IF, IHC (P) MA5-11981

mTOR-PI3K 26 3559 IL-2R alpha / CD25 Mouse Hu WB, IF, ICC, IHC, FACS, IP M10AR

mTOR-PI3K 27 3643 INSR / Insulin Receptor alpha Mouse Bv, Hu, Ov, Po,

Rb, RtIF, ICC, IHC (P), FACS, ELISA MA5-13767

mTOR-PI3K 28 3815 c-Kit / CD117 Rabbit Ca, Hu, Rt WB, IF, ICC, IHC (P), FACS PA5-16770

mTOR-PI3K 29 5728 PTEN Mouse Hu WB, IF, ICC, IHC (P) MA5-12278

mTOR-PI3K 30 6198 Phospho-p70 S6 Kinase pThr389 Rabbit Hu, Rt WB, IF, ICC, FACS, ChIP 710095

mTOR-PI3K 31 7422 VEGF Mouse Hu WB, IHC (P) MA5-12184

mTOR-PI3K 32 3672 Integrin alpha-1 / CD49a Mouse Hu WB, IHC (F), FACS, IP MA49A0

mTOR-PI3K 33 3688 Integrin beta-1 / CD29 Mouse Hu FACS MA2910

mTOR-PI3K 34 4804 NGFR / p75 NGF Re-ceptor Mouse Fe, Ft, Hu, Nhp,

Rb, Rt WB, IF, ICC, FACS MA5-13311

mTOR-PI3K 35 4846 eNOS Rabbit Bv, Ca, Hu, Ms, Rt WB, IF, ICC, IHC, IHC (P) PA3-031A

mTOR-PI3K 36 208 AKT2 Mouse Hu, Ms, Nhp, Rt WB, IF, ICC, IHC, IP, ChIP MA1-034

mTOR-PI3K 37 842 Caspase 9 Rabbit Bv, Hu, Ms, Ov, Rt WB, IHC (P), IP PA5-16358

mTOR-PI3K 38 1017 Cdk2 Mouse Hu, Ms, Rt WB, IF, IHC (P) MA5-13479

mTOR-PI3K 39 1026 p21 Waf1/Cip1 Rabbit Ca, Hu, Nhp WB, IF, ICC, IHC (P), FACS, IP MA5-14949

mTOR-PI3K 40 1977 eIF4E Mouse Hu, Ms WB, IF, ICC, IP MA1-089

Target List Rank GeneID Target Host Reactivity Applications Catalog Number

WNT/ β-Catenin 1 1387 CREB Binding Protein Rabbit Hu, Ms WB, IF, ICC, IHC (P),

ChIP PA1-847

WNT/ β-Catenin 2 4609 c-Myc Mouse HuWB, IF, ICC, IHC (P, F), FACS, IP, ChIP, ELISA

MA1-980

WNT/ β-Catenin 3 4772 NFATc1 Mouse Hu, Ms, Nhp, RtWB, IF, ICC, IHC, IHC (P), IHC (PFA), IP, ChIP, GS

MA3-024

WNT/ β-Catenin 4 4773 NFATc2 Mouse Hu, Ms, Rt WB, IF, ICC, IHC (P, F), IP, ChIP, GS MA1-025

WNT/ β-Catenin 5 4776 NFAT3 Rabbit Hu WB, IF, IHC, IP PA1-021

WNT/ β-Catenin 6 7157 p53 Mouse Bv, Hu WB, IF, ICC, IHC (P), FACS, IP MA5-12557

WNT/ β-Catenin 7 595 Cyclin D1 / Bcl-1 Rabbit Hu, Ms WB, IF, ICC, IHC (P) MA5-14512

WNT/ β-Catenin 8 896 Cyclin D3 Mouse Hu, Ms, Nhp, Rt WB, IF, IHC (P), FACS, IP MA5-12717

WNT/ β-Catenin 9 5663 Presenilin 1 Mouse Hu, Ms, Nhp, Rt WB, IF, ICC, IHC, ELISA MA1-752

WNT/ β-Catenin 10 815 Phospho-CaM Kinase II pThr286 Mouse Hu, Ms, Rt WB, IF, ICC, IHC,

FACS, IP, ELISA MA1-047

WNT/ β-Catenin 11 894 Cyclin D2 Mouse Hu, Ms, Rt WB, IF, FACS, IP MA5-12712

WNT/ β-Catenin 12 1499 beta Catenin Mouse Hu, Ms WB, IF, IP MA1-2001

WNT/ β-Catenin 13 5467 PPAR delta Rabbit Hu, Ms, Rt WB, IF, IHC (F) PA1-823A

WNT/ β-Catenin 14 816 CaM Kinase II beta Mouse Fs, Hu, Ms, Ov, Rt, Su WB, IHC, IP, ELISA 13-9800

WNT/ β-Catenin 15 2033 EP300 Mouse Hu WB, IF, IHC, IP 33-7600

WNT/ β-Catenin 16 4316 MMP-7 (Matrilysin) Mouse Hu IF MA5-14215

WNT/ β-Catenin 17 5879 Rac1 Rabbit Hu, Ms WB, IF, IHC (P) PA1-091

WNT/ β-Catenin 18 6885 TAK1 / MAP3K7 Rabbit Hu WB, IF, ICC, FACS 700113

WNT/ β-Catenin 19 8312 Axin Rabbit Hu WB, IF, IP 34-5900

WNT/ β-Catenin 20 5578 PKC alpha Mouse Bv, Ca, Hu, Ms, Nhp, Rb, Rt WB, IF, IHC (P), IP MA1-157

WNT/ β-Catenin 21 2535 Frizzled-2 / FZD2 Rabbit Hu WB, IP 38-4700

WNT/ β-Catenin 22 2932 GSK3 Rabbit Hu WB, IF, ICC 701102

WNT/ β-Catenin 23 3725 c-Jun Mouse Hu, Ms, Nhp WB, IF, ICC, IHC, FACS MA5-15881

WNT/ β-Catenin 24 4041 LRP-5 Rabbit Hu, Ms WB, IF 36-5400

WNT/ β-Catenin 25 4088 SMAD3 Rabbit Hu WB, IF, IHC, ELISA 51-1500

WNT/ β-Catenin 26 4089 Smad4 Rabbit Hu, Ms, Nhp, Rt WB, IF, ChIP PA5-16191

WNT/β-Catenin 27 6932 TCF1 Rabbit Hu, Ms WB, IF, ICC, IHC (P), FACS, IP MA5-14965

WNT/β-Catenin 28 7471 WNT1 Mouse Hu, Ms WB, IF, ICC, IHC, FACS MA5-15544

WNT/β-Catenin 29 8945 BTRC Mouse Hu WB, IP, ELISA 37-3400

WNT/β-Catenin 30 51176 LEF1 Rabbit Hu, Ms, Rt WB, IF, ICC, FACS MA5-14966

WNT/β-Catenin 31 1460 Casein Kinase 2 beta Rabbit Hu, Ms WB, IF, ICC, IHC (P), ChIP PA5-27416

WNT/β-Catenin 32 5582 PKC-gamma Mouse Hu, Ms, Rt WB, IHC 13-3800

WNT/β-Catenin 33 8454 CUL-1 Rabbit Hu WB, IP, ELISA 71-8700

WNT/β-Catenin 34 9978 ROC1C Rabbit Hu, Ms WB, IP 34-2500

WNT/β-Catenin 35 817 CaMKII delta Rabbit Hu, Ms, Rb, Rt WB, IF, ICC PA5-22168

WNT/β-Catenin 36 5566 PKA C-alpha Rabbit Hu, Ms, Rt WB, IF, ICC, FACS, IP PA5-17626

WNT/β-Catenin 37 5599 JNK1 Rabbit Hu, Ms, Rt WB 44-690G

WNT/β-Catenin 38 5881 Rac1, 2, 3 Rabbit Bv, Hu, Ms, Nhp, Rt, Xl WB, FACS PA5-17519

WNT/β-Catenin 39 6934 TCF4 Rabbit Hu, Ms, Rt WB, IP, ChIP MA5-14975

WNT/β-Catenin 40 7473 WNT3 Mouse Hu, Ms, Rt WB, ELISA 39-0300

C

M

Y

CM

MY

CY

CMY

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