Negative feedback regulation of the ERK1/2 MAPK pathway

Cellular and Molecular Life Sciences

Volumn 73, Issue 23, 2016, Pages 4397-4413

  Lake, David ^a   Corrêa, Sonia A L ^b,c   Müller, Jürgen ^a,d  

^a UNIVERSITY OF WARWICK   (United Kingdom)

^b UNIVERSITY OF WARWICK   (United Kingdom)

^c UNIVERSITY OF BRADFORD   (United Kingdom)

^d ASTON UNIVERSITY   (United Kingdom)

Author keywords

Cancer; Cell signalling; Negative feedback; Pathway modelling; Signalling dynamics; Spatiotemporal regulation

Indexed keywords

B RAF KINASE; DUAL SPECIFICITY PHOSPHATASE; DUAL SPECIFICITY PHOSPHATASE 2; DUAL SPECIFICITY PHOSPHATASE 6; EPIDERMAL GROWTH FACTOR; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 3; FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR RECEPTOR; FIBROBLAST GROWTH FACTOR RECEPTOR 1; GROWTH FACTOR RECEPTOR BOUND PROTEIN 2; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; MITOGEN ACTIVATED PROTEIN KINASE PHOSPHATASE; MITOGEN ACTIVATED PROTEIN KINASE PHOSPHATASE 1; NEU DIFFERENTIATION FACTOR; NEUROFIBROMIN; P21 ACTIVATED KINASE; PROTEIN 14 3 3; PROTEIN TYROSINE PHOSPHATASE; RAF PROTEIN; S6 KINASE; SOS PROTEIN; SPROUTY PROTEIN; STRESS ACTIVATED PROTEIN KINASE; T LYMPHOCYTE RECEPTOR; TUMOR NECROSIS FACTOR; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN KINASE INHIBITOR;

AMINO TERMINAL SEQUENCE; CANCER GROWTH; CARBOXY TERMINAL SEQUENCE; DOWN REGULATION; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME LOCALIZATION; ENZYME PHOSPHORYLATION; HUMAN; NEGATIVE FEEDBACK; NONHUMAN; PROTEIN EXPRESSION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; UPREGULATION; ANIMAL; DISEASE COURSE; DRUG EFFECTS; METABOLISM; PHOSPHORYLATION; PHYSIOLOGICAL FEEDBACK;

ANIMALS; DISEASE PROGRESSION; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; FEEDBACK, PHYSIOLOGICAL; HUMANS; MAP KINASE SIGNALING SYSTEM; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS;

EID: 84976333432     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-016-2297-8     Document Type: Review

References (133)

1. McKay MM, Morrison DK (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26(22):3113–3121
2. Gureasko J, Galush WJ, Boykevisch S, Sondermann H, Bar-Sagi D, Groves JT, Kuriyan J (2008) Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol 15(5):452–461
3. Chong H, Vikis HG, Guan K-L (2003) Mechanisms of regulating the Raf kinase family. Cell Signal 15(5):463–469
4. Lavoie H, Therrien M (2015) Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 16(5):281–298
5. Hagemann C, Rapp UR (1999) Isotype-specific functions of Raf kinases. Exp Cell Res 253(1):34–46
6. Yoon S, Seger R (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24(1):21–44
7. Northwood IC, Gonzalez FA, Wartmann M, Raden DL, Davis RJ (1991) Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669. J Biol Chem 266(23):15266–15276
8. Takishima K, Griswold-Prenner I, Ingebritsen T, Rosner MR (1991) Epidermal growth factor (EGF) receptor T669 peptide kinase from 3T3-L1 cells is an EGF-stimulated “MAP” kinase. Proc Natl Acad Sci USA 88(6):2520–2524
9. Sato K, Shin M-S, Sakimura A, Zhou Y, Tanaka T, Kawanishi M, Kawasaki Y, Yokoyama S, Koizumi K, Saiki I, Sakurai H (2013) Inverse correlation between Thr-669 and constitutive tyrosine phosphorylation in the asymmetric epidermal growth factor receptor dimer conformation. Cancer Sci 104(10):1315–1322
10. Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM, Engelman JA (2012) MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res 72(13):3228–3237
11. Li X, Huang Y, Jiang J, Frank SJ (2008) ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling. Cell Signal 20(11):2145–2155
12. Sorkin A, Goh LK (2009) Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res 315(4):683–696
13. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483(7387):100–103
14. Zakrzewska M, Haugsten EM, Nadratowska-Wesolowska B, Oppelt A, Hausott B, Jin Y, Otlewski J, Wesche J, Wiedlocha A (2013) ERK-mediated phosphorylation of fibroblast growth factor receptor 1 on Ser777 inhibits signaling. Sci Signal 6(262):ra11
15. Ueki K, Matsuda S, Tobe K, Gotoh Y, Tamemoto H, Yachi M, Akanuma Y, Yazaki Y, Nishida E, Kadowaki T (1994) Feedback regulation of mitogen-activated protein kinase kinase kinase activity of c-Raf-1 by insulin and phorbol ester stimulation. J Biol Chem 269(22):15756–15761
16. Langlois WJ, Sasaoka T, Saltiel AR, Olefsky JM (1995) Negative feedback regulation and desensitization of insulin- and epidermal growth factor-stimulated p21ras activation. J Biol Chem 270(43):25320–25323
17. Corbalan-Garcia S, Yang SS, Degenhardt KR, Bar-Sagi D (1996) Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2. Mol Cell Biol 16(10):5674–5682
18. Porfiri E, McCormick F (1996) Regulation of epidermal growth factor receptor signaling by phosphorylation of the Ras exchange factor hSOS1. J Biol Chem 271(10):5871–5877
19. Kamioka Y, Yasuda S, Fujita Y, Aoki K, Matsuda M (2010) Multiple decisive phosphorylation sites for the negative feedback regulation of SOS1 via ERK. J Biol Chem 285(43):33540–33548
20. Douville E, Downward J (1997) EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2. Oncogene 15(4):373–383
21. Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, Roux PP, Ballif BA (2012) RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. Biochem J 447(1):159–166
22. Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J (1997) A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89(5):693–702
23. Lax I, Wong A, Lamothe B, Lee A, Frost A, Hawes J, Schlessinger J (2002) The docking protein FRS2α controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Mol Cell 10(4):709–719
24. Wu Y, Chen Z, Ullrich A (2003) EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2. Biol Chem 384(8):1215–1226
25. Fuller DM, Zhang W (2009) Regulation of lymphocyte development and activation by the LAT family of adapter proteins. Immunol Rev 232(1):72–83
26. Matsuda S, Miwa Y, Hirata Y, Minowa A, Tanaka J, Nishida E, Koyasu S (2004) Negative feedback loop in T-cell activation through MAPK-catalyzed threonine phosphorylation of LAT. EMBO J 23(13):2577–2585
27. Hennig A, Markwart R, Wolff K, Schubert K, Cui Y, Prior IA, Esparza-Franco MA, Ladds G, Rubio I (2016) Feedback activation of neurofibromin terminates growth factor-induced Ras activation. Cell Commun Signal 14(1):5
28. Wartmann M, Hofer P, Turowski P, Saltiel AR, Hynes NE (1997) Negative modulation of membrane localization of the Raf-1 protein kinase by hyperphosphorylation. J Biol Chem 272(7):3915–3923
29. Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270(46):27489–27494
30. Weiss RH, Maga EA, Ramirez A (1998) MEK inhibition augments Raf activity, but has variable effects on mitogenesis, in vascular smooth muscle cells. Am J Physiol 274(6 Pt 1):C1521–C1529
31. Dougherty MK, Müller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17(2):215–224
32. Müller J, Morrison DK (2002) Assay of Raf-1 activity. Methods Enzymol 345:490–498
33. Hekman M, Fischer A, Wennogle LP, Wang YK, Campbell SL, Rapp UR (2005) Novel C-Raf phosphorylation sites: serine 296 and 301 participate in Raf regulation. FEBS Lett 579(2):464–468
34. Balan V, Leicht DT, Zhu J, Balan K, Kaplun A, Singh-Gupta V, Qin J, Ruan H, Comb MJ, Tzivion G (2006) Identification of novel in vivo Raf-1 phosphorylation sites mediating positive feedback Raf-1 regulation by extracellular signal-regulated kinase. Mol Biol Cell 17(3):1141–1153
35. Brummer T, Naegele H, Reth M, Misawa Y (2003) Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf. Oncogene 22(55):8823–8834
36. Ritt DA, Monson DM, Specht SI, Morrison DK (2010) Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling. Mol Cell Biol 30(3):806–819
37. Weber CK, Slupsky JR, Kalmes HA, Rapp UR (2001) Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res 61(9):3595–3598
38. Brunet A, Pagès G, Pouyssègur J (1994) Growth factor-stimulated MAP kinase induces rapid retrophosphorylation and inhibition of MAP kinase kinase (MEK1). FEBS Lett 346(2–3):299–303
39. Coles LC, Shaw PE (2002) PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. Oncogene 21(14):2236–2244
40. Eblen ST, Slack-Davis JK, Tarcsafalvi A, Parsons JT, Weber MJ, Catling AD (2004) Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion. Mol Cell Biol 24(6):2308–2317
41. Rossomando AJ, Dent P, Sturgill TW, Marshak DR (1994) Mitogen-activated protein kinase kinase 1 (MKK1) is negatively regulated by threonine phosphorylation. Mol Cell Biol 14(3):1594–1602
42. Slack-Davis JK, Eblen ST, Zecevic M, Boerner SA, Tarcsafalvi A, Diaz HB, Marshall MS, Weber MJ, Parsons JT, Catling AD (2003) PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol 162(2):281–291
43. Catalanotti F, Reyes G, Jesenberger V, Galabova-Kovacs G, de Matos Simoes R, Carugo O, Baccarini M (2009) A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol 16(3):294–303
44. Brown MD, Sacks DB (2009) Protein scaffolds in MAP kinase signalling. Cell Signal 21(4):462–469
45. Casar B, Arozarena I, Sanz-Moreno V, Pinto A, Agudo-Ibáñez L, Marais R, Lewis RE, Berciano MT, Crespo P (2009) Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Mol Cell Biol 29(5):1338–1353
46. Zeke A, Lukács M, Lim WA, Reményi A (2009) Scaffolds: interaction platforms for cellular signalling circuits. Trends Cell Biol 19(8):364–374
47. Kornfeld K, Hom DB, Horvitz HR (1995) The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 83(6):903–913
48. Therrien M, Chang HC, Solomon NM, Karim FD, Wassarman DA, Rubin GM (1995) KSR, a novel protein kinase required for RAS signal transduction. Cell 83(6):879–888
49. Sundaram M, Han M (1995) The C. elegans ksr-1 gene encodes a novel raf-related kinase involved in Ras-mediated signal transduction. Cell 83(6):889–901
50. Denouel-Galy A, Douville EM, Warne PH, Papin C, Laugier D, Calothy G, Downward J, Eychène A (1998) Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Curr Biol CB 8(1):46–55
51. Yu W, Fantl WJ, Harrowe G, Williams LT (1998) Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Curr Biol CB 8(1):56–64
52. Müller J, Ory S, Copeland T, Piwnica-Worms H, Morrison DK (2001) C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol Cell 8(5):983–993
53. Müller J, Ritt DA, Copeland TD, Morrison DK (2003) Functional analysis of C-TAK1 substrate binding and identification of PKP2 as a new C-TAK1 substrate. EMBO J 22(17):4431–4442
54. Volle DJ, Fulton JA, Chaika OV, McDermott K, Huang H, Steinke LA, Lewis RE (1999) Phosphorylation of the kinase suppressor of Ras by associated kinases†. Biochemistry 38(16):5130–5137
55. Cacace AM, Michaud NR, Therrien M, Mathes K, Copeland T, Rubin GM, Morrison DK (1999) Identification of constitutive and Ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Mol Cell Biol 19(1):229–240
56. Canal F, Palygin O, Pankratov Y, Corrêa SAL, Müller J (2011) Compartmentalization of the MAPK scaffold protein KSR1 modulates synaptic plasticity in hippocampal neurons. FASEB J 25(7):2362–2372
57. McKay MM, Ritt DA, Morrison DK (2009) Signaling dynamics of the KSR1 scaffold complex. Proc Natl Acad Sci 106(27):11022–11027
58. Müller J, Cacace AM, Lyons WE, McGill CB, Morrison DK (2000) Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling. Mol Cell Biol 20(15):5529–5539
59. Shalin SC, Hernandez CM, Dougherty MK, Morrison DK, Sweatt JD (2006) Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation. Neuron 50(5):765–779
60. Keyse SM (2000) Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr Opin Cell Biol 12(2):186–192
61. Caunt CJ, Keyse SM (2013) Dual-specificity MAP kinase phosphatases (MKPs). FEBS J 280(2):489–504
62. Huang CY, Tan TH (2012) DUSPs, to MAP kinases and beyond. Cell Biosci 2(1):24
63. Ekerot M, Stavridis MP, Delavaine L, Mitchell MP, Staples C, Owens DM, Keenan ID, Dickinson RJ, Storey KG, Keyse SM (2008) Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J 412(2):287–298
64. Zhang Z, Kobayashi S, Borczuk AC, Leidner RS, LaFramboise T, Levine AD, Halmos B (2010) Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis 31(4):577–586
65. Karlsson M, Mathers J, Dickinson RJ, Mandl M, Keyse SM (2004) Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J Biol Chem 279(40):41882–41891
66. Mandl M, Slack DN, Keyse SM (2005) Specific inactivation and nuclear anchoring of extracellular signal-regulated kinase 2 by the inducible dual-specificity protein phosphatase DUSP5. Mol Cell Biol 25(5):1830–1845
67. Guy GR, Jackson RA, Yusoff P, Chow SY (2009) Sprouty proteins: modified modulators, matchmakers or missing links? J Endocrinol 203(2):191–202
68. Casci T, Vinós J, Freeman M (1999) Sprouty, an intracellular inhibitor of Ras signaling. Cell 96(5):655–665
69. Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA (1998) Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the drosophila airways. Cell 92(2):253–263
70. Kramer S, Okabe M, Hacohen N, Krasnow MA, Hiromi Y (1999) Sprouty: a common antagonist of FGF and EGF signaling pathways in Drosophila. Development 126(11):2515–2525
71. Ozaki K, Kadomoto R, Asato K, Tanimura S, Itoh N, Kohno M (2001) ERK pathway positively regulates the expression of sprouty genes. Biochem Biophys Res Commun 285(5):1084–1088
72. Panagiotaki N, Dajas-Bailador F, Amaya E, Papalopulu N, Dorey K (2010) Characterisation of a new regulator of BDNF signalling, Sprouty3, involved in axonal morphogenesis in vivo. Development 137(23):4005–4015
73. Haimov-Kochman R, Ravhon A, Prus D, Greenfield C, Finci-Yeheskel Z, S Goldman-Wohl D, Natanson-Yaron S, Reich R, Yagel S, Hurwitz A (2005) Expression and regulation of Sprouty-2 in the granulosa-lutein cells of the corpus luteum. Mol Hum Reprod 11(8):537–542
74. Yang X, Webster JB, Kovalenko D, Nadeau RJ, Zubanova O, Chen PY, Friesel R (2006) Sprouty genes are expressed in osteoblasts and inhibit fibroblast growth factor-mediated osteoblast responses. Calcif Tissue Int 78(4):233–240
75. Sylvestersen KB, Herrera PL, Serup P, Rescan C (2011) Fgf9 signalling stimulates Spred and Sprouty expression in embryonic mouse pancreas mesenchyme. Gene Expr Patterns 11(1–2):105–111
76. Jiang ZL, Ripamonte P, Buratini J, Portela VM, Price CA (2011) Fibroblast growth factor-2 regulation of sprouty and NR4A genes in bovine ovarian granulosa cells. J Cell Physiol 226(7):1820–1827
77. Mason JM, Morrison DJ, Albert Basson M, Licht JD (2006) Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol 16(1):45–54
78. Hanafusa H, Torii S, Yasunaga T, Nishida E (2002) Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 4(11):850–858
79. Yusoff P, Lao D-H, Ong SH, Wong ESM, Lim J, Lo TL, Leong HF, Fong CW, Guy GR (2002) Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf. J Biol Chem 277(5):3195–3201
80. Sasaki A, Taketomi T, Kato R, Saeki K, Nonami A, Sasaki M, Kuriyama M, Saito N, Shibuya M, Yoshimura A (2003) Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nat Cell Biol 5(5):427–432
81. Masoumi-Moghaddam S, Amini A, Morris DL (2014) The developing story of Sprouty and cancer. Cancer Metastasis Rev 33(2–3):695–720
82. Traverse S, Gomez N, Paterson H, Marshall C, Cohen P (1992) Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J 288:351–355
83. Brightman FA, Fell DA (2000) Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells. FEBS Lett 482(3):169–174
84. Santos SD, Verveer PJ, Bastiaens PI (2007) Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol 9(3):324–330
85. Kortum RL, Costanzo DL, Haferbier J, Schreiner SJ, Razidlo GL, Wu MH, Volle DJ, Mori T, Sakaue H, Chaika NV, Chaika OV, Lewis RE (2005) The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis. Mol Cell Biol 25(17):7592–7604
86. Kortum RL, Lewis RE (2004) The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells. Mol Cell Biol 24(10):4407–4416
87. Sturm OE, Orton R, Grindlay J, Birtwistle M, Vyshemirsky V, Gilbert D, Calder M, Pitt A, Kholodenko B, Kolch W (2010) The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Sci Signal 3(153):ra90
88. Fritsche-Guenther R, Witzel F, Sieber A, Herr R, Schmidt N, Braun S, Brummer T, Sers C, Blüthgen N (2011) Strong negative feedback from Erk to Raf confers robustness to MAPK signalling. Mol Syst Biol 7(1):489
89. Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5(3):173–183
90. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954
91. Gorden A, Osman I, Gai W, He D, Huang W, Davidson A, Houghton AN, Busam K, Polsky D (2003) Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res 63(14):3955–3957
92. Ross JS, Fletcher JA (1999) The HER-2/neu oncogene: prognostic factor, predictive factor and target for therapy. Semin Cancer Biol 9(2):125–138
93. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101(36):13306–13311
94. Mason CS, Springer CJ, Cooper RG, Superti-Furga G, Marshall CJ, Marais R (1999) Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J 18(8):2137–2148
95. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439(7074):358–362
96. Garnett MJ, Rana S, Paterson H, Barford D, Marais R (2005) Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 20(6):963–969
97. Rushworth LK, Hindley AD, O’Neill E, Kolch W (2006) Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol 26(6):2262–2272
98. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, Marais R (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140(2):209–221
99. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464(7287):427–430
100. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, Rosen N (2009) V600EBRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci 106(11):4519–4524
101. Dultz LA, Dhar S, Ogilvie JB, Heller KS, Bar-Sagi D, Patel KN (2013) Clinical and therapeutic implications of Sprouty2 feedback dysregulation in BRAF V600E-mutation-positive papillary thyroid cancer. Surgery 154(6):1239–1245
102. Lito P, Pratilas Christine A, Joseph Eric W, Tadi M, Halilovic E, Zubrowski M, Huang A, Wong Wai L, Callahan Margaret K, Merghoub T, Wolchok Jedd D, de Stanchina E, Chandarlapaty S, Poulikakos Poulikos I, Fagin James A, Rosen N (2012) Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22(5):668–682
103. Yao Z, Torres NM, Tao A, Gao YJ, Luo LS, Li Q, de Stanchina E, Abdel-Wahab O, Solit DB, Poulikakos PI, Rosen N (2015) BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell 28(3):370–383
104. Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M (1997) Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 17(9):5598–5611
105. Zhu J, Woods D, McMahon M, Bishop JM (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12(19):2997–3007
106. Leboeuf R, Baumgartner JE, Benezra M, Malaguarnera R, Solit D, Pratilas CA, Rosen N, Knauf JA, Fagin JA (2008) BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines. J Clin Endocrinol Metab 93(6):2194–2201
107. Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, Shigematsu H, Yamamoto H, Sawai A, Janakiraman M, Taylor BS, Pao W, Toyooka S, Ladanyi M, Gazdar A, Rosen N, Solit DB (2008) Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 68(22):9375–9383
108. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819
109. Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, Guckert M, Schadendorf D, Kefford RF, Grob J-J, Hamid O, Amaravadi R, Simeone E, Wilhelm T, Kim KB, Long GV, Martin A-M, Mazumdar J, Goodman VL, Trefzer U (2013) Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 31(26):3205–3211
110. Ravnan MC, Matalka MS (2012) Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma. Clin Ther 34(7):1474–1486
111. Robert C, Arnault JP, Mateus C (2011) RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr Opin Oncol 23(2):177–182
112. Poulikakos PI, Solit DB (2011) Resistance to MEK inhibitors: should we co-target upstream? Sci Signal 4(166):pe16
113. Lito P, Rosen N, Solit DB (2013) Tumor adaptation and resistance to RAF inhibitors. Nat Med 19(11):1401–1409
114. Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, Edwards PA, Smith PD, Cook SJ (2011) Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal 4(166):ra17
115. Maertens O, Johnson B, Hollstein P, Frederick DT, Cooper ZA, Messiaen L, Bronson RT, McMahon M, Granter S, Flaherty K, Wargo JA, Marais R, Cichowski K (2013) Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov 3(3):338–349
116. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee M-K, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468(7326):973–977
117. Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, Tiwari S, Kong L, Hanrahan AJ, Yao Z, Merghoub T, Ribas A, Chapman PB, Yaeger R, Taylor BS, Schultz N, Berger MF, Rosen N, Solit DB (2014) Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res 74(8):2340–2350
118. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM, Zecchin D, Hobor S, Bajpe PK, Lieftink C, Mateus C, Vagner S, Grernrum W, Hofland I, Schlicker A, Wessels LF, Beijersbergen RL, Bardelli A, Di Nicolantonio F, Eggermont AM, Bernards R (2014) Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508(7494):118–122
119. Whittaker SR, Theurillat J-P, Van Allen E, Wagle N, Hsiao J, Cowley GS, Schadendorf D, Root DE, Garraway LA (2013) A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov 3(3):350–362
120. Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong X-Q, Buchanan S, Henry JR, Starling JJ, Peng S-B (2012) Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 287(33):28087–28098
121. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Haber DA, Settleman J (2008) Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 68(12):4853–4861
122. Shi H, Moriceau G, Kong X, Lee M-K, Lee H, Koya RC, Ng C, Chodon T, Scolyer RA, Dahlman KB, Sosman JA, Kefford RF, Long GV, Nelson SF, Ribas A, Lo RS (2012) Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3:724
123. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa JP, Gibbs P, James B, Powis G, Nolop KB, Bhattacharya S, Saltz L (2015) Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol 33(34):4032–4038
124. Bollag G, Hirth P, Tsai J, Zhang JZ, Ibrahim PN, Cho HN, Spevak W, Zhang C, Zhang Y, Habets G, Burton E, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KYJ, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu XW, Nathanson KL, Nolop K (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467(7315):596–599
125. Goldinger SM, Zimmer L, Schulz C, Ugurel S, Hoeller C, Kaehler KC, Schadendorf D, Hassel JC, Becker J, Hauschild A, Dummer R (2014) Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients. Eur J Cancer (Oxford, England: 1990) 50(2):406–410
126. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703
127. Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y, Van Horn RD, Yin T, Zhang X, Yadav V, Chen SH, Gong X, Ma X, Webster Y, Buchanan S, Mochalkin I, Huber L, Kays L, Donoho GP, Walgren J, McCann D, Patel P, Conti I, Plowman GD, Starling JJ, Flynn DL (2015) Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell 28(3):384–398
128. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D’Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18(6):683–695
129. Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B, Glaspy JA, Comin-Anduix B, Mischel PS, Lo RS, Ribas A (2011) Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One 6(12):e28973
130. Shi H, Kong X, Ribas A, Lo RS (2011) Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res 71(15):5067–5074
131. Yaeger R, Cercek A, O’Reilly EM, Reidy DL, Kemeny N, Wolinsky T, Capanu M, Gollub MJ, Rosen N, Berger MF, Lacouture ME, Vakiani E, Saltz LB (2015) Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res 21(6):1313–1320
132. Mao M, Tian F, Mariadason JM, Tsao CC, Lemos R Jr, Dayyani F, Gopal YN, Jiang ZQ, Wistuba II, Tang XM, Bornman WG, Bollag G, Mills GB, Powis G, Desai J, Gallick GE, Davies MA, Kopetz S (2013) Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res 19(3):657–667
133. Fattore L, Marra E, Pisanu M, Noto A, de Vitis C, Belleudi F, Aurisicchio L, Mancini R, Torrisi M, Ascierto P, Ciliberto G (2013) Activation of an early feedback survival loop involving phospho-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies. J Transl Med 11(1):180