PERSPECTIVE CANCER Because the Wnt/β-catenin signaling pathway is oncogenic in most cancers, yet Wnt/␤-Catenin and MAPK Signaling: anti-oncogenic and a marker for good prog- nosis in melanoma, Biechele and colleagues Allies and Enemies in Different (7) searched for previously unknown regula- tors of Wnt/β-catenin signaling in melano- Battlefi elds ma. They used an RNA interference–based genetic screen for protein kinases, whose si- Daniele Guardavaccaro and Hans Clevers* lencing synergized with Wnt in stimulating β-catenin transcriptional activity in a hu- Two papers published in Science Signaling reveal extensive crosstalk between Wnt/␤-catenin and mitogen-activated protein kinase (MAPK) signaling in cancer. man melanoma cell line. Using this screen, Although both studies describe previously unknown links between these two they unexpectedly found that silencing of signaling pathways, the relationship between Wnt/␤-catenin and MAPK signaling BRAF enhanced β-catenin activity in the depends on the specifi c cellular context. Indeed, in melanoma, hyperactivated presence of Wnt. This fi nding is particularly MAPK signaling down-regulates the Wnt/␤-catenin signal transduction cascade, interesting because oncogenic mutations in thereby establishing a negative crosstalk between the two signaling pathways. BRAF occur in about 60% of human mela- In contrast, in colorectal cancer, stimulation of the Wnt/␤-catenin pathway leads nomas (8–10). The most frequent BRAF to activation of the MAPK pathway through Ras stabilization, representing an mutation in melanoma is Val600 → Glu (V600E). BRAF(V600E) induces cell prolif- example of positive crosstalk. Moreover, activation of Wnt/␤-catenin signaling Downloaded from has context-dependent functions that trigger opposing effects on tumor growth. eration, survival, and invasion in melanoma In melanoma, aberrant activation of Wnt/␤-catenin signaling may have anti- cells and stimulates tumor angiogenesis. oncogenic functions by promoting programmed cell death; by contrast, in the Remark ably, small-molecule compounds intestine, Wnt/␤-catenin signaling drives malignant transformation. Thus, there such as PLX-4720 that selectively inhibit is no single correct way to target the Wnt/␤-catenin pathway for all cancers. oncogenic BRAF display potent activity 11 12 against melanoma ( , ). Biechele and http://stke.sciencemag.org/ Signal transduction cascades transduce ex- quence of events leads to the inactivation of colleagues found that PLX-4720 treatment tracellular signals into cellular responses. the destruction complex and accumulation of a melanoma cell line that harbors the Modifi cations of proto-oncogenic signaling of β-catenin. The latter interacts with tran- BRAF(V600E) mutation enhanced Wnt/β- pathways contribute to the acquisition of can- scription factors of the TCF/LEF1 family to catenin signaling. The oncogenic activity of cer traits. When two well-studied proto-onco- regulate the expression of Wnt target genes, BRAF(V600E) in melanoma results mostly genic pathways—the Wnt/β-catenin pathway which regulate various biological processes from the activation of the MAPK pathway. and the mitogen-activated protein kinase (such as proliferation, fate determination, Accordingly, Biechele et al. found that inhi- (MAPK) pathway—are deregulated, they and differentiation) in a tissue-specifi c bition of MEK, the kinase phosphorylated play prominent roles in cancer pathogenesis. fashion. Mutations in the genes encoding and stimulated by BRAF, also enhanced on May 9, 2018 Wnt/β-catenin signaling controls nor- β-catenin, Axin, or APC, which occur in di- Wnt/β-catenin signaling. mal embryonic development and regulates verse human tumors, lead to accumulation To examine the underlying molecular self-renewal in various adult tissues [re- of β-catenin and transactivation of TCF/ mechanism responsible for the inhibitory ef- viewed in (1, 2)]. This signal transduction LEF1 transcription factors. fect of BRAF on the Wnt/β-catenin signaling pathway is initiated by the binding of Wnt The MAPK cascade, which consists of pathway, the authors focused on two compo- ligands to receptor complexes that include three sequentially activated protein kinas- nents of the β-catenin destruction complex, the transmembrane receptors of the Friz- es [reviewed in (3–5)], is activated by the Axin and GSK3. In melanoma cells, inhibi- zled family. In the absence of Wnt ligands, GTP-bound Ras protein, a small guanosine tion of BRAF combined with Wnt/β-catenin the “destruction complex,” which includes triphosphatase (GTPase) for which onco- activation caused proteasome-dependent de- a scaffolding core composed of two tumor genic mutations have been reported in one- gra dation of Axin, inhibition of GSK3, and suppressor proteins, Axin and Adenoma- third of all human cancers [reviewed in (6)]. consequent dephosphorylation of β-catenin tous Polyposis Coli (APC), enables two Ras activates the kinase Raf and its close on the GSK3 target sites. protein kinases—glycogen synthase kinase relative BRAF, both of which phosphorylate The relationship between the Wnt/β- 3 (GSK3) and casein kinase 1 (CK1)—to and activate the second kinase in the cas- catenin and MAPK signaling pathways was phosphorylate β-catenin, triggering its cade, MEK. In turn, MEK phosphorylates also investigated by Jeong and colleagues ubiquitylation by the SCFβTrCP ubiquitin and activates the third kinase, ERK. The lat- (13), although within the different context ligase and subsequent degradation by the ter phosphorylates a number of cytoplasmic of intestinal tumorigenesis. In contrast to proteasome. When a Wnt ligand interacts substrates (such as regulators of translation) the opposing effects of Wnt/β-catenin and with a Frizzled receptor, a complicated se- as well as nuclear targets (such as transcrip- MAPK signaling found in melanoma, in tion factors). Constitutive activation of the colon cancer, Wnt/β-catenin and MAPK Ras-Raf-MEK-ERK signaling cascade has signaling synergized in a combined effort to Hubrecht Institute-KNAW and University Medi- cal Center Utrecht, Uppsalalaan 8, 3584 CT been reported in a large number of human promote transformation. Jeong et al. found Utrecht, Netherlands. cancers, where it induces growth-promoting that the same negative regulators of Wnt/β- *Corresponding author. E-mail: h.clevers@ genes, regulates cell adhesion and migra- catenin signaling analyzed by Biechele and hubrecht.eu tion, and causes changes in cell shape. colleagues, the destruction complex com- www.SCIENCESIGNALING.org 10 April 2012 Vol 5 Issue 219 pe15 1 PERSPECTIVE ponents Axin and GSK3, along with the E3 catenin and MAPK signaling cascades. 8. M. S. Brose, P. Volpe, M. Feldman, M. Kumar, I. ubiquitin ligase SCFβTrCP, conspired to trig- Both studies have strong implications for Rishi, R. Gerrero, E. Einhorn, M. Herlyn, J. Minna, A. Nicholson, J. A. Roth, S. M. Albelda, H. Davies, ger not only the proteolysis of β-catenin but the development of combination therapies C. Cox, G. Brignell, P. Stephens, P. A. Futreal, R. also the degradation of Ras. As a result, in for melanoma and colon cancer. Indeed, the Wooster, M. R. Stratton, B. L. Weber, BRAF and colon cancer, aberrant activation of Wnt/β- paper by Biechele and colleagues suggests RAS mutations in human lung cancer and mela- catenin signaling caused the stabilization of that melanoma patients might benefi t from noma. Cancer Res. 62, 6997–7000 (2002). 9. H. Davies, G. R. Bignell, C. Cox, P. Stephens, S. both β-catenin and Ras through the inacti- simultaneous inhibition of BRAF(V600E) Edkins, S. Clegg, J. Teague, H. Woffendin, M. vation of the destruction complex. and the downstream MAPK cascade, along J. Garnett, W. Bottomley, N. Davis, E. Dicks, R. The effects on tumor growth of the ac- with the activation of Wnt/β-catenin signal- Ewing, Y. Floyd, K. Gray, S. Hall, R. Hawes, J. Hughes, V. Kosmidou, A. Menzies, C. Mould, A. tivation of Wnt/β-catenin signaling in the ing. In contrast, in intestinal tumorigenesis, Parker, C. Stevens, S. Watt, S. Hooper, R. Wil- two different contexts, son, H. Jayatilake, B. A. Gusterson, C. Cooper, melanoma and colon J. Shipley, D. Hargrave, K. Pritchard-Jones, N. cancer, are also strik- Maitland, G. Chenevix-Trench, G. J. Riggins, D. D. Bigner, G. Palmieri, A. Cossu, A. Flanagan, A. ingly different. In mel- Nicholson, J. W. Ho, S. Y. Leung, S. T. Yuen, B. L. anoma, stimulation of Growth factor Weber, H. F. Seigler, T. L. Darrow, H. Paterson, R. Wnt/β-catenin signal- Wnt Marais, C. J. Marshall, R. Wooster, M. R. Stratton, P. A. Futreal, Mutations of the BRAF gene in hu- ing synergized with the RTK man cancer. Nature 417, 949–954 (2002). ability of BRAF inhibi- Frizzled 10. P. M. Pollock, U. L. Harper, K. S. Hansen, L. M. Yudt, tors to reduce tumor Colon cancer M. Stark, C. M. Robbins, T. Y. Moses, G. Hostetter, Downloaded from cell size. This reduction Ras U. Wagner, J. Kakareka, G. Salem, T. Pohida, P. Axin Heenan, P. Duray, O. Kallioniemi, N. K. Hayward, in tumor size was due Dishevelled J. M. Trent, P. S. Meltzer, High frequency of BRAF GSK3 APC to apoptotic cell death Raf mutations in nevi. Nat. 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