Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 306 (5705): 2267-2270

Copyright © 2004 by the American Association for the Advancement of Science

Role of the Kinase MST2 in Suppression of Apoptosis by the Proto-Oncogene Product Raf-1

Eric O'Neill,1 Linda Rushworth,1 Manuela Baccarini,3 Walter Kolch1,2*

Abstract: The ablation of the protein kinase Raf-1 renders cells hypersensitive to apoptosis despite normal regulation of extracellular signal–regulated kinases, which suggests that apoptosis protection is mediated by a distinct pathway. We used proteomic analysis of Raf-1 signaling complexes to show that Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20–like kinase (MST2). Raf-1 prevents dimerization and phosphorylation of the activation loop of MST2 independently of its protein kinase activity. Depletion of MST2 from Raf-1–/– mouse or human cells abrogated sensitivity to apoptosis, whereas overexpression of MST2 induced apoptosis. Conversely, depletion of Raf-1 from Raf-1+/+ mouse or human cells led to MST2 activation and apoptosis. The concomitant depletion of both Raf-1 and MST2 prevented apoptosis.

1 The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2 Sir Henry Wellcome Functional Genomics Facility, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
3 Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Microbiology and Genetics, University of Vienna, Dr. Bohr Gasse 9, A-1030 Vienna, Austria.

* To whom correspondence should be addressed. E-mail: wkolch{at}beatson.gla.ac.uk


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Interaction proteome of human Hippo signaling: modular control of the co-activator YAP1.
S. Hauri, A. Wepf, A. van Drogen, M. Varjosalo, N. Tapon, R. Aebersold, and M. Gstaiger (2014)
Mol Syst Biol 9, 713
   Abstract »    Full Text »    PDF »
The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics.
D. Romano, H. Maccario, C. Doherty, N. P. Quinn, W. Kolch, and D. Matallanas (2013)
Mol. Cell. Biol. 33, 1859-1868
   Abstract »    Full Text »    PDF »
A Genome-Scale RNA Interference Screen Implicates NF1 Loss in Resistance to RAF Inhibition.
S. R. Whittaker, J.-P. Theurillat, E. Van Allen, N. Wagle, J. Hsiao, G. S. Cowley, D. Schadendorf, D. E. Root, and L. A. Garraway (2013)
Cancer Discovery 3, 350-362
   Abstract »    Full Text »    PDF »
Increased BRAF Heterodimerization Is the Common Pathogenic Mechanism for Noonan Syndrome-Associated RAF1 Mutants.
X. Wu, J. Yin, J. Simpson, K.-H. Kim, S. Gu, J. H. Hong, P. Bayliss, P. H. Backx, B. G. Neel, and T. Araki (2012)
Mol. Cell. Biol. 32, 3872-3890
   Abstract »    Full Text »    PDF »
A RASSF1A Polymorphism Restricts p53/p73 Activation and Associates with Poor Survival and Accelerated Age of Onset of Soft Tissue Sarcoma.
K. S. Yee, L. Grochola, G. Hamilton, A. Grawenda, E. E. Bond, H. Taubert, P. Wurl, G. L. Bond, and E. O'Neill (2012)
Cancer Res. 72, 2206-2217
   Abstract »    Full Text »    PDF »
Computational Approaches for Analyzing Information Flow in Biological Networks.
B. Kholodenko, M. B. Yaffe, and W. Kolch (2012)
Science Signaling 5, re1
   Abstract »    Full Text »    PDF »
c-Myc Regulates RNA Splicing of the A-Raf Kinase and Its Activation of the ERK Pathway.
J. Rauch, K. Moran-Jones, V. Albrecht, T. Schwarzl, K. Hunter, O. Gires, and W. Kolch (2011)
Cancer Res. 71, 4664-4674
   Abstract »    Full Text »    PDF »
Mammalian Hippo pathway: from development to cancer and beyond.
Y. Bao, Y. Hata, M. Ikeda, and K. Withanage (2011)
J. Biochem. 149, 361-379
   Abstract »    Full Text »    PDF »
Raf Family Kinases: Old Dogs Have Learned New Tricks.
D. Matallanas, M. Birtwistle, D. Romano, A. Zebisch, J. Rauch, A. von Kriegsheim, and W. Kolch (2011)
Genes & Cancer 2, 232-260
   Abstract »    Full Text »    PDF »
Hippo signaling: growth control and beyond.
G. Halder and R. L. Johnson (2011)
Development 138, 9-22
   Abstract »    Full Text »    PDF »
The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner.
E. W. Joseph, C. A. Pratilas, P. I. Poulikakos, M. Tadi, W. Wang, B. S. Taylor, E. Halilovic, Y. Persaud, F. Xing, A. Viale, et al. (2010)
PNAS 107, 14903-14908
   Abstract »    Full Text »    PDF »
Merlin in organ size control and tumorigenesis: Hippo versus EGFR?.
C. Yi and J. L. Kissil (2010)
Genes & Dev. 24, 1673-1679
   Abstract »    Full Text »    PDF »
Targets of Raf in tumorigenesis.
T. S. Niault and M. Baccarini (2010)
Carcinogenesis 31, 1165-1174
   Abstract »    Full Text »    PDF »
Cardiovascular Safety of VEGF-Targeting Therapies: Current Evidence and Handling Strategies.
F. Girardi, E. Franceschi, and A. A. Brandes (2010)
Oncologist 15, 683-694
   Abstract »    Full Text »    PDF »
Mammalian Ste20-like Kinase (Mst2) Indirectly Supports Raf-1/ERK Pathway Activity via Maintenance of Protein Phosphatase-2A Catalytic Subunit Levels and Consequent Suppression of Inhibitory Raf-1 Phosphorylation.
G. K. Kilili and J. M. Kyriakis (2010)
J. Biol. Chem. 285, 15076-15087
   Abstract »    Full Text »    PDF »
The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version.
B. Zhao, L. Li, Q. Lei, and K. L. Guan (2010)
Genes & Dev. 24, 862-874
   Abstract »    Full Text »    PDF »
c-Jun N-terminal Kinase Enhances MST1-mediated Pro-apoptotic Signaling through Phosphorylation at Serine 82.
W. Bi, L. Xiao, Y. Jia, J. Wu, Q. Xie, J. Ren, G. Ji, and Z. Yuan (2010)
J. Biol. Chem. 285, 6259-6264
   Abstract »    Full Text »    PDF »
Heterogeneous Nuclear Ribonucleoprotein H Blocks MST2-Mediated Apoptosis in Cancer Cells by Regulating a-raf Transcription.
J. Rauch, E. O'Neill, B. Mack, C. Matthias, M. Munz, W. Kolch, and O. Gires (2010)
Cancer Res. 70, 1679-1688
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase/Akt Inhibits MST1-Mediated Pro-apoptotic Signaling through Phosphorylation of Threonine 120.
Z. Yuan, D. Kim, S. Shu, J. Wu, J. Guo, L. Xiao, S. Kaneko, D. Coppola, and J. Q. Cheng (2010)
J. Biol. Chem. 285, 3815-3824
   Abstract »    Full Text »    PDF »
Proapoptotic Kinase MST2 Coordinates Signaling Crosstalk between RASSF1A, Raf-1, and Akt.
D. Romano, D. Matallanas, G. Weitsman, C. Preisinger, T. Ng, and W. Kolch (2010)
Cancer Res. 70, 1195-1203
   Abstract »    Full Text »    PDF »
MST Kinases Monitor Actin Cytoskeletal Integrity and Signal via c-Jun N-Terminal Kinase Stress-Activated Kinase To Regulate p21Waf1/Cip1 Stability.
R. M. Densham, E. O'Neill, J. Munro, I. Konig, K. Anderson, W. Kolch, and M. F. Olson (2009)
Mol. Cell. Biol. 29, 6380-6390
   Abstract »    Full Text »    PDF »
From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-{alpha} kinase activity.
T. Niault, I. Sobczak, K. Meissl, G. Weitsman, D. Piazzolla, G. Maurer, F. Kern, K. Ehrenreiter, M. Hamerl, I. Moarefi, et al. (2009)
J. Cell Biol. 187, 335-342
   Abstract »    Full Text »    PDF »
A Short Hairpin DNA Analogous to miR-125b Inhibits C-Raf Expression, Proliferation, and Survival of Breast Cancer Cells.
M. H. Hofmann, J. Heinrich, G. Radziwil, and K. Moelling (2009)
Mol. Cancer Res. 7, 1635-1644
   Abstract »    Full Text »    PDF »
Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP).
T. Oka, V. Mazack, and M. Sudol (2008)
J. Biol. Chem. 283, 27534-27546
   Abstract »    Full Text »    PDF »
BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins.
B. B. Friday, C. Yu, G. K. Dy, P. D. Smith, L. Wang, S. N. Thibodeau, and A. A. Adjei (2008)
Cancer Res. 68, 6145-6153
   Abstract »    Full Text »    PDF »
Raf Signaling but not the ERK Effector SAP-1 Is Required for Regulatory T Cell Development.
J. E. Willoughby, P. S. Costello, R. H. Nicolas, N. J. Robinson, G. Stamp, F. Powrie, and R. Treisman (2007)
J. Immunol. 179, 6836-6844
   Abstract »    Full Text »    PDF »
The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1.
B. Cinar, P.-K. Fang, M. Lutchman, D. Di Vizio, R. M. Adam, N. Pavlova, M. A. Rubin, P. C. Yelick, and M. R. Freeman (2007)
EMBO J. 26, 4523-4534
   Abstract »    Full Text »    PDF »
Mitogen-Activated Protein Kinases in Heart Development and Diseases.
Y. Wang (2007)
Circulation 116, 1413-1423
   Abstract »    Full Text »    PDF »
Caspase-dependent Cleavage Disrupts the ERK Cascade Scaffolding Function of KSR1.
M. M. McKay and D. K. Morrison (2007)
J. Biol. Chem. 282, 26225-26234
   Abstract »    Full Text »    PDF »
Dissection of a Signaling Pathway by Which Pathogen-associated Molecular Patterns Recruit the JNK and p38 MAPKs and Trigger Cytokine Release.
J. Zhong and J. M. Kyriakis (2007)
J. Biol. Chem. 282, 24246-24254
   Abstract »    Full Text »    PDF »
Grb10 and Active Raf-1 Kinase Promote Bad-dependent Cell Survival.
S. Kebache, J. Ash, M. G. Annis, J. Hagan, M. Huber, J. Hassard, C. L. Stewart, M. Whiteway, and A. Nantel (2007)
J. Biol. Chem. 282, 21873-21883
   Abstract »    Full Text »    PDF »
Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila.
X. Wei, T. Shimizu, and Z.-C. Lai (2007)
EMBO J. 26, 1772-1781
   Abstract »    Full Text »    PDF »
Sorafenib Blocks the RAF/MEK/ERK Pathway, Inhibits Tumor Angiogenesis, and Induces Tumor Cell Apoptosis in Hepatocellular Carcinoma Model PLC/PRF/5.
L. Liu, Y. Cao, C. Chen, X. Zhang, A. McNabola, D. Wilkie, S. Wilhelm, M. Lynch, and C. Carter (2006)
Cancer Res. 66, 11851-11858
   Abstract »    Full Text »    PDF »
Inhibition of Cell Migration by Autophosphorylated Mammalian Sterile 20-Like Kinase 3 (MST3) Involves Paxillin and Protein-tyrosine Phosphatase-PEST.
T.-J. Lu, W.-Y. Lai, C.-Y. F. Huang, W.-J. Hsieh, J.-S. Yu, Y.-J. Hsieh, W.-T. Chang, T.-H. Leu, W.-C. Chang, W.-J. Chuang, et al. (2006)
J. Biol. Chem. 281, 38405-38417
   Abstract »    Full Text »    PDF »
A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation.
C. Rubiolo, D. Piazzolla, K. Meissl, H. Beug, J. C. Huber, A. Kolbus, and M. Baccarini (2006)
Blood 108, 152-159
   Abstract »    Full Text »    PDF »
Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma..
D. J. Panka, M. B. Atkins, and J. W. Mier (2006)
Clin. Cancer Res. 12, 2371s-2375s
   Abstract »    Full Text »    PDF »
Regulation and Role of Raf-1/B-Raf Heterodimerization.
L. K. Rushworth, A. D. Hindley, E. O'Neill, and W. Kolch (2006)
Mol. Cell. Biol. 26, 2262-2272
   Abstract »    Full Text »    PDF »
Role of the Tumor Suppressor RASSF1A in Mst1-Mediated Apoptosis..
H. J. Oh, K.-K. Lee, S. J. Song, M. S. Jin, M. S. Song, J. H. Lee, C. R. Im, J.-O. Lee, S. Yonehara, and D.-S. Lim (2006)
Cancer Res. 66, 2562-2569
   Abstract »    Full Text »    PDF »
The Raf Inhibitor BAY 43-9006 (Sorafenib) Induces Caspase-Independent Apoptosis in Melanoma Cells.
D. J. Panka, W. Wang, M. B. Atkins, and J. W. Mier (2006)
Cancer Res. 66, 1611-1619
   Abstract »    Full Text »    PDF »
Raf-1 sets the threshold of Fas sensitivity by modulating Rok-{alpha} signaling.
D. Piazzolla, K. Meissl, L. Kucerova, C. Rubiolo, and M. Baccarini (2005)
J. Cell Biol. 171, 1013-1022
   Abstract »    Full Text »    PDF »
Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity.
J. An and M. B. Rettig (2005)
Mol. Cell. Biol. 25, 7546-7556
   Abstract »    Full Text »    PDF »
Mammalian Sterile 20-Like Kinases in Tumor Suppression: An Emerging Pathway.
E. E. O'Neill, D. Matallanas, and W. Kolch (2005)
Cancer Res. 65, 5485-5487
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882