Home LiteratureArticle Details
PMID: 17889669 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein.

Molecular cell ·Vol. 27 ·No. 6 ·2007-09-21 ·Pages 962-75

Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D, Baccarini M, Vass JK, Kolch W, O'neill E

Abstract

RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of MST kinases. The Raf1 proto-oncogene binds to MST2, preventing its activation and proapoptotic signaling. Here we show that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSF1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1. Subsequently, RASSF1A-activated LATS1 phosphorylates and releases the transcriptional regulator YAP1, allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Apoptosis Apoptosis Regulatory Proteins/genetics,metabolism Cell Line, Tumor Cell Nucleus/metabolism DNA-Binding Proteins/metabolism Humans Models, Biological Nuclear Proteins/metabolism Phosphoproteins/metabolism Phosphorylation Protein Binding Protein Serine-Threonine Kinases/metabolism Protein Transport Proto-Oncogene Mas Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-raf/metabolism Serine-Threonine Kinase 3 Signal Transduction Transcription Factors Transcription, Genetic Tumor Protein p73 Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins/metabolism YAP-Signaling Proteins
Chemicals
Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins BBC3 protein, human DNA-Binding Proteins MAS1 protein, human Nuclear Proteins Phosphoproteins Proto-Oncogene Mas Proto-Oncogene Proteins RASSF1 protein, human TP73 protein, human Transcription Factors Tumor Protein p73 Tumor Suppressor Protein p53 Tumor Suppressor Proteins YAP-Signaling Proteins YAP1 protein, human LATS1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-raf STK3 protein, human Serine-Threonine Kinase 3
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Matallanas David
Signaling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Romano David
Yee Karen
Meissl Katrin
Kucerova Lucia
Piazzolla Daniela
Baccarini Manuela
Vass J Keith
Kolch Walter
O'neill Eric
References (45)
45 references, click to expand
  1. Of flies and men; p53, a tumour suppressor.
    FEBS Lett. 2004 Jun 1;567(1):86-91 PMID: 15165898
  2. Analysis of protein complexes using mass spectrometry.
    Nat Rev Mol Cell Biol. 2007 Aug;8(8):645-54 PMID: 17593931
  3. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras.
    Biochem J. 2004 Jul 15;381(Pt 2):453-62 PMID: 15109305
  4. Induction of apoptosis in fibroblasts by c-myc protein.
    Cell. 1992 Apr 3;69(1):119-28 PMID: 1555236
  5. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase.
    Development. 1995 Apr;121(4):1053-63 PMID: 7743921
  6. Apoptosis and the cell cycle.
    Curr Opin Cell Biol. 1995 Dec;7(6):825-34 PMID: 8608013
  7. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction.
    Nat Genet. 1999 Feb;21(2):182-6 PMID: 9988269
  8. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1.
    Science. 2004 Dec 24;306(5705):2267-70 PMID: 15618521
  9. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.
    Oncogene. 2005 Mar 17;24(12):2076-86 PMID: 15688006
  10. p73-induced apoptosis: a question of compartments and cooperation.
    Biochem Biophys Res Commun. 2005 Jun 10;331(3):688-93 PMID: 15865923
  11. p73 induces apoptosis by different mechanisms.
    Biochem Biophys Res Commun. 2005 Jun 10;331(3):713-7 PMID: 15865927
  12. Role of the Ras-association domain family 1 tumor suppressor gene in human cancers.
    Cancer Res. 2005 May 1;65(9):3497-508 PMID: 15867337
  13. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage.
    Mol Cell. 2005 May 13;18(4):447-59 PMID: 15893728
  14. The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death.
    Mol Cell. 2005 Jun 10;18(6):637-50 PMID: 15949439
  15. Mammalian sterile 20-like kinases in tumor suppression: an emerging pathway.
    Cancer Res. 2005 Jul 1;65(13):5485-7 PMID: 15994916
  16. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP.
    Cell. 2005 Aug 12;122(3):421-34 PMID: 16096061
  17. Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha signaling.
    J Cell Biol. 2005 Dec 19;171(6):1013-22 PMID: 16365167
  18. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis.
    Nat Cell Biol. 2006 Jan;8(1):27-36 PMID: 16341207
  19. RASSF1A interacts with microtubule-associated proteins and modulates microtubule dynamics.
    Cancer Res. 2004 Jun 15;64(12):4112-6 PMID: 15205320
  20. Protective role of Raf-1 in Salmonella-induced macrophage apoptosis.
    J Exp Med. 2001 Feb 5;193(3):353-64 PMID: 11157055
  21. Physical interaction with Yes-associated protein enhances p73 transcriptional activity.
    J Biol Chem. 2001 May 4;276(18):15164-73 PMID: 11278685
  22. MST1-JNK promotes apoptosis via caspase-dependent and independent pathways.
    Genes Cells. 2001 Jun;6(6):519-30 PMID: 11442632
  23. Activation and activities of the p53 tumour suppressor protein.
    Br J Cancer. 2001 Dec 14;85(12):1813-23 PMID: 11747320
  24. On the shoulders of giants: p63, p73 and the rise of p53.
    Trends Genet. 2002 Feb;18(2):90-5 PMID: 11818141
  25. The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1.
    Oncogene. 2002 Feb 21;21(9):1381-90 PMID: 11857081
  26. Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma.
    Lab Invest. 2002 Oct;82(10):1427-35 PMID: 12379777
  27. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis.
    Mol Cell. 2003 Jan;11(1):11-23 PMID: 12535517
  28. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts.
    Cell. 2003 Aug 22;114(4):445-56 PMID: 12941273
  29. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis.
    Cell. 2003 Aug 22;114(4):457-67 PMID: 12941274
  30. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway.
    Nat Cell Biol. 2003 Oct;5(10):914-20 PMID: 14502294
  31. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila.
    Nat Cell Biol. 2003 Oct;5(10):921-7 PMID: 14502295
  32. The dark side of Ras: regulation of apoptosis.
    Oncogene. 2003 Dec 8;22(56):8999-9006 PMID: 14663478
  33. p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation.
    J Biol Chem. 2004 Feb 27;279(9):8076-83 PMID: 14634023
  34. Control of APC-Cdc20 by the tumor suppressor RASSF1A.
    Cell Cycle. 2004 May;3(5):574-6 PMID: 15107619
  35. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila.
    Cell. 2003 Apr 4;113(1):25-36 PMID: 12679032
  36. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase.
    Cell. 2003 May 16;113(4):507-17 PMID: 12757711
  37. Mass spectrometry-based proteomics turns quantitative.
    Nat Chem Biol. 2005 Oct;1(5):252-62 PMID: 16408053
  38. From cell structure to transcription: Hippo forges a new path.
    Cell. 2006 Jan 27;124(2):267-73 PMID: 16439203
  39. The RASSF1A tumor suppressor activates Bax via MOAP-1.
    J Biol Chem. 2006 Feb 24;281(8):4557-63 PMID: 16344548
  40. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis.
    Cancer Res. 2006 Mar 1;66(5):2562-9 PMID: 16510573
  41. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span.
    Cell. 2006 Jun 2;125(5):987-1001 PMID: 16751106
  42. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.
    Cell. 2006 Jun 30;125(7):1253-67 PMID: 16814713
  43. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.
    Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10 PMID: 16894141
  44. The Drosophila RASSF homolog antagonizes the hippo pathway.
    Curr Biol. 2006 Dec 19;16(24):2459-65 PMID: 17174922
  45. RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network.
    Curr Biol. 2007 Apr 17;17(8):700-5 PMID: 17379520
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-2765
DOI
10.1016/j.molcel.2007.08.008
Published
2007-09-21
Pages
962-75
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC2821687
Subset
IM
Grants
Cancer Research UK · A9318 · United Kingdom
Wellcome Trust · United Kingdom
Corrections
CommentIn
PMID: 17889659
External Links
PubMed source DOI: 10.1016/j.molcel.2007.08.008 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2