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A dimerization-dependent mechanism drives RAF catalytic activation

Author

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  • Thanashan Rajakulendran

    (Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, Toronto, Ontario M5S 1A8, Canada)

  • Malha Sahmi

    (Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling,)

  • Martin Lefrançois

    (Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling,)

  • Frank Sicheri

    (Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, Toronto, Ontario M5S 1A8, Canada)

  • Marc Therrien

    (Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling,
    Université de Montréal, Montréal, Québec H3C 3J7, Canada)

Abstract

The raf oncogene: dimerization drives RAF kinase Activation of the kinase RAF is triggered by growth factors binding to receptor tyrosine kinases, and raf is the most frequently mutated oncogene within the kinase superfamily. Here, the activation mechanism of RAF is shown to involve a dimeric conformation of its kinase domain. Dimerization is relevant for the action of the RAF activator KSR and certain oncogenic mutations. The work resolves a long-standing conundrum about the precise mechanism of RAF catalytic activation and offers new possibilities for future therapeutic development.

Suggested Citation

  • Thanashan Rajakulendran & Malha Sahmi & Martin Lefrançois & Frank Sicheri & Marc Therrien, 2009. "A dimerization-dependent mechanism drives RAF catalytic activation," Nature, Nature, vol. 461(7263), pages 542-545, September.
  • Handle: RePEc:nat:nature:v:461:y:2009:i:7263:d:10.1038_nature08314
    DOI: 10.1038/nature08314
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    Cited by:

    1. Aline Chessel & Noémie Crozé & Maria Dolores Molina & Laura Taberner & Philippe Dru & Luc Martin & Thierry Lepage, 2023. "RAS-independent ERK activation by constitutively active KSR3 in non-chordate metazoa," Nature Communications, Nature, vol. 14(1), pages 1-26, December.
    2. Eunyoung Park & Shaun Rawson & Anna Schmoker & Byeong-Won Kim & Sehee Oh & Kangkang Song & Hyesung Jeon & Michael J. Eck, 2023. "Cryo-EM structure of a RAS/RAF recruitment complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Huagang He & Zhaozhao Chen & Renchun Fan & Jie Zhang & Shanying Zhu & Jiale Wang & Qianyuan Zhang & Anli Gao & Shuangjun Gong & Lu Zhang & Yanan Li & Yitong Zhao & Simon G. Krattinger & Qian-Hua Shen , 2024. "A kinase fusion protein from Aegilops longissima confers resistance to wheat powdery mildew," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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