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Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation

Author

Listed:
  • Yoshihito Kano

    (University of Toronto
    University of Toronto)

  • Teklab Gebregiworgis

    (University of Toronto)

  • Christopher B. Marshall

    (University of Toronto)

  • Nikolina Radulovich

    (University of Toronto)

  • Betty P. K. Poon

    (University of Toronto)

  • Jonathan St-Germain

    (University of Toronto)

  • Jonathan D. Cook

    (University of Toronto)

  • Ivette Valencia-Sama

    (University of Toronto
    The Hospital for Sick Children)

  • Benjamin M. M. Grant

    (University of Toronto)

  • Silvia Gabriela Herrera

    (University of North Carolina)

  • Jinmin Miao

    (Purdue University)

  • Brian Raught

    (University of Toronto)

  • Meredith S. Irwin

    (The Hospital for Sick Children)

  • Jeffrey E. Lee

    (University of Toronto)

  • Jen Jen Yeh

    (University of North Carolina
    University of North Carolina
    University of North Carolina)

  • Zhong-Yin Zhang

    (Purdue University)

  • Ming-Sound Tsao

    (University of Toronto)

  • Mitsuhiko Ikura

    (University of Toronto)

  • Michael Ohh

    (University of Toronto
    University of Toronto)

Abstract

Deregulation of the RAS GTPase cycle due to mutations in the three RAS genes is commonly associated with cancer development. Protein tyrosine phosphatase SHP2 promotes RAF-to-MAPK signaling pathway and is an essential factor in RAS-driven oncogenesis. Despite the emergence of SHP2 inhibitors for the treatment of cancers harbouring mutant KRAS, the mechanism underlying SHP2 activation of KRAS signaling remains unclear. Here we report tyrosyl-phosphorylation of endogenous RAS and demonstrate that KRAS phosphorylation via Src on Tyr32 and Tyr64 alters the conformation of switch I and II regions, which stalls multiple steps of the GTPase cycle and impairs binding to effectors. In contrast, SHP2 dephosphorylates KRAS, a process that is required to maintain dynamic canonical KRAS GTPase cycle. Notably, Src- and SHP2-mediated regulation of KRAS activity extends to oncogenic KRAS and the inhibition of SHP2 disrupts the phosphorylation cycle, shifting the equilibrium of the GTPase cycle towards the stalled ‘dark state’.

Suggested Citation

  • Yoshihito Kano & Teklab Gebregiworgis & Christopher B. Marshall & Nikolina Radulovich & Betty P. K. Poon & Jonathan St-Germain & Jonathan D. Cook & Ivette Valencia-Sama & Benjamin M. M. Grant & Silvia, 2019. "Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08115-8
    DOI: 10.1038/s41467-018-08115-8
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    Cited by:

    1. András Zeke & Tamás Takács & Péter Sok & Krisztina Németh & Klára Kirsch & Péter Egri & Ádám Levente Póti & Isabel Bento & Gábor E. Tusnády & Attila Reményi, 2022. "Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Teklab Gebregiworgis & Yoshihito Kano & Jonathan St-Germain & Nikolina Radulovich & Molly L. Udaskin & Ahmet Mentes & Richard Huang & Betty P. K. Poon & Wenguang He & Ivette Valencia-Sama & Claire M. , 2021. "The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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