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

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 Gabriela Herrera, Jinmin Miao, Brian Raught, Meredith S. Irwin, Jeffrey E. Lee, Jen Jen Yeh, Zhong-Yin Zhang, Ming-Sound Tsao, Mitsuhiko Ikura and Michael Ohh ()
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Yoshihito Kano: 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
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
Zhong-Yin Zhang: Purdue University
Ming-Sound Tsao: University of Toronto
Mitsuhiko Ikura: University of Toronto
Michael Ohh: University of Toronto

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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’.

Date: 2019
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DOI: 10.1038/s41467-018-08115-8

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