Kinase-independent role for CRAF-driving tumour radioresistance via CHK2

Nature Communications
Sunil J AdvaniDavid A Cheresh

Abstract

Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response. Accordingly, a phospho-mimetic mutant of CRAF (S338D) is sufficient to induce the CRAF/CHK2 association enhancing tumour radioresistance, while an allosteric CRAF inhibitor sensitizes tumour cells to ionizing radiation or genotoxic drugs. Our findings establish a role for CRAF in the DNA damage response that is independent from its canonical function as a kinase.

References

Aug 29, 1996·Nature·U KasidT W Sturgill
Dec 9, 1998·International Journal of Radiation Oncology, Biology, Physics·J A BonnerL M Karnitz
Mar 10, 2001·Nature Genetics·K K Khanna, S P Jackson
Dec 26, 2001·The Journal of Biological Chemistry·Mengwei ZangZhijun Luo
Aug 30, 2003·Oncogene·W Gillies McKennaEric J Bernhard
Jun 11, 2004·Annual Review of Biochemistry·Aziz SancarStuart Linn
Jun 16, 2004·Cancer Metastasis Reviews·Andrew R Snyder, William F Morgan
Mar 9, 2005·The Journal of Cell Biology·Karin EhrenreiterManuela Baccarini
Dec 28, 2005·Seminars in Radiation Oncology·Ananya ChoudhuryRobert G Bristow
Feb 21, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anatoly DritschiloUsha N Kasid
May 26, 2006·Nature Reviews. Cancer·Rakesh KumarChristopher J Barnes
May 8, 2008·Cancer Metastasis Reviews·Ramesh RenganStephen M Hahn
May 10, 2008·Journal of Cellular Biochemistry·Xiaochong WuJeffrey A Frost
Feb 21, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Liane M McGlynnTimothy G Cooke
Feb 16, 2010·Proceedings of the National Academy of Sciences of the United States of America·Eric A MurphyDavid A Cheresh
Nov 3, 2010·Advances in Cancer Research·Joanne SmithDavid A Gillespie
Apr 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Christy C OngKlaus P Hoeflich
Jul 23, 2011·Genes & Cancer·David MatallanasWalter Kolch
Nov 15, 2011·Nature Medicine·Ainhoa MielgoDavid A Cheresh
May 18, 2013·Cancer Cell·Matthew HolderfieldTobi E Nagel
Apr 22, 2014·Nature Cell Biology·Laetitia SeguinDavid A Cheresh

❮ Previous
Next ❯

Citations

Jan 18, 2017·Critical Reviews in Biochemistry and Molecular Biology·Joseph W Fischer, Anthony K L Leung
Aug 15, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Benjamin R NixonJason R Becker
Jan 19, 2018·Journal of Ovarian Research·Guobo Quan, Julang Li
Apr 30, 2019·Small GTPases·Ian Aj Lorimer
Jan 9, 2020·Journal of Experimental & Clinical Cancer Research : CR·Federica FrancescangeliAnn Zeuner
Mar 11, 2017·Nature Reviews. Drug Discovery·Lenka Munoz
May 6, 2017·Clinical and Translational Medicine·Osamu Tetsu, Frank McCormick
Aug 21, 2020·Cancer Metastasis Reviews·Rakesh KumarM Radhakrishna Pillai
Apr 15, 2020·Cancer Cell·Matthias Drosten, Mariano Barbacid
Apr 3, 2021·Frontiers in Cell and Developmental Biology·Hui LiuZigang Dong

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPases
xenografts
reverse
immunoprecipitation

Software Mentioned

CometScore

Related Concepts

Related Feeds

Cell Cycle Pathways

Cell cycle is a complex process regulated by several signal transduction pathways and enzymes. Here is the latest research on regulation of cell cycle and cell cycle pathways.

Related Papers

International Journal of Radiation Oncology, Biology, Physics
Debbie SprongAdrian C Begg
DNA Repair
Marco Muzi-Falconi, John Petrini
Radiation Research
Shannon L GibsonPeter M Glazer
Journal of Molecular Cell Biology
Laura ZanniniGiacomo Buscemi
© 2021 Meta ULC. All rights reserved