Boned Del Río, I;
Young, LC;
Sari, S;
Jones, GG;
Ringham-Terry, B;
Hartig, N;
Rejnowicz, E;
... Rodriguez-Viciana, P; + view all
(2019)
SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics.
Proceedings of the National Academy of Sciences of the United States of America
10.1073/pnas.1902658116.
(In press).
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Abstract
Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps for RAF activation but the precise mechanisms and dynamics remain unclear. A ternary complex comprised of SHOC2, MRAS, and PP1 (SHOC2 complex) functions as a RAF S259 holophosphatase and gain-of-function mutations in SHOC2, MRAS, and PP1 that promote complex formation are found in Noonan syndrome. Here we show that SHOC2 complex-mediated S259 RAF dephosphorylation is critically required for growth factor-induced RAF heterodimerization as well as for MEK dissociation from BRAF. We also uncover SHOC2-independent mechanisms of RAF and ERK pathway activation that rely on N-region phosphorylation of CRAF. In DLD-1 cells stimulated with EGF, SHOC2 function is essential for a rapid transient phase of ERK activation, but is not required for a slow, sustained phase that is instead driven by palmitoylated H/N-RAS proteins and CRAF. Whereas redundant SHOC2-dependent and -independent mechanisms of RAF and ERK activation make SHOC2 dispensable for proliferation in 2D, KRAS mutant cells preferentially rely on SHOC2 for ERK signaling under anchorage-independent conditions. Our study highlights a context-dependent contribution of SHOC2 to ERK pathway dynamics that is preferentially engaged by KRAS oncogenic signaling and provides a biochemical framework for selective ERK pathway inhibition by targeting the SHOC2 holophosphatase.
Type: | Article |
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Title: | SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1073/pnas.1902658116 |
Publisher version: | https://doi.org/10.1073/pnas.1902658116 |
Language: | English |
Additional information: | © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | ERK, MRAS, RAF, RAS, SHOC2 |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
URI: | https://discovery.ucl.ac.uk/id/eprint/10077115 |
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