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SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics

Isabel Boned Del Rio,L. C. Young,Sibel Sarı,Greg G. Jones,Benjamin Ringham-Terry,N. Hartig,Ewa Rejnowicz,Winnie Lei,Amandeep Bhamra,S. Surinova,P. Rodriguez-Viciana

Published 2019 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance The ERK signaling pathway is hyperactivated in a majority of cancers. However, because it mediates myriad physiological responses, the clinical efficacy of current ERK pathway inhibitors has been severely limited by toxicity. This study uncovers both SHOC2 phosphatase complex-dependent and -independent mechanisms of RAF and ERK activation that are differentially engaged in a context and spatio-temporal–dependent manner. KRAS oncogenic signaling preferentially depends on SHOC2 dependent-mechanisms, which thus presents a therapeutic opportunity. This study provides a molecular framework for how targeting the SHOC2-holophosphatase regulatory node of the RAF activation process provides a mechanism for selective inhibition of ERK signaling. 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.

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