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, 2 (5), 276-281

Complexity in KSR Function Revealed by Raf Inhibitor and KSR Structure Studies

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Complexity in KSR Function Revealed by Raf Inhibitor and KSR Structure Studies

Melissa M McKay et al. Small GTPases.

Abstract

The Ras, Raf, MEK and ERK proteins form an essential signal transduction pathway that is aberrantly activated in many human cancers. Kinase suppressor of Ras (KSR) is a conserved positive modulator of this pathway, and since its discovery, there has been a concerted effort to elucidate KSR function in both normal and aberrant Ras/ERK signaling. The KSR proteins possess a C-terminal region that is closely related to the Raf family kinase domain; however, mammalian KSR proteins lack a key catalytic residue, suggesting a role as a pseudokinase. Like many other pseudokinases, KSR has scaffolding activities and interacts with Raf, MEK and ERK to provide spatio-temporal regulation of ERK activation. Recently, significant advances have been made that further our understanding of how KSR proteins function in normal and oncogenic signaling. The newly solved KSR2/MEK1 structure has revealed important mechanistic details for how KSR regulates MEK activation and has raised questions regarding KSR kinase activity. In addition, KSR expression levels have been found to alter the effects of Raf inhibitors on oncogenic Ras/ERK signaling. Specifically, KSR1 competes with C-Raf for inhibitor-induced binding to B-Raf and in doing so attenuates the paradoxical activating effect of these drugs on ERK signaling.

Figures

Figure 1
Figure 1
Raf inhibitor and growth factor treatment induces KSR1/B-Raf binding. (A) KSR1 competes with C-Raf for inhibitor-induced binding to B-Raf. Cycling KSR-/- MEFs and those expressing WT-KSR1 were treated with 10 µM GDC0879 for 1 h. KSR1 or endogenous C-Raf complexes were isolated and examined for endogenous B-Raf. Lysates were analyzed for pERK and KSR levels. (B) Serum-starved HeLa cells were treated with EGF for 5 min. Endogenous KSR1 complexes were isolated and examined for endogenous B-Raf or C-Raf binding.
Figure 2
Figure 2
KSR1 attenuates ERK activation in GDC0879, but not PLX4720-treated cells. A549 cells expressing either the pLKO.1 vector or pLKO.1-KSR1 shRNA were treated as indicated for 1 hr. Lysates were analyzed for pERK and tubulin levels. Depletion of KSR1 is also shown.
Figure 3
Figure 3
Model for KSR function. (A) In a quiescent cell, C-Raf, B-Raf, and the inactive KSR/MEK complex are localized in the cytosol, with transient binding interactions occurring between B-Raf and the KSR/MEK complex. (B) Ras activation recruits the Rafs to the plasma membrane where B-Raf participates in C-Raf activation. (C) The KSR/MEK complex also localizes to the membrane and interacts with B-Raf, inducing conformational changes that expose the MEK activation segment for phosphorylation by C-Raf in trans. (D) Inhibitor-induced KSR1/B-Raf complexes can form in the cytosol, thus antagonizing the formation of C-Raf/B-Raf dimers at the membrane.

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