title: Complexity in KSR function revealed by Raf inhibitor and KSR structure studies.
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.
authors.affiliation: Laboratory of Cell and Developmental Signaling; Center for Cancer Research; National Cancer Institute-Frederick; Frederick, MD USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: McKay
authors.forename: Alyson K
authors.initials: AK
authors.lastname: Freeman
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison