Inflammatory bowel disease reveals the kinase activity of KSR1
J. Clin. Invest. Richard Kolesnick, et al. 114:1233 doi:10.1172/JCI23441 [Go to this article.]

Figure 1
Model for the regulation of c-Raf-1 signaling by KSR1. (A) In quiescent cells, KSR1 is phosphorylated on Ser297 by an unknown kinase and on Ser392 by C-TAK1, creating docking sites for 14-3-3. The 14-3-3–KSR1 interaction results in sequestration of KSR1 and MEK1, to which it is constitutively bound, in the cytosol (17). Both KSR1 and its target, c-Raf-1, are also constitutively bound to the PP2A core enzyme (subunit A and catalytic subunit C) (18). In addition, IMP interacts with the N-terminus of KSR1, maintaining KSR1 in an inactive state (21). (B) During growth factor stimulation (such as via EGF), KSR1 and c-Raf-1 acquire the PP2A regulatory B subunit, and the holoenzyme dephosphorylates the Ser392 site of KSR1 and the Ser259 site of c-Raf-1, leading to partial release of 14-3-3 from each protein (18). In the case of KSR1, this opens up the MAPK-binding site, while for c-Raf-1, it confers binding to activated Ras at the plasma membrane. In addition, Ras GTP binds IMP, relieving the inhibition of KSR1 (21). Dissociation of KSR1 from IMP and displacement of 14-3-3 on Ser392 leads to rapid translocation of KSR1 to the plasma membrane (PM) and localizes MEK1 and MAPK to membrane-bound c-Raf-1. There is debate as to the mechanism of c-Raf-1 activation through KSR1, whether activation occurs via a scaffold or kinase function. The scaffold model argues that KSR1-bound c-Raf-1 becomes activated by an unknown mechanism (15, 19, 41) while the KSR1 kinase model ascribes KSR1-mediated transphosphorylation at Thr269 as the mechanism of c-Raf-1 kinase activation (8, 23). Active c-Raf-1 stimulates MEK1, which in turn activates MAPK, conferring cell proliferation. RBD, Ras-binding domain; Y on EGFR, autophosphorylated tyrosine residues; SOS, son of sevenless; SHC, src homologous and collagen protein. (C) At the onset of IBD, KSR1 is activated and confers colon epithelial cell survival. In colon epithelial cells, ligation of TNF receptor 1 by TNF-α leads to acid sphingomyelinase (ASMase) activation, ceramide generation, and KSR1 and c-Raf-1 translocation to the PM, perhaps by binding of their C1b domains to ceramide. There is emerging evidence in other cell types that ceramide converts sphingolipid-enriched microdomains (rafts) into large platforms into which signaling proteins compartmentalize (28, 29). However, it is not known if KSR1 translocates into a ceramide-rich platform. In the current studies, Polk and coworkers (4) provide strong evidence that in IBD the ceramide-KSR1 interaction triggers KSR1 kinase activity, resulting in transphosphorylation and transactivation of c-Raf-1, which in turn activates MEK1 and MAPK, conferring epithelial cell survival. SM, sphingomyelin; CA3, the C1b homologous domain of KSR1.