Inflammatory bowel disease reveals the kinase activity of KSR1
Richard Kolesnick, H. Rosie Xing
Richard Kolesnick, H. Rosie Xing
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1233-1237. https://doi.org/10.1172/JCI23441.
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Commentary

Inflammatory bowel disease reveals the kinase activity of KSR1

Abstract

Kinase suppressor of Ras-1 (KSR1) is a recently identified member of the EGFR–Ras–Raf-1–MAPK signaling pathway. A new study demonstrates that KSR1 protects intestinal epithelium from TNF-α–induced apoptosis, abrogating inflammatory bowel disease (IBD). Since its discovery, there has been disagreement as to whether KSR1 possesses intrinsic kinase activity. Using transgenic mouse models and genetically modified mouse colon epithelial cells, Polk and coworkers show that the kinase activity of KSR1 is off in normal colon epithelial cells, becoming activated only at the onset of IBD. They also provide strong evidence that KSR1 kinase activity is essential for anti-apoptotic protection of the intestinal epithelium. These new data in support of KSR1 as a kinase highlight an ongoing debate as to whether KSR1 does indeed serve as a specific kinase in transphosphorylating and transactivating c-Raf–1 toward MEK1.

Authors

Richard Kolesnick, H. Rosie Xing

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Figure 1

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Model for the regulation of c-Raf-1 signaling by KSR1. (A) In quiescent ...
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.