Apoptosis Scaffold Succumbs to Caspase Cleavage

L. Bryan Ray

Science, Science’s STKE, AAAS, Washington, DC 20005, USA

Activation of the ERK (extracellular signal-regulated kinase) members of the mitogen-activated protein (MAP) kinase family is associated with cell survival signaling. In cells stimulated to undergo apoptosis, such survival signaling is often disrupted. McKay and Morrison provide insight into molecular mechanisms by which ERK signaling may be shut down in apoptotic cells. The protein known as kinase suppressor of Ras 1 (KSR1) is a scaffold that contributes to ERK activation by bringing together the kinases that participate in a cascade of sequential activation to ultimately stimulate the phosphorylation and activation of ERKs. The authors noted that KSR1 has a characteristic caspase cleavage site that would be expected to effectively break up KSR1’s scaffolding function by separating the C-terminal domain that binds to MEK (MAP kinase or ERK kinase) from the N-terminal domain that binds ERK (a substrate for MEK) and a domain that mediates targeting of the whole complex to the plasma membrane. An epitope-tagged version of KSR1 expressed in KSR^–/– mouse embryo fibroblasts was indeed cleaved in cells stimulated to undergo apoptosis by treatment with tumor necrosis factor and cycloheximide. Although the N-terminal fragment of KSR1 appeared to be further degraded, immunoblotting showed that the C-terminal fragment of KSR1 accumulated in apoptotic cells. This fragment can potentially act as a dominant-negative inhibitor, and expression of this fragment in KSR1^–/– cells resulted in increased apoptotic signaling and reduced amounts of active, phosphorylated ERK. On the other hand, expression of a cleavage-resistant version of KSR1 in the knockout cells led to accumulation of more activated ERK and diminished apoptotic signaling. Cleavage of KSR1 was also observed in a natural model of apoptosis--the involuting mammary gland. The authors propose that caspase-dependent dismantling of KSR1 may provide a one-two punch to the cell’s survival signaling by removing a scaffold that facilitates ERK activation and, at the same time, generating an inhibitor of ERK activation.

M. M. McKay, D. K. Morrison, Caspase-dependent cleavage disrupts the ERK cascade scaffolding function of KSR1. J. Biol. Chem. 282, 26225-26234 (2007). [Abstract] [Full Text]