Abstract
Kinase suppressor of Ras (KSR) is a molecular scaffold that interacts with the components of the Raf/MEK/ERK kinase cascade and positively regulates ERK signaling. Phosphorylation of KSR1, particularly at Ser(392), is a critical regulator of KSR1 subcellular localization and ERK activation. We examined the role of phosphorylation of both Ser(392) and Thr(274) in regulating ERK activation and cell proliferation. We hypothesized that KSR1 phosphorylation is involved in generating signaling specificity through the Raf/MEK/ERK kinase cascade in response to stimulation by different growth factors. In fibroblasts, platelet-derived growth factor stimulation induces sustained ERK activation and promotes S-phase entry. Treatment with epidermal growth factor induces transient ERK activation but fails to drive cells into S phase. Mutation of Ser(392) and Thr(274) (KSR1.TVSA) promotes sustained ERK activation and cell cycle progression with either platelet-derived growth factor or epidermal growth factor treatment. KSR1(-/-) mouse embryo fibroblasts expressing KSR1.TVSA proliferate two times faster and grow to a higher density than cells expressing the same level of wild-type KSR1. In addition, KSR1.TVSA is more stable than wild-type KSR1. These data demonstrate that phosphorylation and stability of the molecular scaffold KSR1 are critical regulators of growth factor-specific responses that promote cell proliferation.
Highlights
Specific signal transduction pathways in mammalian cells are potent regulators of mitogenesis
We hypothesized that phosphorylation of KSR1 contributes to its role in ERK activation by EGF and PDGF
To determine whether prolonged ERK activation in cells expressing KSR1.TVSA was a result of the effect of the mutated scaffold on MEK, we characterized the activation of MEK1/2 in response to PDGF and EGF
Summary
Specific signal transduction pathways in mammalian cells are potent regulators of mitogenesis. Similar expression of KSR1 mutated at phosphorylation sites Thr274 or Ser392 promoted sustained ERK activation in response to stimulation with both EGF and PDGF and accelerated cell proliferation. In cells treated with EGF, KSR1.SA promoted a burst of ERK activation that was sustained above the level obtained in cells expressing wild-type KSR1 (Fig. 2B).
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