Phosphorylation regulates KSR1 stability, ERK activation, and cell proliferation

Gina L. Razidlo, Robert L. Kortum, Jamie L. Haferbier, Robert E. Lewis

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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 Ser392, is a critical regulator of KSR1 subcellular localization and ERK activation. We examined the role of phosphorylation of both Ser392 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 Ser392 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.

Original languageEnglish (US)
Pages (from-to)47808-47814
Number of pages7
JournalJournal of Biological Chemistry
Issue number46
StatePublished - Nov 12 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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