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A novel mitogen-activated protein kinase is responsive to Raf and mediates growth factor specificity

M Janulis1, N Trakul, G Greene

  • 1Ben May Institute for Cancer Research, Pharmacology and Physiology, University of Chicago, Chicago, Illinois 60637, USA.

Molecular and Cellular Biology
|March 10, 2001
PubMed

Insights

Researchers discovered a new Raf-activated signaling pathway involving p97, a kinase distinct from the classic ERK pathway. This pathway offers specific cellular responses to growth factors like FGF and EGF, impacting cell signaling and outcomes.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Oncogene research

Background:

  • The proto-oncogene Raf regulates cell growth and differentiation.
  • A Raf-activated signaling pathway independent of MEK1,2-ERK1,2 exists, but its components were unknown.

Purpose of the Study:

  • To identify novel signaling cascades downstream of Raf.
  • To characterize a new kinase activated by Raf and its role in cellular specificity.

Main Methods:

  • Identification and characterization of a novel mitogen-activated protein kinase, p97.
  • Assessing p97 activation and association with Raf upon cellular stimulation.
  • Investigating p97's selective responsiveness to fibroblast growth factor (FGF) versus epidermal growth factor (EGF) in neuronal cells.
  • Analyzing p97's substrate specificity, including phosphorylation of transcription factors Elk-1, Ets-2, and MEF2C.
  • Determining p97 expression patterns in different cell types.

Main Results:

  • A new ERK5-related kinase, p97, was identified and found to be activated and associated with Raf.
  • p97 exhibits selective activation by FGF but not EGF in neuronal cells, contrasting with ERK5's response to EGF.
  • p97 phosphorylates Elk-1 and Ets-2, but not MEF2C, at transactivating sites.
  • ERK5 phosphorylates MEF2C but not Elk-1 or Ets-2.
  • p97 is expressed in primary neural and NIH 3T3 cells.

Conclusions:

  • A novel Raf-activated signaling pathway distinct from the canonical Raf-MEK1,2-ERK1,2 cascade has been identified.
  • The p97 pathway provides a mechanism for selective cellular responses to different growth factors, leading to discrete biological outcomes.
  • This discovery expands our understanding of Raf-mediated signaling and its role in cellular specificity.

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