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Molecular and Cellular Biology, March 2001, p. 2235-2247, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.2235-2247.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

A Novel Mitogen-Activated Protein Kinase Is Responsive to Raf and Mediates Growth Factor Specificity

Mark Janulis,1,2 Nicholas Trakul,1,3 Geoffrey Greene,1 Erik M. Schaefer,4 J. D. Lee,5 and Marsha Rich Rosner1,2,*

Ben May Institute for Cancer Research,1 Committee on Cancer Biology,3 and Department of Neurobiology, Pharmacology and Physiology,2 University of Chicago, Chicago, Illinois 60637; Quality Controlled Biochemicals, Inc., Hopkinton, Massachusetts 017484; and Department of Immunology, The Scripps Research Institute, La Jolla, California 920375

Received 18 July 2000/Returned for modification 21 August 2000/Accepted 21 December 2000

The proto-oncogene Raf is a major regulator of growth and differentiation. Previous studies from a number of laboratories indicate that Raf activates a signaling pathway that is independent of the classic MEK1,2-ERK1,2 cascade. However, no other signaling cascade downstream of Raf has been identified. We describe a new member of the mitogen-activated protein kinase family, p97, an ERK5-related kinase that is activated and Raf associated when cells are stimulated by Raf. Furthermore, p97 is selectively responsive to different growth factors, providing a mechanism for specificity in cellular signaling. Thus, p97 is activated by the neurogenic factor fibroblast growth factor (FGF) but not the mitogenic factor epidermal growth factor (EGF) in neuronal cells. Conversely, the related kinase ERK5 is activated by EGF but not FGF. p97 phosphorylates transcription factors such as Elk-1 and Ets-2 but not MEF2C at transactivating sites, whereas ERK5 phosphorylates MEF2C but not Elk-1 or Ets-2. Finally, p97 is expressed in a number of cell types including primary neural and NIH 3T3 cells. Taken together, these results identify a new signaling pathway that is distinct from the classic Raf-MEK1,2-ERK1,2 kinase cascade and can be selectively stimulated by growth factors that produce discrete biological outcomes.

* Corresponding author. Mailing address: Ben May Institute for Cancer Research, University of Chicago, 5841 S. Maryland Ave., MC 6027, Chicago, IL 60637-1470. Phone: (773) 702-0380. Fax: (773) 702-4634. E-mail: mrosner{at}ben-may.bsd.uchicago.edu.

Molecular and Cellular Biology, March 2001, p. 2235-2247, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.2235-2247.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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