A novel mitogen-activated protein kinase is responsive to Raf and mediates growth factor specificity.
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.
Ben May Institute for Cancer Research, Pharmacology and Physiology, University of Chicago, Chicago, Illinois 60637, USA.
M
M
Janulis
N
N
Trakul
G
G
Greene
E M
EM
Schaefer
J D
JD
Lee
M R
MR
Rosner
D000818:Animals; D000918:Antibody Specificity; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D003429:Cross Reactions; D004789:Enzyme Activation; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048671:MAP Kinase Kinase 5; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*
D006133:Growth Substances; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048671:MAP Kinase Kinase 5; C482125:MAP2K1 protein, human; C482563:MAP2K5 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases