Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control.
The activity of the catalytic domain of the orphan MAP kinase ERK5 is increased by Ras but not Raf-1 in cells, which suggests that ERK5 might mediate Raf-independent signaling by Ras. We found that Raf-1 does contribute to Ras activation of ERK5 but in a manner that does not correlate with Raf-1 catalytic activity. A clue to the mechanism of action of Raf-1 on ERK5 comes from the observation that endogenous Raf-1 binds to endogenous ERK5, suggesting the involvement of regulatory protein-protein interactions. This interaction is specific because Raf-1 binds only to ERK5 and not ERK2 or SAPK. Finally, we demonstrate the ERK5/MEK5 pathway is required for Raf-dependent cellular transformation and that a constitutively active form of MEK5, MEK5DD, synergizes with Raf to transform NIH 3T3 cells. These observations suggest that ERK5 plays a large role in Raf-1-mediated signal transduction.
English
J M
JM
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-9041, USA.
Pearson
G
G
Hockenberry
T
T
Shivakumar
L
L
White
M A
MA
Cobb
M H
MH
D000818:Animals; D002471:Cell Transformation, Neoplastic; D048671:MAP Kinase Kinase 5; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D019908:Proto-Oncogene Proteins c-raf; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048671:MAP Kinase Kinase 5; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins