Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor.
Epidermal growth factor (EGF) induces cell proliferation in a variety of cell types by binding to a prototype transmembrane tyrosine kinase receptor. Ligation of this receptor by EGF activates Erk1 and Erk2, members of the mitogen-activated protein (MAP) kinase family, through a Ras-dependent signal transduction pathway. Despite our detailed understanding of these events, the exact mechanism by which EGF causes cells to proliferate is unclear. Big MAP kinase (Bmk1), also known as Erk5, is a member of the MAP kinase family that is activated in cells in response to oxidative stress, hyperosmolarity and treatment with serum. Here we show that EGF is a potent activator of Bmk1. In contrast to Erk1/2, EGF-mediated activation of Bmk1 occurs independently of Ras and requires the MAP-kinase kinase Mek5. Expression of a dominant-negative form of Bmk1 blocks EGF-induced cell proliferation and prevents cells from entering the S phase of the cell cycle. These results demonstrate that Bmk1 is part of a distinct MAP-kinase signalling pathway that is required for EGF-induced cell proliferation and progression through the cell cycle.
Kato
Y
Y
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Tapping
R I
RI
Huang
S
S
Watson
M H
MH
Ulevitch
R J
RJ
Lee
J D
JD
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048671:MAP Kinase Kinase 5; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins