Mechanism of mitosis-specific activation of MEK1.
Activation of cyclin B-Cdc2 is an absolute requirement for entry into mitosis, but other protein kinase pathways that also have mitotic functions are activated during G(2)/M progression. The MAPK cascade has well established roles in entry and exit from mitosis in Xenopus, but relatively little is known about the regulation and function of this pathway in mammalian mitosis. Here we report a detailed analysis of the activity of all components of the Ras/Raf/MEK/ERK pathway in HeLa cells during normal G(2)/M. The focus of this pathway is the dramatic activation of an endomembrane-associated MEK1 without the corresponding activation of the MEK substrate ERK. This is because of the uncoupling of MEK1 activation from ERK activation. The mechanism of this uncoupling involves the cyclin B-Cdc2-dependent proteolytic cleavage of the N-terminal ERK-binding domain of MEK1 and the phosphorylation of Thr(286). These results demonstrate that cyclin B-Cdc2 activity regulates signaling through the MAPK pathway in mitosis.
Harding
Angus
A
Cancer Biology Program, Centre for Immunology and Cancer Research, University of Queensland, Queensland 4102, Australia.
Giles
Nichole
N
Burgess
Andrew
A
Hancock
John F
JF
Gabrielli
Brian G
BG
D016203:CDC2 Protein Kinase / Q000502:physiology; D019926:Cyclin B / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D008938:Mitosis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*
D019926:Cyclin B; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases