Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
A novel role for Cdk1/cyclin B in regulating B-raf activation at mitosis.
Borysov SI
,
Guadagno TM
.
???displayArticle.abstract??? MAPK activity is important during mitosis for spindle assembly and maintenance of the spindle checkpoint arrest. We previously identified B-Raf as a critical activator of the MAPK cascade during mitosis in Xenopus egg extracts and showed that B-Raf activation is regulated in an M-phase-dependent manner. The mechanism that mediates B-Raf activation at mitosis has not been elucidated. Interestingly, activation of 95-kDa B-Raf at mitosis does not require phosphorylation of Thr-599 and Ser-602 residues (Thr-633 and Ser-636 in Xenopus B-Raf), previously shown to be essential for B-Raf activation by Ras. Instead, we provide evidence for Cdk1/cyclin B in mediating mitotic activation of B-Raf. In particular, Cdk1/cyclin B complexes associate with B-Raf at mitosis in Xenopus egg extracts and contribute to its phosphorylation. Mutagenesis and in vitro kinase assays demonstrated that Cdk1/cyclin B directly phosphorylates B-Raf at Serine-144, which is part of a conserved Cdk1 preferential consensus site (S(144)PQK). Importantly, phosphorylation of Ser-144 is absolutely required for mitotic activation of B-Raf and subsequent activation of the MAPK cascade. However, substitution of a phospho-mimicking amino acid at Ser-144 failed to produce a constitutive active B-Raf indicating that, in addition of Ser-144 phosphorylation, other regulatory events may be needed to activate B-Raf at mitosis. Taken together, our data reveal a novel cell cycle mechanism for activating the B-Raf/MEK/MAPK cascade.
Borysov,
B-Raf is critical for MAPK activation during mitosis and is regulated in an M phase-dependent manner in Xenopus egg extracts.
2006, Pubmed,
Xenbase
Borysov,
B-Raf is critical for MAPK activation during mitosis and is regulated in an M phase-dependent manner in Xenopus egg extracts.
2006,
Pubmed
,
Xenbase
Castro,
Cyclin B/cdc2 induces c-Mos stability by direct phosphorylation in Xenopus oocytes.
2001,
Pubmed
,
Xenbase
Catling,
Partial purification of a mitogen-activated protein kinase kinase activator from bovine brain. Identification as B-Raf or a B-Raf-associated activity.
1994,
Pubmed
Chong,
Mechanisms of regulating the Raf kinase family.
2003,
Pubmed
Cui,
B-Raf(V600E) signaling deregulates the mitotic spindle checkpoint through stabilizing Mps1 levels in melanoma cells.
2008,
Pubmed
Daum,
The ins and outs of Raf kinases.
1994,
Pubmed
Garcia,
Thrombopoietin-mediated sustained activation of extracellular signal-regulated kinase in UT7-Mpl cells requires both Ras-Raf-1- and Rap1-B-Raf-dependent pathways.
2001,
Pubmed
Guadagno,
Requirement for MAPK activation for normal mitotic progression in Xenopus egg extracts.
1998,
Pubmed
,
Xenbase
Guan,
Negative regulation of the serine/threonine kinase B-Raf by Akt.
2000,
Pubmed
Hagemann,
Isotype-specific functions of Raf kinases.
1999,
Pubmed
Horne,
A requirement for MAP kinase in the assembly and maintenance of the mitotic spindle.
2003,
Pubmed
,
Xenbase
Hüser,
MEK kinase activity is not necessary for Raf-1 function.
2001,
Pubmed
Jackman,
Active cyclin B1-Cdk1 first appears on centrosomes in prophase.
2003,
Pubmed
Jaiswal,
The mitogen-activated protein kinase cascade is activated by B-Raf in response to nerve growth factor through interaction with p21ras.
1994,
Pubmed
Kolch,
Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions.
2000,
Pubmed
Luckett,
Expression of the A-raf proto-oncogene in the normal adult and embryonic mouse.
2000,
Pubmed
Marais,
Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases.
1997,
Pubmed
Mason,
Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation.
1999,
Pubmed
Mercer,
Raf proteins and cancer: B-Raf is identified as a mutational target.
2003,
Pubmed
Minshull,
A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts.
1994,
Pubmed
,
Xenbase
Morrison,
The complexity of Raf-1 regulation.
1997,
Pubmed
Murray,
Cell cycle extracts.
1991,
Pubmed
Nigg,
The substrates of the cdc2 kinase.
1991,
Pubmed
Ohtsuka,
Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein.
1996,
Pubmed
Papin,
Modulation of kinase activity and oncogenic properties by alternative splicing reveals a novel regulatory mechanism for B-Raf.
1998,
Pubmed
Pritchard,
Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene.
1996,
Pubmed
Rattner,
p34cdc2 kinase is localized to distinct domains within the mitotic apparatus.
1990,
Pubmed
Reuter,
Biochemical analysis of MEK activation in NIH3T3 fibroblasts. Identification of B-Raf and other activators.
1995,
Pubmed
Riabowol,
The cdc2 kinase is a nuclear protein that is essential for mitosis in mammalian cells.
1989,
Pubmed
,
Xenbase
Roovers,
Integrating the MAP kinase signal into the G1 phase cell cycle machinery.
2000,
Pubmed
Shapiro,
Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol.
2004,
Pubmed
Storm,
Expression of raf family proto-oncogenes in normal mouse tissues.
1990,
Pubmed
Takenaka,
MAP kinase is required for the spindle assembly checkpoint but is dispensable for the normal M phase entry and exit in Xenopus egg cell cycle extracts.
1997,
Pubmed
,
Xenbase
Tran,
B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms.
2005,
Pubmed
Vossler,
cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway.
1997,
Pubmed
Walsh,
Phosphorylation of the cyclin b1 cytoplasmic retention sequence by mitogen-activated protein kinase and Plx.
2003,
Pubmed
,
Xenbase
Wang,
A role for mitogen-activated protein kinase in the spindle assembly checkpoint in XTC cells.
1997,
Pubmed
,
Xenbase
Watanabe,
Specific proteolysis of the c-mos proto-oncogene product by calpain on fertilization of Xenopus eggs.
1989,
Pubmed
,
Xenbase
Watanabe,
Independent inactivation of MPF and cytostatic factor (Mos) upon fertilization of Xenopus eggs.
1991,
Pubmed
,
Xenbase
Wellbrock,
The RAF proteins take centre stage.
2004,
Pubmed
Wojnowski,
Endothelial apoptosis in Braf-deficient mice.
1997,
Pubmed
Wojnowski,
Craf-1 protein kinase is essential for mouse development.
1998,
Pubmed
Wojnowski,
Overlapping and specific functions of Braf and Craf-1 proto-oncogenes during mouse embryogenesis.
2000,
Pubmed
Yue,
Mechanistic studies of the mitotic activation of Mos.
2006,
Pubmed
,
Xenbase
Yue,
Mos mediates the mitotic activation of p42 MAPK in Xenopus egg extracts.
2004,
Pubmed
,
Xenbase
Zhang,
Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601.
2000,
Pubmed
Zhang,
Regulation of the Raf kinase by phosphorylation.
2001,
Pubmed
Zhao,
Mps1 phosphorylation by MAP kinase is required for kinetochore localization of spindle-checkpoint proteins.
2006,
Pubmed
,
Xenbase
