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.
Mammalian Raf-1 is activated by mutations that restore Raf signaling in Drosophila.
Cutler RE
,
Morrison DK
.
???displayArticle.abstract???
An interaction with the Ras proto-oncogene product is a requirement for Raf-1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras-Raf interaction severely impairs the function of both mammalian (Raf-1) and Drosophila (D-Raf) Raf proteins. In D-Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras-binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf-1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras-Raf-1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf-1, allowing Raf-1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf-1, it also abolishes the ability of wild-type Raf-1 to become activated by Ras. This mutation occurs in the cysteine-rich domain (CRD) of Raf-1 and demonstrates the importance of this region for a productive Ras-Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf-1 activity by introducing a novel phosphorylation site into the L12 activation loop of the Raf-1 kinase domain.
Alessi,
Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1.
1994, Pubmed
Alessi,
Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1.
1994,
Pubmed
Birchmeier,
ras proteins can induce meiosis in Xenopus oocytes.
1985,
Pubmed
,
Xenbase
Block,
Quantitative structure-activity analysis correlating Ras/Raf interaction in vitro to Raf activation in vivo.
1996,
Pubmed
Boyle,
Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates.
1991,
Pubmed
Brtva,
Two distinct Raf domains mediate interaction with Ras.
1995,
Pubmed
,
Xenbase
Chow,
Functional mapping of the N-terminal regulatory domain in the human Raf-1 protein kinase.
1995,
Pubmed
Dent,
Expression, purification and characterization of recombinant mitogen-activated protein kinase kinases.
1994,
Pubmed
Dickson,
Raf functions downstream of Ras1 in the Sevenless signal transduction pathway.
1992,
Pubmed
Drugan,
Ras interaction with two distinct binding domains in Raf-1 may be required for Ras transformation.
1996,
Pubmed
Fabian,
Requirement for Raf and MAP kinase function during the meiotic maturation of Xenopus oocytes.
1993,
Pubmed
,
Xenbase
Fabian,
A single amino acid change in Raf-1 inhibits Ras binding and alters Raf-1 function.
1994,
Pubmed
,
Xenbase
Fabian,
Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase.
1993,
Pubmed
,
Xenbase
Fantl,
Activation of Raf-1 by 14-3-3 proteins.
1994,
Pubmed
,
Xenbase
Finney,
Association of pRas and pRaf-1 in a complex correlates with activation of a signal transduction pathway.
1993,
Pubmed
Freed,
Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation.
1994,
Pubmed
Ghosh,
The cysteine-rich region of raf-1 kinase contains zinc, translocates to liposomes, and is adjacent to a segment that binds GTP-ras.
1994,
Pubmed
Hallberg,
Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation.
1994,
Pubmed
Han,
C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation.
1993,
Pubmed
Hou,
The torso receptor tyrosine kinase can activate Raf in a Ras-independent pathway.
1995,
Pubmed
Irie,
Stimulatory effects of yeast and mammalian 14-3-3 proteins on the Raf protein kinase.
1994,
Pubmed
Lu,
Genetic and molecular analyses of mutations involved in Drosophila raf signal transduction.
1994,
Pubmed
Mansour,
Transformation of mammalian cells by constitutively active MAP kinase kinase.
1994,
Pubmed
Mansour,
Constitutively active mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 mediate similar transcriptional and morphological responses.
1996,
Pubmed
Marshall,
MAP kinase kinase kinase, MAP kinase kinase and MAP kinase.
1994,
Pubmed
Marshall,
Signal transduction. Hot lips and phosphorylation of protein kinases.
1994,
Pubmed
Melnick,
Developmental and molecular characterization of mutations in the Drosophila-raf serine/threonine protein kinase.
1993,
Pubmed
Michaud,
14-3-3 is not essential for Raf-1 function: identification of Raf-1 proteins that are biologically activated in a 14-3-3- and Ras-independent manner.
1995,
Pubmed
,
Xenbase
Moodie,
The 3Rs of life: Ras, Raf and growth regulation.
1994,
Pubmed
Moodie,
Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase.
1993,
Pubmed
Morrison,
Identification of the major phosphorylation sites of the Raf-1 kinase.
1993,
Pubmed
Morrison,
Mechanisms regulating Raf-1 activity in signal transduction pathways.
1995,
Pubmed
,
Xenbase
Mott,
The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site.
1996,
Pubmed
Nassar,
The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue.
1995,
Pubmed
Pearson,
Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations.
1991,
Pubmed
Scheffler,
Characterization of a 78-residue fragment of c-Raf-1 that comprises a minimal binding domain for the interaction with Ras-GTP.
1994,
Pubmed
,
Xenbase
Stokoe,
Activation of Raf as a result of recruitment to the plasma membrane.
1994,
Pubmed
Szeberényi,
Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells.
1990,
Pubmed
Therrien,
KSR modulates signal propagation within the MAPK cascade.
1996,
Pubmed
,
Xenbase
Vojtek,
Mammalian Ras interacts directly with the serine/threonine kinase Raf.
1993,
Pubmed
Wigler,
Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor.
1978,
Pubmed
Wood,
ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK.
1992,
Pubmed
Zhang,
Atomic structure of the MAP kinase ERK2 at 2.3 A resolution.
1994,
Pubmed
Zhang,
Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1.
1993,
Pubmed
