The Ras/p120 GTPase-activating Protein (GAP) Interaction Is Regulated by the p120 GAP Pleckstrin Homology Domain

Pleckstrin homology domains are structurally conserved functional domains that can undergo both protein/protein and protein/lipid interactions. Pleckstrin homology domains can mediate inter- and intra-molecular binding events to regulate enzyme activity. They occur in numerous proteins including man...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-11, Vol.275 (45), p.35021-35027
Main Authors: Drugan, Jonelle K., Rogers-Graham, Kelley, Gilmer, Tona, Campbell, Sharon, Clark, Geoffrey J.
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Blood Proteins - chemistry
Cell Division
COS Cells
DNA, Complementary - metabolism
Glutathione Transferase - metabolism
JNK Mitogen-Activated Protein Kinases
Lipid Metabolism
MAP Kinase Kinase 4
MAP Kinase Signaling System
Mice
Mitogen-Activated Protein Kinase Kinases - metabolism
p120 GTPase Activating Protein - metabolism
Phosphoproteins - chemistry
Polymerase Chain Reaction
Protein Binding
Protein Structure, Tertiary
Proto-Oncogene Proteins c-raf - metabolism
ras Proteins - metabolism
Recombinant Proteins - metabolism
Signal Transduction
Time Factors
Transfection
Transformation, Genetic
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Summary:Pleckstrin homology domains are structurally conserved functional domains that can undergo both protein/protein and protein/lipid interactions. Pleckstrin homology domains can mediate inter- and intra-molecular binding events to regulate enzyme activity. They occur in numerous proteins including many that interact with Ras superfamily members, such as p120 GAP. The pleckstrin homology domain of p120 GAP is located in the NH2-terminal, noncatalytic region of p120 GAP. Overexpression of the noncatalytic domains of p120 GAP may modulate Ras signal transduction pathways. Here, we demonstrate that expression of the isolated pleckstrin homology domain of p120 GAP specifically inhibits Ras-mediated signaling and transformation but not normal cellular growth. Furthermore, we show that the pleckstrin homology domain binds the catalytic domain of p120 GAP and interferes with the Ras/GAP interaction. Thus, we suggest that the pleckstrin homology domain of p120 GAP may specifically regulate the interaction of Ras with p120 GAP via competitive intra-molecular binding.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M004386200