Abstract
Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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Animals
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Binding Sites
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COS Cells
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Guanine Nucleotide Exchange Factors
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Humans
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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MAP Kinase Signaling System
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Mitogen-Activated Protein Kinase Kinase Kinase 11
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Molecular Sequence Data
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Neoplasm Proteins
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Plant Proteins*
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Proteins / genetics
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Proteins / metabolism*
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Rats
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Sequence Homology, Amino Acid
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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p38 Mitogen-Activated Protein Kinases
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ras-GRF1 / genetics
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ras-GRF1 / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DNA-Binding Proteins
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Guanine Nucleotide Exchange Factors
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IBP2 protein, Zea mays
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MAPK8IP2 protein, human
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Neoplasm Proteins
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Plant Proteins
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Proteins
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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TIAM1 protein, human
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Tiam1 protein, rat
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ras-GRF1
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases