Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade.
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.
Buchsbaum
Rachel J
RJ
Department of Biochemistry, Tufts University School of Medicine and Division of Hematology/Oncology, New England Medical Center, Boston, Massachusetts 02111, USA.
Connolly
Beth A
BA
Feig
Larry A
LA
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D010940:Plant Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017386:Sequence Homology, Amino Acid; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D048051:p38 Mitogen-Activated Protein Kinases; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D010940:Plant Proteins; D011506:Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D048051:p38 Mitogen-Activated Protein Kinases; D020666:ras-GRF1; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C088758:IBP2 protein, Zea mays; C408376:MAPK8IP2 protein, human; C087334:TIAM1 protein, human; C513259:Tiam1 protein, rat