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Molecular and Cellular Biology, June 2002, p. 4073-4085, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4073-4085.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interaction of Rac Exchange Factors Tiam1 and Ras-GRF1 with a Scaffold for the p38 Mitogen-Activated Protein Kinase Cascade

Rachel J. Buchsbaum,1,2 Beth A. Connolly,1 and Larry A. Feig1*

Department of Biochemistry, Tufts University School of Medicine,1 Division of Hematology/Oncology, New England Medical Center, Boston, Massachusetts 021112

Received 24 October 2001/ Returned for modification 10 December 2001/ Accepted 25 February 2002

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.

* Corresponding author. Mailing address: Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111. Phone: (617) 636-6956. Fax: (617) 636-2409. E-mail: larry.feig{at}tufts.edu.

Molecular and Cellular Biology, June 2002, p. 4073-4085, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4073-4085.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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