RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity.

MEKK1 is a mitogen-activated protein kinase kinase kinase (MAP3K) that can regulate the c-Jun amino-terminal kinase (JNK) MAP kinase cascade. MEKK1 is comprised of a kinase domain and a long amino-terminal regulatory domain. This amino-terminal domain has a scaffold function in that it can assemble modules of the JNK and ...
ERK MAP kinase cascades. Recently, we have demonstrated that MEKK1 binds to p115 Rho GTPase-activating protein, which has GTPase-activating protein activity toward RhoA. Thus, we tested whether Rho GTPases interact with the regulatory domain of MEKK1. RhoA, but not Rac or Cdc42, binds to a site in the aminoterminal one-third of MEKK1, which includes its PHD domain. The interaction is prevented by mutation of the essential cysteine in the MEKK1 PHD domain. Rho-GTP stimulates the kinase activity of full-length MEKK1 as much as 10-fold toward MEK4 but does not appear to be ubiquitinated by MEKK1 under conditions that result in modification of ERK2. In summary, we have characterized a novel point at which Rho GTPases impinge upon the regulation and function of MEKK1.
Mesh Terms:
Amino Acid Sequence, Animals, Cells, Cultured, Dogs, Humans, MAP Kinase Kinase Kinase 1, MAP Kinase Kinase Kinases, Molecular Sequence Data, Ubiquitin, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, rhoA GTP-Binding Protein
J. Biol. Chem.
Date: Jan. 16, 2004
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