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J. Biol. Chem., Vol. 276, Issue 7, 5093-5100, February 16, 2001
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From the MEKK2 and MEKK3 are two closely related
mitogen-activated protein kinase (MAPK) kinase kinases. The kinase
domains of MEKK2 and MEKK3 are nearly identical, although their
N-terminal regulatory domains are significantly divergent. By yeast
two-hybrid library screening, we have identified MEK5, the MAPK kinase
in the big mitogen-activated protein kinase 1 (BMK1)/ERK5 pathway, as a
binding partner for MEKK2. MEKK2 expression stimulates BMK1/ERK5
activity, the downstream substrate for MEK5. Compared with MEKK3, MEKK2 activated BMK1/ERK5 to a greater extent, which might correlate with a
higher affinity MEKK2-MEK5 interaction. A dominant negative form of
MEK5 blocked the activation of BMK1/ERK5 by MEKK2, whereas activation
of c-Jun N-terminal kinase (JNK) was unaffected, showing that
MEK5 is a specific downstream effector of MEKK2 in the BMK1/ERK5 pathway. Activation of BMK1/ERK5 by epidermal growth factor and H2O2 in Cos7 and HEK293 cells was
completely blocked by a kinase-inactive MEKK3 (MEKK3kin
MEKK2 Associates with the Adapter Protein Lad/RIBP and
Regulates the MEK5-BMK1/ERK5 Pathway*
,,,,,
Department of Pharmacology, University of
Colorado Health Sciences Center and University of Colorado Cancer
Center, Denver, Colorado 80262 and the Departments of
§ Immunology and ¶ Pediatrics, National Jewish Medical
and Research Center, Denver, Colorado 80206
),
whereas MEKK2kin had no effect. However, in D10 T cells,
expression of MEKK2kin but not
MEKK3kin inhibited BMK1/ERK5 activity. Two-hybrid
screening also identified Lck-associated adapter/Rlk- and Itk-binding
protein (Lad/RIBP), a T cell adapter protein, as a binding
partner for MEKK2. MEKK2 and Lad/RIBP colocalize at the T cell contact
site with antigen-loaded presenting cells, demonstrating
cotranslocation of MEKK2 and Lad/RIBP during T cell activation. MEKK3
neither binds Lad/RIBP nor is recruited to the T cell contact with
antigen presenting cell. MEKK2 and MEKK3 are differentially
associated with signaling from specific upstream receptor systems,
whereas both activate the MEK5-BMK1/ERK5 pathway.
*
Supported by National Institutes of Health Grants GM30324,
DK37871, and AI42246.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pharmacology, C-236, University of Colorado Health Sciences Center,
4200 East 9th Ave., Denver, CO 80262. Tel.: 303-315-1009; Fax:
303-315-1022; E-mail: gary.johnson@uchsc.edu.
**
Special Fellow of the Leukemia and Lymphoma Society.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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