MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway

Citation
Wy. Sun et al., MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway, J BIOL CHEM, 276(7), 2001, pp. 5093-5100
Citations number
65
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
7
Year of publication
2001
Pages
5093 - 5100
Database
ISI
SICI code
0021-9258(20010216)276:7<5093:MAWTAP>2.0.ZU;2-S
Abstract
MEKK2 and MEKK3 are two closely related mitogen-activated protein kinase (M APK) kinase kinases, The kinase domains of MEKK2 and MEKK3 are nearly ident ical, although their N-terminal regulatory domains are significantly diverg ent. By yeast two-hybrid library screening, we have identified MEK5, the MA PK kinase in the big mitogen-activated protein kinase 1 (BMK1)/ ERK5 pathwa y, as a binding partner for MEKK2. MEKK2 expression stimulates BMK1/ERK5 ac tivity, the downstream substrate for MEK5. Compared with MEKK3, MEKK2 activ ated BMK1/ERK5 to a greater extent, which might correlate with a higher aff inity MEKK2-MEK5 interaction. A dominant negative form of MEK5 blocked the activation of BMK1/ERK5 by MEKK2, whereas activation of c-Jun N-terminal ki nase (JNK) was unaffected, showing that MEK5 is a specific downstream effec tor 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(-)), whereas MEKK2kin(-) had no effect. H owever, in D10 T cells, expression of MEKK2kin(-) but not MEKK3kin(-) inhib ited BMK1/ERK5 activity. Two-hybrid screening also identified Lck-associate d 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 ce ll contact site with antigen-loaded presenting cells, demonstrating cotrans location of MEKK2 and Lad/RIBP during T cell activation. MEKK3 neither bind s Lad/RIBP nor is recruited to the T cell contact with antigen presenting c ell. MEKK2 and MEKK3 are differentially associated with signaling from spec ific upstream receptor systems, whereas both activate the MEK5-BMK1/ERK5 pa thway.