Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: EC:2.7.11.25 (
MEKK1
)
1,856
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
MEKK2
and
MEKK3
are MAPK kinase kinases that activate the ERK5 pathway by phosphorylating and activating the MAPK kinase, MEK5. Activated MEK5 then phosphorylates and activates ERK5. PB1 domains were first defined in the
p67phox
and Bem1p proteins and have been shown to mediate protein-protein heterodimerization. A PB1 domain is encoded within the N-terminal portion of
MEKK2
,
MEKK3
, and MEK5. Herein, we analyze the functional role of
MEKK2
,
MEKK3
, and MEK5 PB1 domains in the ERK5 activation pathway. The PB1 domains of
MEKK2
and
MEKK3
bind the PB1 domain of MEK5 but do not significantly homo- or heterodimerize with one another in vitro. Furthermore, co-immunoprecipitation of
MEKK2
and MEK5 from cell lysates shows that they form a complex in vivo. Deletion or mutation of the
MEKK2
PB1 domain abolishes
MEKK2
-MEK5 complexes, demonstrating that the PB1 domain interaction is required for
MEKK2
-MEK5 interactions. Expression in cells of the
MEKK2
or
MEKK3
PB1 domain inhibits ERK5 activation, whereas expression of a mutant
MEKK2
unable to bind the MEK5 PB1 domain or expression of the
p67phox
PB1 domain has no effect on ERK5 activation. These findings demonstrate that the PB1 domain mediates the association of
MEKK2
and
MEKK3
with MEK5 and that the respective PB1 domains of these kinases are critical for regulation of the ERK5 pathway. The free PB1 domain of
MEKK2
or
MEKK3
functions effectively to inhibit the ERK5 pathway but not the p38 or JNK pathways, demonstrating the specific and unique requirement of the
MEKK2
and
MEKK3
PB1 domain in regulating ERK5 activation.
...
PMID:PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. 1291 94
