Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.25 (
MEKK1
)
1,856
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Mitogen-activated protein kinases (MAPKs) are activated through the kinase cascades of MAPK, MAPK kinase (MAPKK) and MAPKK kinase (MAPKKK). MAPKKKs phosphorylate and activate their downstream MAPKKs, which in turn phosphorylate and activate their downstream MAPKs. MAPKKK proteins relay upstream signals through the MAPK cascades to induce cellular responses. However, the molecular mechanisms by which given MAPKKKs are regulated remain largely unknown. Here, we found that serine-threonine protein kinase 38,
STK38
, physically interacts with the MAPKKKs
MEKK1
and
MEKK2
(
MEKK1
/2). The carboxy terminus, including the catalytic domain, but not the amino terminus of
MEKK1
/2 was necessary for the interaction with
STK38
.
STK38
inhibited
MEKK1
/2 activation without preventing
MEKK1
/2 binding to its substrate, SEK1. Importantly,
STK38
suppressed the autophosphorylation of
MEKK2
without interfering with
MEKK2
dimer formation, and converted
MEKK2
from its phosphorylated to its nonphosphorylated form. The negative regulation of
MEKK1
/2 was not due to its phosphorylation by
STK38
. On the other hand, stk38 short hairpin RNA enhanced sorbitol-induced activation of
MEKK2
and phosphorylation of the downstream MAPKKs, MKK3/6. Taken together, our results indicate that
STK38
negatively regulates the activation of
MEKK1
/2 by direct interaction with the catalytic domain of
MEKK1
/2, suggesting a novel mechanism of
MEKK1
/2 regulation.
...
PMID:Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38). 1790 93
Aberrant activation of
MEKK
-MEK-ERK signaling is frequently observed in lung cancer. Several inhibitors, which target this pathway, have shown clinical potential for the lung cancer treatment. Better understanding the regulation of this pathway would help the development of treatment strategies. In this study, we have identified the DIAPH3 as an up-regulated gene in lung adenocarcinoma. DIAPH3 promoted the growth of lung cancer cells both in the liquid culture and in the soft agar, and knockdown DIAPH3 inhibited the tumorigenesis both in the nude mice and in the de novo mouse model. In the molecular mechanism study, DIAPH3 was identified as the binding protein of
STK38
, impaired the interaction between
STK38
and
MEKK
, and activated ERK signaling. Taken together, this study demonstrated the oncogenic roles of DIAPH3 in the tumorigenesis of lung cancer by interacting with
STK38
.
...
PMID:DIAPH3 promotes the tumorigenesis of lung adenocarcinoma. 3158 48
