Literature summary for 2.7.11.25 extracted from

Cuevas, B.D.; Abell, A.N.; Johnson, G.L.
Role of mitogen-activated protein kinase kinase kinases in signal integration (2007), Oncogene, 26, 3159-3171.

Activating Compound

Activating Compound	Comment	Organism	Structure
progesterone	induces c-Mos expression	Xenopus sp.

Application	Comment	Organism
medicine	gene amplification and corresponding increased Tpl-2 expression in some human breast cancers	Homo sapiens

Protein Variants	Comment	Organism
additional information	MEKK1 knockdown in invasive human breast carcinoma cells leads to reduced uPA expression, cell migration, and invasiveness	Homo sapiens
additional information	MEKK1-4 knockout mice, MEKK3 knockout is embryo-lethal, displaying inadequate fetal-maternal vascularization. MEKK4 knockout is largely perinatal lethal, and associated with defective neural tube closure, shows loss of JNK and p38 activation. MEKK1-2 knockouts are associated with impaired tissue remodeling associated with wound healing and homeostasis, expression of JunB and Fra-2 is markedly increased in MEKK1-deficient mouse fibroblasts. MLK3-deficient mice are viable and fertile with only a mild defect in the epidermal tissue of the dorsal midline. Mouse embryos deficient in either B-Raf or C-Raf die before day E12.5. A-Raf deficient mice die perinatally at 1-3 weeks of age. Tpl2-deficient mice are viable and appear indistinguishable from littermates, produce reduced levels of TNFalpha in response to LPS injection, are resistant to LPS/D-galactosamine-induced pathology. TAK1-deficient mouse embryo fibroblasts show decreased IL-1beta-induced IL-6 expression, TAK1-deficient keratinocytes develop a severe postnatal inflammation, loss of MEKK1 does not alter the course of tumorigenesis or inhibit primary tumor growth, intimal hyperplasia is significantly reduced	Mus musculus

Inhibitors	Comment	Organism	Structure
BAY 43-9006	c-Raf inhibitor, shows promising response rate in patients with primary renal cell carcinomas	Homo sapiens
CEP-1347	inhibits MLKs and is well tolerated in human trials, does not perform in trials for neurodegenerative disorders such as Parkinson´s disease	Homo sapiens

Organism	UniProt	Comment	Textmining
Homo sapiens	-	-	-
Mus musculus	-	-	-
Rattus norvegicus	-	-	-
Xenopus sp.	-	-	-

Source Tissue	Comment	Organism	Textmining
breast carcinoma cell	-	Homo sapiens	-
carcinoma cell line	A-Raf is rarely mutated in human cancers	Homo sapiens	-
embryo	-	Mus musculus	-
fibroblast	constitutive c-Mos expression transforms fibroblasts	Mus musculus	-
keratinocyte	-	Mus musculus	-
MOLT-4 cell	mutated A-Raf	Homo sapiens	-
oocyte	-	Xenopus sp.	-
renal cell carcinoma cell	c-Raf	Homo sapiens	-
thymoma cell	Tpl-2 isolated from Moloney leukemia virus-induced thymoma cells	Rattus norvegicus	-

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + ERK5	-	Mus musculus	ADP + phosphorylated ERK5	-	?
additional information	MEKK3 is required for IL-1R and LPS-induced IL-6 production in fibroblasts	Mus musculus	?	-	?

Synonyms	Comment	Organism
A-Raf	-	Mus musculus
B-Raf	-	Mus musculus
c-mos	-	Mus musculus
c-mos	-	Xenopus sp.
C-Raf	-	Mus musculus
C-Raf	-	Homo sapiens
MEKK1	-	Mus musculus
MEKK1	-	Homo sapiens
MEKK2	-	Mus musculus
MEKK2	-	Homo sapiens
MEKK3	-	Mus musculus
MEKK3	-	Homo sapiens
MEKK4	-	Mus musculus
MEKK4	-	Homo sapiens
mitogen-activated protein kinase kinase kinase	-	Mus musculus
mitogen-activated protein kinase kinase kinase	-	Homo sapiens
mitogen-activated protein kinase kinase kinase	-	Rattus norvegicus
mitogen-activated protein kinase kinase kinase	-	Xenopus sp.
MKKK	-	Mus musculus
MKKK	-	Homo sapiens
MKKK	-	Rattus norvegicus
MKKK	-	Xenopus sp.
MKL3	-	Mus musculus
MLK	-	Homo sapiens
TAK1	-	Mus musculus
TPL-2	-	Mus musculus
TPL-2	-	Homo sapiens
TPL-2	-	Rattus norvegicus