Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with advanced metastatic melanoma have poor prognosis and the genetics underlying its pathogenesis are poorly understood. High-throughput sequencing has allowed comprehensive discovery of somatic mutations in cancer samples. Here, on analysis of our whole-genome and whole-exome sequencing data of 29 melanoma samples, we identified several genes that harbor recurrent nonsynonymous mutations. These included MAP3K5 (mitogen-activated protein kinase kinase kinase-5), which in a prevalence screen of 288 melanomas was found to harbor a R256C substitution in 5 cases. All MAP3K5-mutated samples were wild type for BRAF, suggesting a mutual exclusivity for these mutations. Functional analysis of the MAP3K5 R256C mutation revealed attenuation of MKK4 (mitogen-activated protein kinase kinase 4) activation through increased binding of the inhibitory protein thioredoxin (TXN/TRX-1/Trx), resulting in increased proliferation and anchorage-independent growth of melanoma cells. This mutation represents a potential target for the design of new therapies to treat melanoma.
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PMID:Somatic mutations in MAP3K5 attenuate its proapoptotic function in melanoma through increased binding to thioredoxin. 2400 24

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored.
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PMID:MAP3K kinases and kidney injury. 3119 60