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)

Aggregated beta-amyloid (Abeta) binds to the neurotrophin receptor p75 and induces signaling. We examined this signaling process in different cell lines which express p75 either naturally (Schwannoma RN22 cells) or which are stably transfected with wild-type p75 (MDCKwt and PCNA cells) or with a truncated form of p75 comprising only extracellular and transmembrane domains (MDCKtm cells). While Abeta in higher concentrations (10-100 microM) is known to cause apoptosis via p75, our experiments focused on the effects of low concentrations of Abeta (25 nM) which may occur in early stages of Alzheimer disease. Application of Abeta caused tyrosine phosphorylation of wild-type p75 and induced the Ras-ERK pathway as has been reported for nerve growth factor (NGF). Since Ras activation and ERK phosphorylation (via MEK) could not be observed in MDCKtm cells and since they were clearly reduced in cells transfected with a p75 antisense construct, these effects should have been mediated by p75. Abeta also induced Ras and ERK activation in cerebellar neurons of 2-day-old rats which express p75 at that developmental stage but not TrkA; other Trk receptors were inhibited by K252a. In these neurons, Abeta led to quick formation, branching and elongation of processes. But while NGF distinctly promoted neurite branching and elongation, Abeta was less effective in neurite elongation and counts of small processes and of growth cones remained clearly elevated after 24-h stimulation; these peculiarities might be linked to aberrant neuronal connections reported for an animal model of Alzheimer disease. Essentially, the observed effects were mediated by interaction of Abeta and p75.
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PMID:Low concentrations of aggregated beta-amyloid induce neurite formation via the neurotrophin receptor p75. 1600 Dec 31

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR), especially in the PNS. Given the invasiveness of nerve biopsy, salivary glands (SG) from FAP patients were used previously in microarray analysis; mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) was down-regulated in FAP. Results were validated by RT-PCR and immunohistochemistry both in SG and in nerve biopsies of different stages of disease progression. MKP-3 was also down-regulated in FAP SG biopsies. Given the relationship between MKPs and MAPKs, the latter were investigated. Only extracellular signal-regulated kinases 1/2 (ERK1/2) displayed increased activation in FAP SG and nerves. ERK1/2 kinase (MEK1/2) activation was also up-regulated in FAP nerves. In addition, an FAP transgenic mouse model revealed increased ERK1/2 activation in peripheral nerve affected with TTR deposition when compared to control animals. Cultured rat Schwannoma cell line treatment with TTR aggregates stimulated ERK1/2 activation, which was partially mediated by the receptor for advanced glycation end-products (RAGE). Moreover, caspase-3 activation triggered by TTR aggregates was abrogated by U0126, a MEK1/2 inhibitor, indicating that ERK1/2 activation is essential for TTR aggregates-induced cytotoxicity. Taken together, these data suggest that abnormally sustained activation of ERK in FAP may represent an early signaling cascade leading to neurodegeneration.
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PMID:Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy. 1651 52