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)

The immune system can be stimulated by microbial molecules as well as by endogenously derived danger/alarm signals of host origin. Using the lepidopteran model insect Galleria mellonella, we recently discovered that fragments of collagen IV, resulting from hydrolysis by microbial metalloproteinases, represent danger/alarm signals in insects. Here, we characterized immune-stimulatory peptides generated by thermolysin-mediated degradation of collagen IV using nanospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) after separation by nanoscale liquid chromatography (nanoLC). The combination of FTICR MS analysis and de novo peptide sequencing resulted in the identification of 38 specific collagen IV fragments of which several peptides included the integrin-binding motif RGD/E known from numerous mammalian immune-related proteins. Custom-synthesized peptides corresponding either to the presently identified collagen peptide GIRGEHyp or to a well-known integrin-binding RGD peptide (GRGDS) were injected into G. mellonella to determine their immune-stimulatory activities in vivo. Both peptides stimulated immune cells and systemically the expression of lysozyme and a specific inhibitor of microbial metalloproteinases. Further examination using specific MAP kinase inhibitors indicated that MEK/ERK and p38 are involved in RGD/E-mediated immune-signaling pathways, whereas JNK seems to play only a minor role.
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PMID:Identification of collagen IV derived danger/alarm signals in insect immunity by nanoLC-FTICR MS. 1966 85

TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER, Thallion's proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity (low micromol/l) when tested in the NCI 60 tumor cell line panel and has shown in-vivo antitumor activity in several xenograft models. Related to its farnesylated moiety, the effect of TLN-4601 on Ras mitogen-activated protein kinase signaling was assessed. Downstream Ras signaling events, Raf-1, MEK, and ERK1/2 phosphorylation in MCF7 cells were evaluated by western blot analysis. TLN-4601 prevented epidermal growth factor-induced phosphorylation of Raf-1, MEK, and ERK1/2. This effect was time-dependent and dose-dependent with complete inhibition of protein phosphorylation within 4-6 h at 10 micromol/l. The inhibition of Ras signaling was not mediated by the inhibition of protein prenylation, documented by the lack of effect TLN-4601 on the prenylation of HDJ2 (specific substrate of farnesyltransferase), RAP1A (specific substrate of geranylgeranyl transferase-1), or Ras. As TLN-4601 did not inhibit EGFR, Raf-1, MEK or ERK1/2 kinase activities, the inhibitory effect of TLN-4601 on Ras signaling is not mediated by direct kinase inhibition. Using an Elk-1 trans-activation reporter assay, we found that TLN-4601 inhibits the MEK/ERK pathway at the level of Raf-1. Interestingly, TLN-4601 induces Raf-1 proteasomal-dependent degradation. These data indicate that TLN-4601 may inhibit the Ras-mitogen-activated protein kinase-signaling pathway by depleting the Raf-1 protein.
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PMID:TLN-4601, a novel anticancer agent, inhibits Ras signaling post Ras prenylation and before MEK activation. 2022 May 16