Tpl-2 and MEK small molecule inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA328166 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3749310.fastq.gz | Fastqsanger.gz | |||
| SRR3749320.fastq.gz | Fastqsanger.gz | |||
| SRR3749301.fastq.gz | Fastqsanger.gz | |||
| SRR3749311.fastq.gz | Fastqsanger.gz | |||
| SRR3749302.fastq.gz | Fastqsanger.gz |
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Project description:Tpl-2 is a serine/threonine kinase that has been studied extensively in monocytes. Tpl-2 is believed to phosphorylate MEK1/2, which is upstream of ERK1/2, and regulates inflammatory gene expression in response to TLR and IL-1b receptor signaling. In the course of performing proof-of-concept studies using a small molecule inhibitor (SMI) of Tpl-2, we were surprised to see the inhibitor affect cytokine production in human neutrophils. Unlike human monocytes, which respond at least some degree to both Tpl-2 and MEK inhibitors, neutrophils showed a disconnect between Tpl-2 and MEK. A panel of genes in this cell type can be fully blocked by a Tpl-2 SMI, and yet show no response to a MEK SMI, suggesting Tpl-2 mediates its effect through substrates other than MEK.
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Project description:Comparison of Tpl-2 small molecule inhibitor (SMI) versus MEK SMI activities in LPS-treated human monocytes will reveal a subset of genes that require Tpl-2 but are independent of MEK. Tpl-2 is a highly conserved (94% human versus mouse) serine-threonine kinase expressed in cells important to the inflammatory response, including monocytes, macrophages, dendritic cells, and B/T cells. The role of Tpl-2 in monocytes and macrophages has been especially well-studied. It has been shown in these cells that Tpl-2 is required for the expression of cytokines in response to Toll-like receptor ligands, including LPS. In resting cells, Tpl-2 forms a complex with p105 and ABIN-2. Upon stimulation, this complex dissociates. Dissociated p105 is processed to p50, which impacts transcription. Dissociated Tpl-2 phosphorylates MEK, which, in turn, phosphorylates ERK. ERK activates the transcription factor AP-1 and its downstream gene targets. An open question in the field is whether Tpl-2 acts solely through MEK to drive gene expression, or does Tpl-2 have any MEK-independent targets. Answering this question is important both for understanding basic Tpl-2 biology as well as its role in disease. Based on published data, Tpl-2 is important for inflammatory cytokine production, and in animal models where these cytokines contribute to disease (septic shock, IBD), blocking Tpl-2 ameliorates disease symptoms. We have a highly selective SMI of Tpl-2 that effectively blocks cytokine production in purified human monocytes. This SMI can block production of the same cytokines that a MEK inhibitor blocks, which is expected given that Tpl-2 lies upstream of MEK. However, the MEK SMI only partially inhibits certain cytokines, while the Tpl-2 SMI fully blocks them, suggesting there are additional factors downstream of Tpl-2 that are not MEK-dependent.
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Project description:Resistance to Ras pathway inhibition is a major challenge in the treatment of colorectal cancer (CRC), but the underlying mechanisms are incompletely understood. Here we performed large-scale small molecule screens in CRC and identified inhibitors of MEK1/2 as potent activators of Wnt/beta-catenin signalling. Targeting MEK increased Wnt activity in different CRC cell lines and in the murine intestine in vivo. The MEK-induced Wnt response was strongly enhanced by truncating mutations in APC and proteomic experiments identified that AXIN1 levels are depleted upon MEK inhibition. We generated patient-derived colon cancer organoids and showed that a clinically approved MEK inhibitor leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stem cells and cancer relapse. This reprogramming was reverted by co-treatment with Wnt inhibitors. Our study demonstrates that MEK inhibition affects cellular plasticity and induces an intestinal stem cell program which constitutes a novel mechanism of drug resistance.
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