Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors

Gannam, Zachary T.K.; Jamali, Haya; Kweon, Oh Sang; Herrington, James; Shillingford, Shanelle R.; Papini, Christina; Gentzel, Erik; Lolis, Elias; Bennett, Anton M.; Ellman, Jonathan A.; Anderson, Karen S.

doi:10.1016/j.ejmech.2022.114712

Cited by 3 publications

(2 citation statements)

References 48 publications

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“…We have identified MKP1 as a target that promotes hepatocyte death which is a prerequisite to transit to fibrotic disease. Given the recent developments that have revealed an allosteric site exists on the MKPs that render them druggable 79 – 81 , these data raise the possibility that MKP1 may represent a potential therapeutic target to curtail the progression of NASH.…”

Section: Discussionmentioning

confidence: 99%

MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

Qiu,

Lawan,

Xirouchaki

et al. 2023

Nat Commun

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Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.

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Section: Discussionmentioning

confidence: 99%

MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

Qiu,

Lawan,

Xirouchaki

et al. 2023

Nat Commun

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“…35 Additional MKP-5 allosteric inhibitors have been developed that either show equipotency or improved potency as compared with Cmpd 1. 40 To more effectively interrogate the role of MKP-5 in TGF-β signaling, we utilized a derivative of Cmpd 1, referred to herein as Cmpd 2, which is more potent than Cmpd 1 and maintains MKP-5 selectivity (Supplementary material, Table S1). MKP-5 preferentially dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK.…”

Section: Mkp-5 Activity Is Required For Tgf-β Signalingmentioning

confidence: 99%

MAPK Phosphatase-5 is required for TGF-β signaling through a JNK-dependent pathway

Dorry,

Perla,

Bennett

2024

Preprint

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Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute members of the dual-specificity family of protein phosphatases that dephosphorylate the MAPKs. MKP-5 dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK, and has been shown to promote tissue fibrosis. Here, we provide insight into how MKP-5 regulates the transforming growth factor-β (TGF-β) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-β are impaired in SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and transcriptional activation of fibrogenic genes. Consistent with this, pharmacological inhibition of MKP-5 is sufficient to block TGF-β signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-β signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-β signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-β signaling and provides insight into the role of MKP-5 in fibrosis.

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MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

Qiu

Lawan

Xirouchaki

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKalpha) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed mice. The focus of this work was to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreased liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed mice released nuclear LKB1 into the cytoplasm to activate AMPKalpha and prevent hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKalpha which triggers hepatocyte death and the development of NASH.

show abstract

Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors

Cited by 3 publications

References 48 publications

MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

MAPK Phosphatase-5 is required for TGF-β signaling through a JNK-dependent pathway

MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

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