Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain

Tassin, Tara C.; Benavides, David R.; Plattner, Florian; Nishi, Akinori; Bibb, James A.

doi:10.1074/jbc.m115.654897

Cited by 22 publications

(13 citation statements)

References 79 publications

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“…Studies have shown that CDK5 can alter pain-related neuronal plasticity by regulating ERK1/2 activation in anesthetized rats [15]. CDK5 has also been characterized to phosphorylate the ERK-activating protein kinase MEK1 in the brain [16]. The present results demonstrated that CDK5 promoted renal tubulointerstitial fibrosis through enhancing phosphorylated ERK1/2 and PPARγ in diabetic nephropathy.…”

Section: Discussionsupporting

confidence: 61%

CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway

et al. 2016

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Cyclin-dependent kinase 5 (CDK5) has been documented in podocyte injuries in diabetic nephropathy (DN), however its role in renal tubular epithelial cells has not been elucidated. We report here that CDK5 is detrimental and promotes tubulointerstitial fibrosis (TIF) via the extracellular signal-regulated kinase 1/2 (ERK1/2)/peroxisome proliferator-activated receptor gamma (PPRAγ) pathway in DN. In high glucose cultured NRK52E cells, blocking CDK5 activity inhibited epithelial-to-mesenchymal transition (EMT) and fibrosis via ERK1/2/PPARγ pathway. In diabetic rats, CDK5 inhibitor roscovitine decreased renal fibrosis and improved renal function as demonstrated by a decrease in levels of blood urine nitrogen (BUN), serum creatinine and β2-microglobulin. Further studies revealed that improved renal fibrosis and function in diabetic rats were associated with inactivation of ERK1/2 and PPARγ signaling pathways. In late staged DN patients, the upregulation of CDK5 and p35 activated phosphorylated ERK1/2 and PPARγ, leading to decreased levels of E-cadherin but increased Vimentin and Collagen IV. Accordingly, renal fibrosis and function were worsened as revealed by decreased estimated glomerular filtration rate (eGFR) and increased serum BUN, creatinine, β2-microglobulin, 24-hour proteinuria and urine albumin to creatinine ratio (UACR). These findings demonstrate a novel mechanism that CDK5 increases tubulointerstitial fibrosis by activating the ERK1/2/PPARγ pathway and EMT in DN. CDK5 might have therapeutic potential in diabetic nephropathy.

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Section: Discussionsupporting

confidence: 61%

CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway

et al. 2016

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“…Further, the autophosphorylation of P-loop residues in RAF proteins serves as another feedback mechanism that impairs their kinase activity [234]. For MEK, it can be phosphorylated at its N-terminus that intercepts its activity [235].…”

Section: Feedback Inhibition and Return To The Inactive Statementioning

confidence: 99%

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Degirmenci

Wang

2020

Cells

399

303

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The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

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“…MEK1 enzymatic activity is regulated by site-specific phosphorylation that can be activated with phosphorylation of Ser217/Ser221 by Raf kinase 40 or suppressed by phosphorylation of Thr286 and Thr292 by CDK1 and CDK5 38 , 39 , 41 or Thr292 and Thr386 by ERK1/2 42 – 44 (Fig. 4a ).…”

Section: Resultsmentioning

confidence: 99%

Detection of the Cell Cycle-Regulated Negative Feedback Phosphorylation of Mitogen-Activated Protein Kinases in Breast Carcinoma using Nanofluidic Proteomics

Urasaki

Fiscus

2018

Sci Rep

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Mitogen-activated protein kinases (MAPKs) play an important role in the regulation of cell proliferation, oncogenic transformation, and drug resistance. This study examined the capability of nanofluidic proteomics to identify aberrations in the MAPK signaling cascade, monitor its drug response, and guide the rational design of intervention strategies. Specifically, the protein post-translational modification (PTM) profiles of MEK1, MEK2, and ERK1/2 were measured in breast carcinoma and breast cancer cell lines. Nanofluidic proteomics revealed hyper-phosphorylation of MAPKs in breast carcinoma and breast cancer cells treated with kinase inhibitors that interfere with cell cycle regulation, such as dinaciclib, an inhibitor of cyclin-dependent kinases, and rigosertib, an inhibitor of polo-like kinase 1. A pMEK1 (Thr286) phosphor-isoform, which serves as a biomarker of cell cycle-regulated negative feedback phosphorylation in breast cancer cells, was detected in breast carcinoma. Inhibition of the MAPK pathway with dabrafenib, a B-Raf inhibitor, or trametinib, a MEK1/2 inhibitor, suppressed both the positively regulated phosphorylation of MAPKs and the negatively regulated phosphorylation of MEK1. Interestingly, the combinations of dabrafenib and rigosertib or trametinib and rigosertib permitted the suppression of positively regulated MAPK phosphorylation together with the promotion of negatively regulated MEK1 phosphorylation. The effectiveness of protein PTM-guided drug combinations for inhibition of the MAPK pathway remains to be experimentally tested. Via protein PTM profiling, nanofluidic proteomics provides a robust means to detect anomalies in the MAPK signaling cascade, monitor its drug response, and guide the possible design of drug combinations for MAPK pathway-focused targeting.

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Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain

Cited by 22 publications

References 79 publications

CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway

CDK5 promotes renal tubulointerstitial fibrosis in diabetic nephropathy via ERK1/2/PPARγ pathway

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Detection of the Cell Cycle-Regulated Negative Feedback Phosphorylation of Mitogen-Activated Protein Kinases in Breast Carcinoma using Nanofluidic Proteomics

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