MEK1 and MEK2 isoforms regulate distinct functions in pancreatic cancer cells

Proper regulation of apoptotic cell death is crucial for normal development and homeostasis in multicellular organisms and is achieved by the balance between pro‐apoptotic processes, such as caspase activation, and pro‐survival signaling, such as extracellular signal‐regulated kinase (ERK) activation. However, the functional interplay between these opposing signaling pathways remains incompletely understood. Here, we identified MAPK/ERK kinase (MEK) 1, a central component of the ERK pathway, as a specific substrate for the executioner caspase‐3. During apoptosis, MEK1 is cleaved at an evolutionarily conserved Asp282 residue in the kinase domain, thereby losing its catalytic activity. Gene knockout experiments showed that MEK1 cleavage was mediated by caspase‐3, but not by the other executioner caspases, caspase‐6 or ‐7. Following exposure of cells to osmotic stress, elevated ERK activity gradually decreased, and this was accompanied by increased cleavage of MEK1. In contrast, the expression of a caspase‐uncleavable MEK1(D282N) mutant in cells maintained stress‐induced ERK activity and thereby attenuated apoptotic cell death. Thus, caspase‐3‐mediated, proteolytic inhibition of MEK1 sensitizes cells to apoptosis by suppressing pro‐survival ERK signaling. Furthermore, we found that a RASopathy‐associated MEK1(Y130C) mutation prevented this caspase‐3‐mediated proteolytic inactivation of MEK1 and efficiently protected cells from stress‐induced apoptosis. Our data reveal the functional crosstalk between ERK‐mediated cell survival and caspase‐mediated cell death pathways and suggest that its dysregulation by a disease‐associated MEK1 mutation is at least partly involved in the pathophysiology of congenital RASopathies.

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Caspase 3‐specific cleavage of MEK1 suppresses ERK signaling and sensitizes cells to stress‐induced apoptosis

Moriizumi

Kubota

Tsuchiya

et al. 2023

FEBS Open Bio

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Quantitative secretomic analysis of pancreatic cancer cells in serum-containing conditioned medium

Liu

Weng

Sui

et al. 2016

Sci Rep

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Pancreatic cancer is a highly metastatic and chemo-resistant disease. Secreted proteins involved in cell-cell interactions play an important role in changing the tumor microenvironment. Previous studies generally focus on the secretome of cancer cell line from serum-free media, due to the serious interference of fetal bovine serum (FBS). However, serum-starvation may alter expression patterns of secreted proteins. Hence, efforts to decrease the interference of serum in proteomic analysis of serum-containing media have been hampered to quantitatively measure the tumor secretion levels. Recently, the metabolic labeling, protein equalization, protein fractionation and filter-aided sample preparation (FASP) strategy (MLEFF) has been successfully used to avoid the disturbance of serum on secretome analysis. Here, this efficient method was applied for comparative secretome analysis of two hamster pancreatic cancer cells with differentially metastatic potentials, enabling the observation of 161 differentially expressed proteins, including 106 proteins that had been previously reported and detected in plasma. By integrated analysis of our data and publicly available bioinformatics resources, we found that a combination panel consisting of CDH3, PLAU, and LFNG might improve the prognosis of overall pancreatic cancer survival. These secreted proteins may serve as a potential therapeutic targets for pancreatic cancer metastasis.

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Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway

Wang

Chen

Liao

et al. 2016

J Virol

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The mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK1/2/ERK1/2) cascade is involved in the replication of several members of the Flaviviridae family, including hepatitis C virus and dengue virus. The effects of the cascade on the replication of classical swine fever virus (CSFV), a fatal pestivirus of pigs, remain unknown. In this study, MEK2 was identified as a novel binding partner of the E2 protein of CSFV using yeast two-hybrid screening. The E2-MEK2 interaction was confirmed by glutathione S-transferase pulldown, coimmunoprecipitation, and laser confocal microscopy assays. The C termini of E2 (amino acids [aa] 890 to 1053) and MEK2 (aa 266 to 400) were mapped to be crucial for the interaction. Overexpression of MEK2 significantly promoted the replication of CSFV, whereas knockdown of MEK2 by lentivirus-mediated small hairpin RNAs dramatically inhibited CSFV replication. In addition, CSFV infection induced a biphasic activation of ERK1/2, the downstream signaling molecules of MEK2. Furthermore, the replication of CSFV was markedly inhibited in PK-15 cells treated with U0126, a specific inhibitor for MEK1/2/ERK1/2, whereas MEK2 did not affect CSFV replication after blocking the interferon-induced Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway by ruxolitinib, a JAK-STAT-specific inhibitor. Taken together, our results indicate that MEK2 positively regulates the replication of CSFV through inhibiting the JAK-STAT signaling pathway.IMPORTANCE Mitogen-activated protein kinase kinase 2 (MEK2) is a kinase that operates immediately upstream of extracellular regulated kinase 1/2 (ERK1/2) and links to Raf and ERK via phosphorylation. Currently, little is known about the role of MEK2 in the replication of classical swine fever virus (CSFV), a devastating porcine pestivirus. Here, we investigated the roles of MEK2 and the MEK2/ERK1/2 cascade in the growth of CSFV for the first time. We show that MEK2 positively regulates CSFV replication. Notably, we demonstrate that MEK2 promotes CSFV replication through inhibiting the interferon-induced JAK-STAT signaling pathway, a key antiviral pathway involved in innate immunity. Our work reveals a novel role of MEK2 in CSFV infection and sheds light on the molecular basis by which pestiviruses interact with the host cell.

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MEK1 and MEK2 isoforms regulate distinct functions in pancreatic cancer cells

Cited by 9 publications

References 16 publications

Caspase 3‐specific cleavage of MEK1 suppresses ERK signaling and sensitizes cells to stress‐induced apoptosis

Caspase 3‐specific cleavage of MEK1 suppresses ERK signaling and sensitizes cells to stress‐induced apoptosis

Quantitative secretomic analysis of pancreatic cancer cells in serum-containing conditioned medium

Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway

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