The Non-Classical MAP Kinase ERK3 Controls T Cell Activation

Marquis, Miriam; Boulet, Salix; Mathien, Simon; Rousseau, Justine; Thébault, Paméla; Daudelin, Jean-François; Rooney, Julie; Turgeon, Benjamin; Beauchamp, Claudine; Meloche, Sylvain; Labrecque, Nathalie

doi:10.1371/journal.pone.0086681

Cited by 20 publications

(24 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17 We have previously shown that ERK3 expression is induced via ERK1/2 in mature T cells following TCR stimulation. 18 We also reported that Erk3 is transcribed during thymic T-cell differentiation with the highest level of expression in DN and DP thymocytes. 19 Inactivation of the Erk3 gene leads to a reduction in thymic cell number that is caused by a twofold reduction in DP thymocyte number because of their reduced survival during the rearrangement of the TCR-a chain.…”

Section: Introductionmentioning

confidence: 76%

“…We have previously shown that ERK3 expression is induced by the classical MAPK ERK1/2 in mature T cells . The fact that ERK3 is already expressed in DP thymocytes, even within the DP thymocytes that have not undergone positive selection, suggests that its expression is induced by pre‐TCR signalling, which activates ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that ERK3 expression is induced via ERK1/2 in mature T cells following TCR stimulation . We also reported that Erk3 is transcribed during thymic T‐cell differentiation with the highest level of expression in DN and DP thymocytes .…”

Section: Introductionmentioning

confidence: 87%

“…Fluorescein digalactopyranoside (FDG; Sigma-Aldrich, Oakville, ON, Canada) staining was performed as previously described. 18 Briefly, cells were surface stained and re-suspended in PBS. Warmed FDG (7Á5 mM) was added to cells while gently vortexing.…”

Section: B-galactosidase Stainingmentioning

confidence: 99%

See 3 more Smart Citations

The atypical MAPK ERK3 controls positive selection of thymocytes

et al. 2015

Self Cite

View full text Add to dashboard Cite

Extracellular signal-regulated kinase 3 (ERK3)is an atypical member of the mitogen-activated protein kinase (MAPK) family. We have previously shown that ERK3 is expressed during thymocyte differentiation and that its expression is induced in mature peripheral T cells following activation of ERK1/2 by T-cell receptor (TCR) signalling. Herein, we have investigated whether ERK3 expression is required for proper T-cell selection. Using a knock-in mouse model in which the coding sequence of ERK3 is replaced by the gene encoding for the b-galactosidase reporter, we show that ERK3 is expressed by double-positive (DP) thymocytes undergoing positive selection. In ERK3-deficient mice with a polyclonal TCR repertoire, we observe a decrease in positive selection. This reduction in positive selection was also observed when ERK3-deficient mice were backcrossed to class I-and class II-restricted TCR transgenic mice. Furthermore, the response of DP thymo-cytes to in vitro TCR stimulation was strongly reduced in ERK3-deficient mice. Together, these results show that ERK3 expression following TCR signalling is critical for proper thymic positive selection.

show abstract

Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: B-galactosidase Stainingmentioning

confidence: 99%

See 2 more Smart Citations

The atypical MAPK ERK3 controls positive selection of thymocytes

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…While ERK4 knockout mice appeared normal, ERK3 knockout mice were not viable, displaying retarded intrauterine growth and pulmonary hypoplasia leading to acute perinatal respiratory failure (17). Furthermore, T-cell development, selection, and activation was impaired only in ERK3, but not in ERK4, knockout mice (19)(20)(21). The lack of phenocopy between both knockouts suggested distinct and nonredundant functions of the ERK3/ MK5 and ERK4/MK5 signaling complexes.…”

mentioning

confidence: 99%

Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3

Ronkina

Schuster-Gossler

Hansmann

et al. 2019

Molecular and Cellular Biology

View full text Add to dashboard Cite

Mitogen-activated protein kinase 6/extracellular signal-regulated kinase 3 (MAPK6/ERK3) is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a lacZ insertion in exon 2 due to pulmonary dysfunction and by defects in function, activation, and positive selection of T cells. To study the role of ERK3 in vivo, we generated mice carrying a conditional Erk3 allele with exon 3 flanked by loxP sites. Loss of ERK3 protein was validated after deletion of Erk3 in the female germ line using zona pellucida 3 (Zp3)-cre and a clear reduction of the protein kinase MK5 is detected, providing the first evidence for the existence of the ERK3/MK5 signaling complex in vivo. In contrast to the previously reported Erk3 knockout phenotype, these mice are viable and fertile and do not display pulmonary hypoplasia, acute respiratory failure, abnormal T-cell development, reduction of thymocyte numbers, or altered T-cell selection. Hence, ERK3 is dispensable for pulmonary and T-cell functions. The perinatal lethality and lung and T-cell defects of the previous ERK3 knockout mice are likely due to ERK3-unrelated effects of the inserted lacZ-neomycin resistance cassette. The knockout mouse of the closely related atypical MAPK ERK4/MAPK4 is also normal, suggesting redundant functions of both protein kinases. KEYWORDS MAPKAPK5/MK5, gene deletion, mitogen-activated protein kinases, protein kinase M itogen-activated protein kinase (MAPK) cascades are conserved eukaryote signaling modules where the downstream effector kinases regulate cell proliferation, differentiation, and cell death by phosphorylation of protein substrates. MAPKs are also regulators in many physiological processes, including development and immune response. Multiple MAPKs were described in mammalian cells, which can be divided in five groups, the classical mitogen-responsive MAPKs (extracellular signal-regulated kinase 1 [ERK1] and ERK2), the stress-activated c-Jun N-terminal kinases (JNK1 to -3), p38 MAPK (␣, ␤, ␥, and ␦), the big MAPK ERK5, and the atypical MAPKs ERK3, ERK4, and ERK7 (1). MAPK activity is classically regulated by dual phosphorylation on a TXY motif in the activation loop of the kinase by MAPK kinases.ERK3/MAPK6/p97 MAPK and the closely related ERK4/MAPK4/p63 MAPK are the only two MAPKs carrying long C-terminal extensions and lacking the dual TXY phosphorylation motif in the activation loop (2-4). Instead of the canonical dual-phosphorylation motif, ERK3 and ERK4 contain only a single phospho-acceptor serine (SEG motif) in the on July 7, 2020 by guest http://mcb.asm.org/ Downloaded from ERK3 and ERK4 were explained by specific nonredundant functions of these closely related atypical MAPKs (18), which contrasts with the similarities in structure and molecular interactions of both kinases (5,33,34). The viability and fertility of mice with deletion of exon 3 of Erk3 is much more similar to the phenotype of the conventional ERK4 knockout. Hence, one cannot exclude a redundant func...

show abstract

A regulatory BMI1/let‐7i/ERK3 pathway controls the motility of head and neck cancer cells

et al. 2017

View full text Add to dashboard Cite

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA (miRNA) let-7i which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. Taken together, our study revealed a molecular pathway consisting of BMI1, miRNA let-7i and ERK3 which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression.

show abstract

The Non-Classical MAP Kinase ERK3 Controls T Cell Activation

Cited by 20 publications

References 46 publications

The atypical MAPK ERK3 controls positive selection of thymocytes

The atypical MAPK ERK3 controls positive selection of thymocytes

Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3

A regulatory BMI1/let‐7i/ERK3 pathway controls the motility of head and neck cancer cells

Contact Info

Product

Resources

About