ERK3/MAPK6 controls IL-8 production and chemotaxis

Bogucka, Katarzyna; Pompaiah, Malvika; Marini, Fédérico; Binder, Harald; Harms, Gregory S.; Klein, Matthias; Michel, Christian; Radsak, Markus P.; Rosigkeit, Sebastian; Grimminger, Peter; Schild, Hansjörg; Rajalingam, Krishnaraj

doi:10.7554/elife.52511

Cited by 29 publications

(44 citation statements)

References 86 publications

(101 reference statements)

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“…In addition, our lab has shown that although ERK3 is not required for the 3D growth of the human gastric epithelium, its expression and rapid protein turnover play an indispensable role in the production and secretion of IL-8, which contributes to chemotaxis and tumor metastasis. In particular, we have shown that loss of ERK3 inhibited the metastasis of MDA-MB231 breast cancer cell line with KRAS G13D mutation [23]. Together, these data warranted investigation of a direct role for ERK3 in mediating KRAS-driven oncogenesis.…”

Section: Introductionmentioning

confidence: 74%

ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis

et al. 2020

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KRAS is one of the most frequently mutated oncogenes, especially in lung cancers. Targeting of KRAS directly or the downstream effector signaling machinery is of prime interest in treating lung cancers. Here, we uncover that ERK3, a ubiquitously expressed atypical MAPK, is required for KRAS-mediated NSCLC tumors. ERK3 is highly expressed in lung cancers, and oncogenic KRAS led to the activation and stabilization of the ERK3 protein. In particular, phosphorylation of serine 189 in the activation motif of ERK3 is significantly increased in lung adenocarcinomas in comparison to adjacent normal controls in patients. Loss of ERK3 prevents the anchorage-independent growth of KRAS G12C-transformed human bronchial epithelial cells. We further find that loss of ERK3 reduces the oncogenic growth of KRAS G12C-driven NSCLC tumors in vivo and that the kinase activity of ERK3 is required for KRAS-driven oncogenesis in vitro. Our results demonstrate an obligatory role for ERK3 in NSCLC tumor progression and suggest that ERK3 kinase inhibitors can be pursued for treating KRAS G12C-driven tumors.

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Section: Introductionmentioning

confidence: 74%

ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis

et al. 2020

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“…ERK3 seems also to play a key role in IL-8 production in a kinase-independent manner through its interaction with c-Jun. ERK3 controls the DNA-binding activity of the activating protein 1 (AP-1) transcription factor, which is critically required for the activation of several cytokines, including IL-8, by regulating c-Jun nuclear abundance [227]. These data indicate that ERK3 plays a central role in the regulation of adipocyte function.…”

Section: The Atypical Mapksmentioning

confidence: 99%

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Kassouf

Sumara

2020

Biomolecules

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The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.

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“…Taken together, these studies suggest that ERK3 plays either tumor-promoting or tumorsuppressive roles depending on specific cancer type. Several different molecular mechanisms underlying the cancer-promoting role of ERK3 have been proposed, such as activating SRC-3/PEA3-mediated MMP gene transcription in lung cancers and breast cancer [3] and c-Jun/AP1mediated IL-8 expression in colon cancer cells and MDA-MB231 breast cancer cells [9]. In addition, ERK3 promotes cancer cell growth and invasion in both kinase-dependent [3,6] and kinase-independent mechanisms [5,9].…”

Section: Introductionmentioning

confidence: 99%

“…Several different molecular mechanisms underlying the cancer-promoting role of ERK3 have been proposed, such as activating SRC-3/PEA3-mediated MMP gene transcription in lung cancers and breast cancer [3] and c-Jun/AP1mediated IL-8 expression in colon cancer cells and MDA-MB231 breast cancer cells [9]. In addition, ERK3 promotes cancer cell growth and invasion in both kinase-dependent [3,6] and kinase-independent mechanisms [5,9]. On the contrary, it is largely unclear how ERK3 inhibits the growth and invasiveness of melanoma and hepatocarcinoma cells.…”

Section: Introductionmentioning

confidence: 99%

Conditional ERK3 overexpression cooperates with PTEN deletion to promote lung adenocarcinoma formation in mice

Vallabhaneni

Liu

Morel

et al. 2021

Preprint

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Extracellular signal-regulated kinase 3 (ERK3), also known as MAPK6, belongs to the atypical mitogen-activated protein kinases (MAPKs) subfamily. In comparison with the well-studied classical MAPKs ERK1 and ERK2, much less is known about the cellular and molecular actions of ERK3. Accumulating studies have revealed the upregulation of ERK3 expression and suggested an important role for ERK3 in promoting tumor cell growth and invasion in multiple cancers, in particular lung cancer. However, it is unknown whether or not ERK3 plays a role in spontaneous tumorigenesis. To determine the role of ERK3 in lung tumorigenesis, we created a conditional ERK3 transgenic mouse line in which ERK3 transgene expression is controlled by Cre recombinase. By crossing with a lung tissue-specific CCSP-iCre mouse line, we have found that conditional ERK3 overexpression cooperates with PTEN deletion to induce the formation of lung adenocarcinomas (LUADs). Mechanistically, ERK3 overexpression stimulates activating phosphorylations of ERBB3 and ERBB2 by upregulating SP1-mediated gene transcription of NRG1, a potent ligand for ERBB3/ERBB2. To our knowledge, our study is the first revealing a bona fide tumor-promoting role for ERK3 using genetically engineered mouse models. Together with previous findings showing important roles of ERK3 in cultured cells and in xenograft lung tumor model, our findings corroborate that ERK3 acts as an oncoprotein in promoting LUAD development and progression.

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ERK3/MAPK6 controls IL-8 production and chemotaxis

Cited by 29 publications

References 86 publications

ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis

ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Conditional ERK3 overexpression cooperates with PTEN deletion to promote lung adenocarcinoma formation in mice

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