The protein kinase MAP3K19 phosphorylates MAP2Ks and thereby activates ERK and JNK kinases and increases viability of KRAS-mutant lung cancer cells.

Identifying additional mitogen-activated protein kinase (MAPK) pathway regulators is invaluable in aiding our understanding of the complex signaling networks that regulate cellular processes, including cell proliferation and survival. Here, using in vitro kinase assays and by expressing WT or kinase-dead MAPK kinase kinase 19 (MAP3K19) in the HEK293T cell line and assessing activation of the extracellular signal-regulated kinase (ERK) and JUN N-terminal kinase (JNK) signaling pathways, we defined MAP3K19 as a novel regulator of MAPK signaling. We also observed that overexpression of WT MAP3K19 activates both the ERK and JNK pathways in a panel of cancer cell lines. Furthermore, MAP3K19 sustained ERK pathway activation in the presence of inhibitors targeting the RAF proto-oncogene Ser/Thr protein kinase (RAF) and MAPK/ERK kinase, indicating that MAP3K19 activates ERK via a RAF-independent mechanism. Findings from in vitro and in-cell kinase assays demonstrate that MAP3K19 is a kinase that directly phosphorylates both MAPK/ERK kinase (MEK) and MAPK kinase 7 (MKK7). Results from an short-hairpin RNA screen indicated that MAP3K19 is essential for maintaining survival in KRAS-mutant cancers; therefore, we depleted or inhibited MAP3K19 in KRAS-mutant cancer cell lines and observed that this reduces viability and decreases ERK and JNK pathway activation. In summary, our results reveal that MAP3K19 directly activates the ERK and JNK cascades and highlight a role for this kinase in maintaining survival of KRAS-mutant lung cancer cells.

MAP3K19 Promotes the Progression of Tuberculosis-Induced Pulmonary Fibrosis Through Activation of the TGF-ß/Smad2 Signaling Pathway.

Tuberculosis-induced pulmonary fibrosis (PF) is a chronic, irreversible interstitial lung disease, which severely affects lung ventilation and air exchange, leading to respiratory distress, impaired lung function, and ultimately death. As previously reported, epithelial-mesenchymal transition (EMT) and fibrosis in type II alveolar epithelial cells (AEC II) are two critical processes that contributes to the initiation and progression of tuberculosis-related PF, but the underlying pathological mechanisms remain unclear. In this study, through performing Real-Time quantitative PCR (RT-qPCR), Western blot, immunohistochemistry, and immunofluorescence staining assay, we confirmed that the expression levels of EMT and fibrosis-related biomarkers were significantly increased in lung tissues with tuberculosis-associated PF in vivo and Mycobacterium bovis Bacillus Calmette-Guérin (BCG) strain-infected AEC II cells in vitro. Besides, we noticed that the mitogen-activated protein kinase 19 (MAP3K19) was aberrantly overexpressed in PF models, and silencing of MAP3K19 significantly reduced the expression levels of fibronectin, collagen type I, and alpha-smooth muscle actin to decrease fibrosis, and upregulated E-cadherin and downregulated vimentin to suppress EMT in BCG-treated AEC II cells. Then, we uncovered the underlying mechanisms and found that BCG synergized with MAP3K19 to activate the pro-inflammatory transforming growth factor-beta (TGF-ß)/Smad2 signal pathway in AEC II cells, and BCG-induced EMT process and fibrosis in AEC II cells were all abrogated by co-treating cells with TGF-ß/Smad2 signal pathway inhibitor LY2109761. In summary, our results uncovered the underlying mechanisms by which the MAP3K19/TGF-ß/Smad2 signaling pathway regulated EMT and fibrotic phenotypes of AEC II cells to facilitate the development of tuberculosis-associated PF, and these findings will provide new ideas and biomarkers to ameliorate tuberculosis-induced PF in clinic.

Expression of Novel Kinase MAP3K19 in Various Cancers and Survival Correlations.

Mitogen Activated Protein (MAP) kinases are a category of serine/threonine kinases that have been demonstrated to regulate intracellular events including stress responses, developmental processes, and cancer progression Although many MAP kinases have been extensively studied in various disease processes, MAP3K19 is an understudied kinase whose activities have been linked to lung disease and fibroblast development. In this manuscript, we use bioinformatics databases starBase, GEPIA, and KMPlotter, to establish baseline expressions of MAP3K19 in different tissue types and its correlation with patient survival in different cancers.