ERK3 is a ubiquitously expressed member of the atypical mitogen activated protein kinases (MAPKs) and the physiological significance of its short half-life remains unclear. By employing gastrointestinal 3D organoids, we detect that ERK3 protein levels steadily decrease during epithelial differentiation. ERK3 is not required for 3D growth of human gastric epithelium. However, ERK3 is stabilized and activated in tumorigenic cells, but deteriorates over time in primary cells in response to lipopolysaccharide (LPS). ERK3 is necessary for production of several cellular factors including interleukin-8 (IL-8), in both, normal and tumorigenic cells. Particularly, ERK3 is critical for AP-1 signaling through its interaction and regulation of c-Jun protein. The secretome of ERK3-deficient cells is defective in chemotaxis of neutrophils and monocytes both in vitro and in vivo. Further, knockdown of ERK3 reduces metastatic potential of invasive breast cancer cells. We unveil an ERK3-mediated regulation of IL-8 and epithelial secretome for chemotaxis.

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.

Kinases still remain the most favorable members of the druggable genome, and there are an increasing number of kinase inhibitors approved by the FDA to treat a variety of cancers. Here, we summarize recent developments in targeting kinases and pseudokinases with some examples. Targeting the cell cycle machinery garnered significant clinical success, however, a large section of the kinome remains understudied. We also review recent developments in the understanding of pseudokinases and discuss approaches on how to effectively target in cancer.

Despite clear evidence of inadequate angiogenesis in ischemic diabetic foot syndrome (DFS) pathogenesis, angiogenic factor level changes in patients with ischemic DFS remain inconsistent. This study aimed to assess circulating angiogenic factors concerning ischemic DFS advancement and describe their relationships with patients’ clinical characteristics, microvascular parameters, and diabetic control. The study included 41 patients with ischemic DFS (67.3 (8.84) years; 82.9% males). Angiogenic processes were assessed by identifying circulating concentrations of five pro- and two anti-angiogenic factors. We found that penetrating ulcers were related to a significantly higher FGF-2 level (8.86 (5.29) vs. 5.23 (4.17) pg/mL, p = 0.02). Moreover, plasma FGF-2 showed a significant correlation with the SINBAD score (r = 0.32, p = 0.04), platelet count (r = 0.43, p < 0.01), white cell count (r = 0.42, p < 0.01), and age (r = −0.35, p = 0.03). We did not observe any significant linear relationship between the studied biomarkers and microcirculatory parameters, nor for glycemic control. In a univariate analysis using logistic regression, an increase in plasma FGF-2 was tied to greater odds of high-grade ulcers (OR 1.16; 95% CI 1.02–1.38, p = 0.043). This suggests that circulating FGF-2 may serve as a potential biomarker for predicting DFU advancement and progression. It is necessary to conduct further studies with follow-up observations to confirm this hypothesis.

Introduction:The role of inflammation in the pathogenesis of atherosclerotic diseases is strongly suggested. There are multiple studies indicating the possibility of a pathophysiological connection between atherosclerotic changes and leukotrienes (LTs) -the products of arachidonic acid metabolism. The goal of this systematic review, performed in line with the PRISMA statement, was to investigate the potential role of LTs in the pathophysiology of atherosclerotic cardiovascular diseases (CVD). Material and methods: The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched to identify the potentially eligible studies. Publications that contained information on any type of LTs identified in blood or urine were included in the review. A database search identified 2082 records. Reliable LTs identification in patients with CVD was used in 30 publications. Results: Stable and acute forms of coronary artery disease are characterized by the overproduction of different types of LTs. The level of LTB 4 and LTC 4 in the blood is elevated in patients with cerebral ischemia. Patients with acute and chronic peripheral artery disease have elevated levels of LTE 4 in urine. Conclusions: The findings of this systematic review show that there is a clear tendency to indicate the association of cardiovascular atherosclerotic diseases with increased production of LTs. This dependency detailed characteristic remains unclear and the question on the impact of elevated leukotrienes on clinical atherosclerotic disease manifestations is still open.