Protein Kinase Signaling Axis Research Articles

To explore the mechanism of Yigong San anti-gastric cancer and immune regulation.

Yigong San (YGS) is a representative prescription for the treatment of digestive disorders, which has been used in clinic for more than 1000 years. However, the mechanism of its anti-gastric cancer and regulate immunity are still remains unclear. To explore the mechanism of YGS anti-gastric cancer and immune regulation. Firstly, collect the active ingredients and targets of YGS, and the differentially expressed genes of gastric cancer. Secondly, constructed a protein-protein interaction network between the targets of drugs and diseases, and screened hub genes. Then the clinical relevance, mutation and repair, tumor microenvironment and drug sensitivity of the hub gene were analyzed. Finally, molecular docking was used to verify the binding ability of YGS active ingredient and hub genes. Firstly, obtained 55 common targets of gastric cancer and YGS. The Kyoto Encyclopedia of Genes and Genomes screened the microtubule-associated protein kinase signaling axis as the key pathway and IL6, EGFR, MMP2, MMP9 and TGFB1 as the hub genes. The 5 hub genes were involved in gastric carcinogenesis, staging, typing and prognosis, and their mutations promote gastric cancer progression. Finally, molecular docking results confirmed that the components of YGS can effectively bind to therapeutic targets. YGS has the effect of anti-gastric cancer and immune regulation.

The effects of air pollutants exposure on the transmission and severity of invasive infection caused by an opportunistic pathogen Streptococcus pyogenes

Currently, urbanization is associated with an increase in air pollutants that contribute to invasive pathogen infections by altering the host's innate immunity and antimicrobial resistance capability. Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is a gram-positive opportunistic pathogen that causes a wide range of diseases, especially in children and immunosuppressed individuals. Diesel exhaust particle (DEP), a significant constituent of particulate matter (PM), are considered a prominent risk factor for respiratory illness and circulatory diseases worldwide. Several clinical and epidemiological studies have identified a close association between PM and the prevalence of viral and bacterial infections. This study investigated the role of DEP exposure in increasing pulmonary and blood bacterial counts and mortality during GAS M1 strain infection in mice. Thus, we characterized the upregulation of reactive oxygen species production and disruption of tight junctions in the A549 lung epithelial cell line due to DEP exposure, leading to the upregulation of GAS adhesion and invasion. Furthermore, DEP exposure altered the leukocyte components of infiltrated cells in bronchoalveolar lavage fluid, as determined by Diff-Quik staining. The results highlighted the DEP-related macrophage dysfunction, neutrophil impairment, and imbalance in pro-inflammatory cytokine production via the toll-like receptor 4/mitogen-activated protein kinase signaling axis. Notably, the tolerance of the GAS biofilms toward potent antibiotics and bacterial resistance against environmental stresses was also significantly enhanced by DEP. This study aimed to provide a better understanding of the physiological and molecular interactions between exposure to invasive air pollutants and susceptibility to invasive GAS infections.

Calcium-Sensing Receptor Regulates Epidermal Intracellular Ca2+ Signaling and Re-Epithelialization after Wounding

Extracellular Ca2+ (Ca2+o) is a crucial regulator of epidermal homeostasis and its receptor, the Ca2+-sensing receptor (CaSR), conveys the Ca2+o signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca2+ (Ca2+i) and E-cadherin-mediated signaling. Here, we took genetic loss-of-function approaches to delineate the functions of CaSR in wound re-epithelialization. Cutaneous injury triggered a robust CaSR expression and a surge of Ca2+i in epidermis. CaSR and E-cadherin were co-expressed at the cell-cell membrane between migratory keratinocytes in the nascent epithelial tongues. Blocking the expression of CaSR or E-cadherin in cultured keratinocytes markedly inhibited the wound-induced Ca2+i propagation and their ability to migrate collectively. Depleting CaSR also suppressed keratinocyte proliferation by downregulating the E-cadherin/epidermal growth factor receptor/mitogen-activated protein kinase signaling axis. Blunted epidermal Ca2+i response to wounding and retarded wound healing were observed in the keratinocyte-specific CaSR knockout (EpidCasr-/-) mice, whose shortened neo-epithelia exhibited declined E-cadherin expression and diminished keratinocyte proliferation and differentiation. Conversely, stimulating endogenous CaSR with calcimimetic NPS-R568 accelerated wound re-epithelialization through enhancing the epidermal Ca2+i signals and E-cadherin membrane expression. These findings demonstrated a critical role for the CaSR in epidermal regeneration and its therapeutic potential for improving skin wound repair.

Liver kinase B1/adenosine monophosphate-activated protein kinase signaling axis induces p21/WAF1 expression in a p53-dependent manner.

Liver kinase B1 (LKB1) encodes a serine/threonine kinase and functions as a tumor suppressor. LKB1 loss-of-function somatic mutations are frequently observed in sporadic types of cancer, particularly in lung cancer. Ectopic LKB1 induces growth arrest by upregulating p21/cyclin dependent kinase inhibitor 1A (WAF1) in LKB1 deficient cervical and melanoma cancer cell lines. However, the underlying molecular mechanism remains to be elucidated. The present study built upon previous observations by confirming that the ectopic expression level of LKB1 significantly reduced colony formation of LKB1-deficient lung cancer cells. Mechanistically, the present study demonstrated that LKB1 overexpression significantly induced p21/WAF1 expression in a kinase-dependent manner. Conversely, LKB1 stable knockdown resulted in a decrease in p21/WAF1 expression level in colon cancer cells. In addition, it was revealed that pharmacological activation of adenosine monophosphate protein kinase (AMPK) by 2-deoxyglucose significantly increased the p21/WAF1 expression level, suggesting that AMPK acts downstream of LKB1 to induce p21/WAF1 expression. Furthermore, the present study demonstrated that functional p53 was required for p21/WAF1 induction by LKB1. Phosphorylation of p53-Ser15 was increased by ectopic LKB1 or AMPK activation. Taken together, these results suggested that LKB1 acts via its substrate, AMPK, to upregulate p21/WAF1 expression in a p53-dependent manner. Therefore, the present study identified an important signaling axis, providing novel molecular insights into the tumor suppressor role of LKB1.

Solute carrier family 35 member F2 is indispensable for papillary thyroid carcinoma progression through activation of transforming growth factor-β type I receptor/apoptosis signal-regulating kinase 1/mitogen-activated protein kinase signaling axis.

Solute carrier family members control essential physiological functions and are tightly linked to human diseases. Solute carrier family 35 member F2 (SLC35F2) is aberrantly activated in several malignancies. However, the biological function and molecular mechanism of SLC35F2 in papillary thyroid carcinoma (PTC) are yet to be fully explored. Here, we showed that SLC35F2 was prominently upregulated in PTC tissues at both protein and mRNA expression level compared with matched adjacent normal tissues. Besides, the high expression of SLC35F2 was significantly associated with lymph node metastasis in patients with PTC. CRISPR/Cas9‐mediated knockout of SLC35F2 attenuated the tumorigenic properties of PTC, including cell proliferation, migration and invasion and induced G1 phase arrest. In contrast, ectopic expression of SLC35F2 brought about aggressive malignant phenotypes of PTC cells. Moreover, SLC35F2 expedited the proliferation and migration of PTC cells by targeting transforming growth factor‐β type I receptor (TGFBR1) and phosphorylation of apoptosis signal‐regulating kinase 1 (p‐ASK‐1), thereby activating the mitogen‐activated protein kinase signaling pathway. The malignant behaviors induced by overexpression of SLC35F2 could be abrogated by silencing of TGFBR1 using a specific inhibitor. We conducted the first study on SLC35F2 in thyroid cancer with the aim of elucidating the functional significance and molecular mechanism of SLC35F2. Our findings suggest that SLC35F2 exerts its oncogenic effect on PTC progression through the mitogen‐activated protein kinase pathway, with dependence on activation of TGFBR‐1 and apoptosis signal‐regulating kinase 1.

Astragaloside IV inhibits isoprenaline‑induced cardiac fibrosis by targeting the reactive oxygen species/mitogen‑activated protein kinase signaling axis.

Cardiac fibrosis is considered an important pathological mechanism in the progression of cardiac remodeling and heart failure. Astragaloside IV (AsIV) is a major active ingredient in Astragalusmembranaceus. In a preliminary experiment, it was demonstrated that this naturally occurring substance exhibited cardioprotective effects via preventing cardiomyocyte hypertrophy and apoptosis. The present study aimed to investigate the effects of AsIV on β‑adrenergic receptor (β‑AR)‑mediated cardiac fibrosis, and the associated mechanism. Cell Counting Kit‑8 (CCK‑8) assay was used to examine the proliferation of rat cardiac fibroblast (CF) cultures. Collagen I secretion was detected by ELISA. Dihydroethidium was used to determine intracellular ROS levels. Western blotting was used to examine the expression level of total and phosphorylated mitogen‑activated protein kinases (MAPKs). In the present study, the effects of AsIV on β‑adrenergic receptor (β‑AR) ‑mediated cardiac fibrosis were investigated, and the associated mechanism was revealed. Isoprenaline (ISO) is a selective β‑AR agonist, and treatment with AsIV significantly inhibited (ISO)‑triggered cardiac fibroblast proliferation and type I collagen synthesis. In addition, ISO resulted in a significant elevation of reactive oxygen species (ROS) levels and phosphorylation of the three profibrotic MAPKs, namely extracellular signal‑regulated kinase, p38MAPK and c‑Jun N‑terminal kinase. AsIV effectively reversed the aforementioned ISO‑induced alterations. In addition, N‑acetylcysteine, a typical ROS scavenger, mimicked the inhibitory effects of AsIV on MAPK activation. The present study demonstrated that AsIV may inhibit ISO‑induced cardiac fibrosis by suppressing ROS‑mediated MAPK activation.

Emerging modes of PINK1 signaling: another task for MARK2.

PTEN-induced kinase 1 (PINK1) acts at multiple levels to promote mitochondrial health, including regulatory influence on ATP-synthesis, protein quality control, apoptosis, mitochondrial transport, and destiny. PINK1 mutations are linked to Parkinson disease (PD) and mostly result in loss of kinase activity. But the molecular events responsible for neuronal death as well as the physiological targets and regulators of PINK1 are still a matter of debate. This review highlights the recent progress evolving the cellular functions of the cytosolic pool of PINK1 in mitochondrial trafficking and neuronal differentiation. Regulation of PINK1 signaling occurs by mitochondrial processing to truncated forms of PINK1, differentially targeted to several subcellular compartments. The first identified activating kinase of PINK1 is MAP/microtubule affinity regulating kinase 2 (MARK2), which phosphorylates T313, a frequent mutation site linked to PD. Kinases of the MARK2 family perform diverse functions in neuronal polarity, transport, migration, and neurodegeneration such as Alzheimer disease (AD). This new protein kinase signaling axis might provide a link between neurodegenerative processes in AD and PD diseases and opens novel possibilities in targeting pathological signaling processes.

Partnering Up for Cardiac Hypertrophy

See related article, pages 1089–1097 The heart must adapt its mechanical activity to the prevailing hemodynamic demands. When an increased demand is brought about by sustained stimuli such as growth and development, pressure overload, or mutations in sarcomeric proteins, the heart will typically undergo an increase in size caused by myocyte hypertrophy. Underlying this hypertrophic response is the coordinated interaction of distinct signaling modules capable of transmitting and executing modifications in gene expression that lead to alterations in myocyte physiology and long-term cardiac adaptation.1 One of the more intriguing characteristics of the hypertrophic response is that despite the ability of a wide variety of both pathologic and physiologic stimuli to induce cardiac hypertrophy, distinct cytoplasmic signaling cascades that initiate changes in gene expression converge on a common set of nuclear factors. These factors will then transactivate or repress cardiac genes through cis-regulatory elements. One of these transcription factors, myocardin, that appears to be capable of relaying hypertrophic signals to the genome is the subject of the studies performed by Xing et al2 detailed below. An important hypertrophic transcriptional regulator is the zinc finger–containing transcription factor, GATA4. GATA4 is widely expressed and has been identified as a pivotal regulator of developmental and stress-induced changes in cardiac gene expression.3,4 GATA4 has been shown to activate numerous genes in the heart by divergent signaling molecules including protein kinase C, calcineurin, and members of the mitogen-activated protein kinase signaling axis.1 Although GATA4-null embryos arrest before birth,5 a point mutation in GATA4 results in …