Necroptosis is one of the regulated cell death, which involves receptor interacting protein kinase (RIPK) 1/RIPK3/mixed lineage kinase domain like protein (MLKL) signaling pathway. Among them, MLKL is the final execution of necroptosis. The formation of RIPK1/RIPK3/MLKL necrosome induces the phosphorylated MLKL, and the activated MLKL penetrates into the membrane bilayer to form membrane pores, which damages the integrity of the membrane and leads to cell death. In addition to participating in necroptosis, MLKL is also closely related to other cell death, such as NETosis, pyroptosis, and autophagy. Therefore, MLKL is involved in the pathological processes of various diseases related to abnormal cell death pathways (such as cardiovascular diseases, neurodegenerative diseases and cancer), and may be a therapeutic target of multiple diseases. Understanding the role of MLKL in different cell death can lay a foundation for seeking various MLKL-related disease targets, and also guide the development and application of MLKL inhibitors.
Protein Kinases/metabolism* ; Necroptosis/physiology* ; Receptor-Interacting Protein Serine-Threonine Kinases ; Signal Transduction ; Pyroptosis ; Apoptosis

Serum and glucocorticoid-regulated kinase 1 (SGK1) plays an important role in the physiological processes of hormone release, neuronal excitation and cell proliferation. SGK1 also participates in the pathophysiological processes of inflammation and apoptosis in the central nervous system (CNS). Increasing evidence demonstrates that SGK1 may serve as a target of the intervention of neurodegenerative diseases. In this article, we summarize the recent progress on the role and molecular mechanisms of SGK1 in the regulation of the function of the CNS. We also discuss the potential of newly discovered SGK1 inhibitors in the treatment of CNS diseases.
Humans ; Cell Proliferation ; Central Nervous System Diseases/drug therapy* ; Inflammation ; Protein Serine-Threonine Kinases/physiology*

Animals ; Cell Differentiation ; Epithelium ; pathology ; Humans ; Kidney Diseases ; etiology ; Mesoderm ; pathology ; Protein-Serine-Threonine Kinases ; chemistry ; physiology ; Signal Transduction

Adiponectin, derived mainly from white adipose tissue, regulates glucose and fatty acid metabolism and has anti-inflammatory and anti-atherosclerotic properties. The decrease in plasma adiponectin concentration contributes to the development of metabolic and cardiovascular diseases. AMP-activated protein kinase (AMPK) is a serine/threonine kinase which plays an important role in regulating many cellular processes, particularly pathways involved in cellular energy status. AMPK is now recognized as a fuel gauge in mammalian cells. Adiponectin activates AMPK phosphorylation and then promotes ATP-generating pathways in heart, including glucose transport, glycolysis, and fatty acid oxidation. The recent evidence has shown that AMPK activation has an important role in the vasculature where it may exert anti-atherosclerotic effects. Phosphorylation of AMPK induced by adiponectin inhibits protein synthesis, and may be an adaptive response to pathological cardiac hypertrophy. AMPK also has a cardioprotective role against myocardial injury and apoptosis in the ischemic heart. This review will discuss the role of AMPK in adiponectin-mediated protective properties of cardiovascular diseases.
AMP-Activated Protein Kinases ; metabolism ; Adiponectin ; physiology ; Animals ; Cardiomegaly ; Cardiovascular Diseases ; physiopathology ; Energy Metabolism ; Glucose ; Heart ; Humans ; Multienzyme Complexes ; Phosphorylation ; Protein-Serine-Threonine Kinases

The innate immune response against viral infection is mainly relies on type I interferon, the production of which is mediated by TANK-binding kinase 1 (TBK1). It is revealed that the downstream TBK1 is activated by viral nucleic acid sensors RIG-I, cGAS and TLR3. The activity of TBK1 is complexly and precisely regulated by different type of protein modifications, including phosphorylation, ubiquitination and Sumolylation. This article focuses on the role of TBK1 in anti-viral innate immunity and the regulatory mechanism for the TBK1 activation.
Humans ; Immunity, Innate ; genetics ; physiology ; Interferon Type I ; Phosphorylation ; Protein Processing, Post-Translational ; immunology ; Protein-Serine-Threonine Kinases ; chemistry ; physiology ; Signal Transduction ; Ubiquitination ; Virus Diseases ; physiopathology

While several organs in mammals retain partial regenerative capability following tissue damage, the underlying mechanisms remain unclear. Recently, the Hippo signaling pathway, better known for its function in organ size control, has been shown to play a pivotal role in regulating tissue homeostasis and regeneration. Upon tissue injury, the activity of YAP, the major effector of the Hippo pathway, is transiently induced, which in turn promotes expansion of tissue-resident progenitors and facilitates tissue regeneration. In this review, with a general focus on the Hippo pathway, we will discuss its major components, functions in stem cell biology, involvement in tissue regeneration in different organs, and potential strategies for developing Hippo pathway-targeted regenerative medicines.
Adaptor Proteins, Signal Transducing ; metabolism ; Animals ; Homeostasis ; physiology ; Humans ; Phosphoproteins ; metabolism ; Protein-Serine-Threonine Kinases ; metabolism ; Regeneration ; physiology ; Signal Transduction ; physiology

Cell cycle plays a crucial role in cell development. Cell cycle progression is mainly regulated by cyclin dependent kinase (CDK), cyclin and endogenous CDK inhibitor (CKI). Among these, CDK is the main cell cycle regulator, binding to cyclin to form the cyclin-CDK complex, which phosphorylates hundreds of substrates and regulates interphase and mitotic progression. Abnormal activity of various cell cycle proteins can cause uncontrolled proliferation of cancer cells, which leads to cancer development. Therefore, understanding the changes in CDK activity, cyclin-CDK assembly and the role of CDK inhibitors will help to understand the underlying regulatory processes in cell cycle progression, as well as provide a basis for the treatment of cancer and disease and the development of CDK inhibitor-based therapeutic agents. This review focuses on the key events of CDK activation or inactivation, and summarizes the regulatory processes of cyclin-CDK at specific times and locations, as well as the progress of research on relevant CDK inhibitor therapeutics in cancer and disease. The review concludes with a brief description of the current challenges of the cell cycle process, with the aim to provide scientific references and new ideas for further research on cell cycle process.
Cyclin-Dependent Kinases/metabolism* ; Cyclins/metabolism* ; Protein Serine-Threonine Kinases ; Cell Cycle Proteins/metabolism* ; Cell Cycle/physiology* ; Cyclin-Dependent Kinase 2

The erectile response of the penis depends on a balance between vasoconstrictor agents, which cause cavernosal smooth muscle to contract limiting blood inflow, and vasodilators, which relax cavernosal smooth muscle leading to increased blood inflow and erection. This review emphasizes the role of the RhoA/Rho-kinase pathway in the cavernosal circulation. While it is widely held that the nitric oxide-cyclic GMP-protein kinase G(NO-cGMP-PKG) pathway mediates vasorelaxation and penile erection, the vasoconstrictor actions of endothelin ET-1 and NE are reported to be mediated by the RhoA/Rho-kinase pathway in the cavernosal circulation and NO relax cavernosal smooth by inhibition of Rho-kinase. The application of Rho-kinase inhibitor on the penile erection may represent a new and promising method of treatment for erectile dysfunction.
Animals ; Erectile Dysfunction ; physiopathology ; Humans ; Intracellular Signaling Peptides and Proteins ; physiology ; Male ; Nitric Oxide ; physiology ; Penile Erection ; physiology ; Protein-Serine-Threonine Kinases ; physiology ; rho-Associated Kinases ; rhoA GTP-Binding Protein ; physiology

Testis specific serine/threonine protein kinase 4 (TSSK4) belongs to the TSSK family, and its members play an important role in spermatogenesis and/or spermiogenesis. Mouse TSSK4 has been reported to be expressed exclusively in the testis and can maintain its kinase activity through autophosphorylation at Thr-197. However, its biological function remains poorly understood. Here we found that GFP-TSSK4-overexpressed HeLa cells showed apoptotic bodies, indicating TSSK4 can lead to apoptosis in vitro. Furthermore, TSSK4 induced apoptosis in different cell lines including HeLa, Cos-7 and H1299 tested by flow cytometry but not its kinase-dead mutant TSSK4-K54M. TSSK4 knockout mice showed increased testes weight and decreased apoptotic spermatogonia and spermatocytes at 21st day after birth tested by TUNEL technology. So TSSK4 was able to induce cell apoptosis in vitro depending on its kinase activity, which leads to abnormal testes weight and apoptosis, shedding light on its function in the process of spermatogenesis and/or spermiogenesis.
Animals ; Apoptosis ; physiology ; Base Sequence ; Cell Line ; DNA Primers ; Flow Cytometry ; Humans ; In Situ Nick-End Labeling ; Male ; Mice ; Polymerase Chain Reaction ; Protein-Serine-Threonine Kinases ; physiology

OBJECTIVETo investigate the expressions of cyclin E, cyclin dependent kinase 2 (CDK-2) and cyclin-dependent kinase inhibitor p57(KIP2) in human gastric cancer, and to evaluate the relationships between protein levels and clinicopathological parameters.

METHODSWestern blot was used to measure the expressions of cyclin E, CDK-2 and p57(KIP2) proteins in the surgically resected gastric carcinoma, adjacent normal mucosa and metastatic lymph nodes from 36 patients.

RESULTSCyclin E and CDK-2 protein levels were higher in gastric cancer tissues in comparison with normal tissues (P < 0.05). Overexpression of cyclin E was correlated with lymph node involvement, poor histological grade and serosa invasion (P < 0.05). Overexpression of CDK-2 was correlated with lymph nodes involvement (P < 0.05). No statistically significant difference between cyclin E and CDK-2 expression was found when samples were stratified according to tumor size (P > 0.05). Expression of cyclin E and CDK-2 showed a positive linear correlation (r = 0.451, P = 0.01). Protein levels of p57(KIP2) were lower in gastric cancer tissues than in the normal mucosa (P < 0.05). Decreased expression of p57(KIP2) was correlated with lymph node involvement (P < 0.05). No statistically significant difference in p57(KIP2) expression was found when sample were stratified according to tumor size, histological grade or serosa invasion (P > 0.05). In metastatic lymph nodes, expression of cyclin E was increased and the expression of p57(KIP2) decreased.

CONCLUSIONOverexpressions of cyclin E, CDK-2 and downregulated expression of p57(KIP2) may play important roles in tumorigenesis and metastatic potential of gastric cancer.

Blotting, Western ; CDC2-CDC28 Kinases ; Cyclin E ; analysis ; physiology ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinase Inhibitor p57 ; Cyclin-Dependent Kinases ; analysis ; physiology ; Humans ; Lymphatic Metastasis ; Nuclear Proteins ; analysis ; physiology ; Protein-Serine-Threonine Kinases ; analysis ; physiology ; Stomach Neoplasms ; chemistry ; pathology