scholarly journals Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Romina Mancinelli ◽  
Guido Carpino ◽  
Simonetta Petrungaro ◽  
Caterina Loredana Mammola ◽  
Luana Tomaipitinca ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Liver Diseases ◽  
Glycogen Synthesis ◽  
Molecular Target ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Natural Substances ◽  
Age Related ◽  
Inhibit Tumor Cell Proliferation

GSK-3 is a ubiquitously expressed serine/threonine kinase existing as GSK-3αand GSK-3βisoforms, both active under basal conditions and inactivated upon phosphorylation by different upstream kinases. Initially discovered as a regulator of glycogen synthesis, GSK-3 is also involved in several signaling pathways controlling many different key functions. Here, we discuss recent advances regarding (i) GSK-3 structure, function, regulation, and involvement in several cancers, including hepatocarcinoma, cholangiocarcinoma, breast cancer, prostate cancer, leukemia, and melanoma (active GSK-3 has been shown to induce apoptosis in some cases or inhibit apoptosis in other cases and to induce cancer progression or inhibit tumor cell proliferation, suggesting that different GSK-3 modulators may address different specific targets); (ii) GSK-3 involvement in autophagy modulation, reviewing signaling pathways involved in neurodegenerative and liver diseases; (iii) GSK-3 role in oxidative stress and autophagic cell death, focusing on liver injury; (iv) GSK-3 as a possible therapeutic target of natural substances and synthetic inhibitors in many diseases; and (v) GSK-3 role as modulator of mammalian aging, related to metabolic alterations characterizing senescent cells and age-related diseases. Studies summarized here underline the GSK-3 multifaceted role and indicate such kinase as a molecular target in different pathologies, including diseases associated with autophagy dysregulation.

scholarly journals Ubl4A is required for insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching

2015 ◽  
Vol 112 (31) ◽  
pp. 9644-9649 ◽  
Author(s):  
Yu Zhao ◽  
Yuting Lin ◽  
Honghong Zhang ◽  
Adriana Mañas ◽  
Wenwen Tang ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Glycogen Synthesis ◽  
Membrane Translocation ◽  
Insulin Stimulation ◽  
Serine Threonine Kinase ◽  
Newborn Mice ◽  
Threonine Kinase ◽  
Cell Mobility ◽  
Close Proximity ◽  
Extracellular Stimuli

The serine-threonine kinase Akt is a key regulator of cell proliferation and survival, glucose metabolism, cell mobility, and tumorigenesis. Activation of Akt by extracellular stimuli such as insulin centers on the interaction of Akt with PIP3 on the plasma membrane, where it is subsequently phosphorylated and activated by upstream protein kinases. However, it is not known how Akt is recruited to the plasma membrane upon stimulation. Here we report that ubiquitin-like protein 4A (Ubl4A) plays a crucial role in insulin-induced Akt plasma membrane translocation. Ubl4A knockout newborn mice have defective Akt-dependent glycogen synthesis and increased neonatal mortality. Loss of Ubl4A results in the impairment of insulin-induced Akt translocation to the plasma membrane and activation. Akt binds actin-filaments and colocalizes with actin-related protein 2 and 3 (Arp2/3) complex in the membrane ruffles and lamellipodia. Ubl4A directly interacts with Arp2/3 to accelerate actin branching and networking, allowing Akt to be in close proximity to the plasma membrane for activation upon insulin stimulation. Our finding reveals a new mechanism by which Akt is recruited to the plasma membrane for activation, thereby providing a missing link in Akt signaling.

GSK-3 Inhibitors in Regulation and Controlling of Colon Carcinoma

2021 ◽  
Vol 22 ◽  
Author(s):  
Sitansu Sekhar Nanda ◽  
Md Imran Hossain ◽  
Heongkyu Ju ◽  
Dong Kee Yi
Keyword(s):  
Colon Carcinoma ◽  
Clinical Studies ◽  
Glycogen Synthesis ◽  
Morphological Examination ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Adenocarcinoma Cells ◽  
Membrane Bound

Background: GSK-3 inhibitors became a novel therapeutic agent treating cancer. There are so many uses of GSK-3 inhibitor for treating cancer like breast cancer, lung cancer, gastric cancer, and no pathological changes are shown by the morphological examination of GSK-3. Objectives: This review describes the recent affairs using GSK-3 inhibitors, mainly treating in colon carcinoma. The authorsAuthors have also shown the different mechanisms of different GSK-3 inhibitors for treating various cancers and proposed some mechanisms that can be useful for further research by GSK-3 inhibitors for various cancerscancer including colon carcinoma. Results: The majority of the cancers and pre-cancerous lesions are stimulated by the transformation of membrane-bound arachidonic acid (AA) to eicosanoids for the viability, proliferation, and spread of cancer. GSK-3 inhibitors can reinstate hostility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) responsiveness in gastric adenocarcinoma cells. GSK-3, the final enzyme in glycogen synthesis, is a serine/threonine kinase that phosphorylates varied sequences that are more than a hundred in number, within proteins in an array of heterogeneous pathways. It is an essential module of an exceptionally huge number of cellular processes, a fundamental role in many metabolic processes and diseases. Many patients achieve long term remission with outstanding survival diagnosed with colon cancer through it. Conclusion: Before the extensive application of these proposed mechanisms of GSK-3 inhibitor, further evaluation and clinical studies are needed. After doing the appropriate clinical studies and morphological examination, it can be appropriate for extensive application.

scholarly journals Dual Roles of Serine-Threonine Kinase Receptor-Associated Protein (STRAP) in Redox-Sensitive Signaling Pathways Related to Cancer Development

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Ravi Manoharan ◽  
Hyun-A Seong ◽  
Hyunjung Ha
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Human Cancer ◽  
Tumor Formation ◽  
Serine Threonine Kinase ◽  
Receptor Associated Protein ◽  
Threonine Kinase

Serine-threonine kinase receptor-associated protein (STRAP) is a transforming growth factor β (TGF-β) receptor-interacting protein that has been implicated in both cell proliferation and cell death in response to various stresses. However, the precise roles of STRAP in these cellular processes are still unclear. The mechanisms by which STRAP controls both cell proliferation and cell death are now beginning to be unraveled. In addition to its biological roles, this review also focuses on the dual functions of STRAP in cancers displaying redox dysregulation, where it can behave as a tumor suppressor or an oncogene (i.e., it can either inhibit or promote tumor formation), depending on the cellular context. Further studies are needed to define the functions of STRAP and the redox-sensitive intracellular signaling pathways that enhance either cell proliferation or cell death in human cancer tissues, which may help in the development of effective treatments for cancer.

scholarly journals SGK1 in Human Cancer: Emerging Roles and Mechanisms

2021 ◽  
Vol 10 ◽  
Author(s):  
Yiwen Sang ◽  
Piaoping Kong ◽  
Shizhen Zhang ◽  
Lingyu Zhang ◽  
Ying Cao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Kinase Activity ◽  
Human Cancer ◽  
Therapy Resistance ◽  
Cancer Cell Proliferation ◽  
Serine Threonine Kinase ◽  
Aberrant Expression ◽  
Threonine Kinase ◽  
Cancer Types

Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.

Retinol binding protein 4 affects the adipogenesis of porcine preadipocytes through insulin signaling pathways

2013 ◽  
Vol 91 (4) ◽  
pp. 236-243 ◽  
Author(s):  
Jia Cheng ◽  
Zi-Yi Song ◽  
Lei Pu ◽  
Hao Yang ◽  
Jia-Meng Zheng ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Insulin Signaling ◽  
Binding Protein ◽  
Mammalian Target Of Rapamycin ◽  
Suppressive Effect ◽  
Retinol Binding Protein ◽  
Serine Threonine Kinase ◽  
Retinol Binding Protein 4 ◽  
Threonine Kinase

Retinol binding protein 4 (RBP4), a novel cytokine, is mainly secreted by hepatocytes and adipocytes. RBP4 reportedly induces insulin resistance and RBP4 secretion is increased in the adipocytes of animals or humans with type 2 diabetes, obesity, and metabolic syndrome, but its role in preadipocyte differentiation remains unclear. In this study, we investigated the effect of RBP4 on the differentiation of porcine preadipocytes into adipocytes. The results suggest that RBP4 significantly suppresses the differentiation of porcine preadipocytes into adipocytes, including those treated with the hormone cocktail methylisobutylxanthine–dexamethasone–insulin. RBP4 also weakened the activity of normal threonine 308, the phosphorylation of serine/threonine kinase AKT, and downstream insulin signaling, including the mammalian target of rapamycin (mTOR) and β-catenin. Moreover, the activation of insulin signaling mediated by knockdown RBP4 in porcine preadipocytes was recovered in the suppression of LY294002. RBP4 also had a suppressive effect on the differentiation of porcine preadipocytes by decreasing the activation of insulin signaling pathways.

scholarly journals Specific deletion of LKB1/Stk11 in the Müllerian duct mesenchyme drives hyperplasia of the periurethral stroma and tumorigenesis in male mice

2017 ◽  
Vol 114 (13) ◽  
pp. 3445-3450 ◽  
Author(s):  
Jitu W. George ◽  
Amanda L. Patterson ◽  
Pradeep S. Tanwar ◽  
André Kajdacsy-Balla ◽  
Gail S. Prins ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Outlet Obstruction ◽  
Prostatic Hyperplasia ◽  
Lineage Tracing ◽  
Urogenital Sinus ◽  
Mullerian Duct ◽  
Serine Threonine Kinase ◽  
Müllerian Duct ◽  
Threonine Kinase ◽  
Conditional Deletion

Nearly all older men will experience lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH), the etiology of which is not well understood. We have generated Stk11CKO mice by conditional deletion of the liver kinase B1 (LKB1) tumor suppressor gene, Stk11 (serine threonine kinase 11), in the fetal Müllerian duct mesenchyme (MDM), the caudal remnant of which is thought to be assimilated by the urogenital sinus primordial mesenchyme in males during fetal development. We show that MDM cells contribute to the postnatal stromal cells at the dorsal aspect of the prostatic urethra by lineage tracing. The Stk11CKO mice develop prostatic hyperplasia with bladder outlet obstruction, most likely because of stromal expansion. The stromal areas from prostates of Stk11CKO mice, with or without significant expansion, were estrogen receptor positive, which is consistent with both MD mesenchyme-derived cells and the purported importance of estrogen receptors in BPH development and/or progression. In some cases, stromal hyperplasia was admixed with epithelial metaplasia, sometimes with keratin pearls, consistent with squamous cell carcinomas. Mice with conditional deletion of both Stk11 and Pten developed similar features as the Stk11CKO mice, but at a highly accelerated rate, often within the first few months after birth. Western blot analyses showed that the loss of LKB1 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) induces activation of the phospho-5′ adenosine monophosphate-activated protein kinase and phospho-AKT serine/threonine kinase 1 signaling pathways, as well as increased total and active β-catenin. These results suggest that activation of these signaling pathways can induce hyperplasia of the MD stroma, which could play a significant role in the etiology of human BPH.

scholarly journals mTOR Pathways in Cancer and Autophagy

Cancers ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 18 ◽  
Author(s):  
Mathieu Paquette ◽  
Leeanna El-Houjeiri ◽  
Arnim Pause
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Signaling Pathways ◽  
Molecular Level ◽  
Clinical Implications ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Evolutionarily Conserved ◽  
Stress Signals ◽  
The Relationship

TOR (target of rapamycin), an evolutionarily-conserved serine/threonine kinase, acts as a central regulator of cell growth, proliferation and survival in response to nutritional status, growth factor, and stress signals. It plays a crucial role in coordinating the balance between cell growth and cell death, depending on cellular conditions and needs. As such, TOR has been identified as a key modulator of autophagy for more than a decade, and several deregulations of this pathway have been implicated in a variety of pathological disorders, including cancer. At the molecular level, autophagy regulates several survival or death signaling pathways that may decide the fate of cancer cells; however, the relationship between autophagy pathways and cancer are still nascent. In this review, we discuss the recent cellular signaling pathways regulated by TOR, their interconnections to autophagy, and the clinical implications of TOR inhibitors in cancer.

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