scholarly journals Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks

2018 ◽  
Vol 475 (1) ◽  
pp. 117-135 ◽  
Author(s):  
Nazma Malik ◽  
Thomas Macartney ◽  
Annika Hornberger ◽  
Karen E. Anderson ◽  
Hannah Tovell ◽  
...  
Keyword(s):  
Growth Factors ◽  
Pi3k Pathway ◽  
Cancer Therapies ◽  
Physiological Conditions ◽  
Oncogenic Ras ◽  
Enhanced Production ◽  
Signalling Network ◽  
Class 1 ◽  
Phox Homology ◽  
Protein Kinase Signalling

Derailment of the PI3K-AGC protein kinase signalling network contributes to many human diseases including cancer. Recent work has revealed that the poorly studied AGC kinase family member, SGK3, promotes resistance to cancer therapies that target the Class 1 PI3K pathway, by substituting for loss of Akt kinase activity. SGK3 is recruited and activated at endosomes, by virtue of its phox homology domain binding to PtdIns(3)P. Here, we demonstrate that endogenous SGK3 is rapidly activated by growth factors such as IGF1, through pathways involving both Class 1 and Class 3 PI3Ks. We provide evidence that IGF1 enhances endosomal PtdIns(3)P levels via a pathway involving the UV-RAG complex of hVPS34 Class 3 PI3K. Our data point towards IGF1-induced activation of Class 1 PI3K stimulating SGK3 through enhanced production of PtdIns(3)P resulting from the dephosphorylation of PtdIns(3,4,5)P3. Our findings are also consistent with activation of Class 1 PI3K promoting mTORC2 phosphorylation of SGK3 and with oncogenic Ras-activating SGK3 solely through the Class 1 PI3K pathway. Our results highlight the versatility of upstream pathways that activate SGK3 and help explain how SGK3 substitutes for Akt following inhibition of Class 1 PI3K/Akt pathways. They also illustrate robustness of SGK3 activity that can remain active and counteract physiological conditions or stresses where either Class 1 or Class 3 PI3K pathways are inhibited.

scholarly journals Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms

2021 ◽  
Vol 12 (2) ◽  
pp. 212-227
Author(s):  
V. V. Povoroznyuk ◽  
N. V. Dedukh ◽  
M. A. Bystrytska ◽  
V. S. Shapovalov
Keyword(s):  
Growth Factors ◽  
Bone Resorption ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Molecular Mechanisms ◽  
Signaling Molecules ◽  
Physiological Conditions ◽  
Bone Cell Differentiation ◽  
Repressive Effect

This review provides a rationale for the cellular and molecular mechanisms of bone remodeling stages under physiological conditions and glucocorticoids (GCs) in excess. Remodeling is a synchronous process involving bone resorption and formation, proceeding through stages of: (1) resting bone, (2) activation, (3) bone resorption, (4) reversal, (5) formation, (6) termination. Bone remodeling is strictly controlled by local and systemic regulatory signaling molecules. This review presents current data on the interaction of osteoclasts, osteoblasts and osteocytes in bone remodeling and defines the role of osteoprogenitor cells located above the resorption area in the form of canopies and populating resorption cavities. The signaling pathways of proliferation, differentiation, viability, and cell death during remodeling are presented. The study of signaling pathways is critical to understanding bone remodeling under normal and pathological conditions. The main signaling pathways that control bone resorption and formation are RANK / RANKL / OPG; M-CSF – c-FMS; canonical and non-canonical signaling pathways Wnt; Notch; MARK; TGFβ / SMAD; ephrinB1/ephrinB2 – EphB4, TNFα – TNFβ, and Bim – Bax/Bak. Cytokines, growth factors, prostaglandins, parathyroid hormone, vitamin D, calcitonin, and estrogens also act as regulators of bone remodeling. The role of non-encoding microRNAs and long RNAs in the process of bone cell differentiation has been established. MicroRNAs affect many target genes, have both a repressive effect on bone formation and activate osteoblast differentiation in different ways. Excess of glucocorticoids negatively affects all stages of bone remodeling, disrupts molecular signaling, induces apoptosis of osteocytes and osteoblasts in different ways, and increases the life cycle of osteoclasts. Glucocorticoids disrupt the reversal stage, which is critical for the subsequent stages of remodeling. Negative effects of GCs on signaling molecules of the canonical Wingless (WNT)/β-catenin pathway and other signaling pathways impair osteoblastogenesis. Under the influence of excess glucocorticoids biosynthesis of biologically active growth factors is reduced, which leads to a decrease in the expression by osteoblasts of molecules that form the osteoid. Glucocorticoids stimulate the expression of mineralization inhibitor proteins, osteoid mineralization is delayed, which is accompanied by increased local matrix demineralization. Although many signaling pathways involved in bone resorption and formation have been discovered and described, the temporal and spatial mechanisms of their sequential turn-on and turn-off in cell proliferation and differentiation require additional research.

scholarly journals Decreased phosphatase PTEN amplifies PI3K signaling and enhances proinflammatory cytokine release in COPD

2017 ◽  
Vol 313 (2) ◽  
pp. L230-L239 ◽  
Author(s):  
Satoru Yanagisawa ◽  
Jonathan R. Baker ◽  
Chaitanya Vuppusetty ◽  
Peter Fenwick ◽  
Louise E. Donnelly ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pi3k Pathway ◽  
Negative Regulator ◽  
Pi3k Signaling ◽  
Pten Protein ◽  
Protein Levels ◽  
Enhanced Production ◽  
Phosphorylated Akt ◽  
Peripheral Lung ◽  
The Impact

The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN protein expression was measured in the peripheral lung of COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of l-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knockdown by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared with the subjects without COPD ( P < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; r = 0.50; P = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels ( r = −0.41; P = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, which was reversed by N-acetyl cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines, such as IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.

scholarly journals Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway

Oncogene ◽  
2002 ◽  
Vol 21 (33) ◽  
pp. 5148-5159 ◽  
Author(s):  
Elzbieta Janda ◽  
Gabi Litos ◽  
Stefan Grünert ◽  
Julian Downward ◽  
Hartmut Beug
Keyword(s):  
Epithelial Cells ◽  
Tumor Growth ◽  
Pi3k Pathway ◽  
3D Cultures ◽  
Oncogenic Ras ◽  
Her 2 ◽  
Polarized Epithelial Cells

scholarly journals Targeting PI3K/Akt signal transduction for cancer therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yan He ◽  
Miao Miao Sun ◽  
Guo Geng Zhang ◽  
Jing Yang ◽  
Kui Sheng Chen ◽  
...  
Keyword(s):  
Pi3k Pathway ◽  
Cancer Drug ◽  
Akt Pathway ◽  
Cancer Therapies ◽  
Cancer Drug Discovery ◽  
Cellular Processes ◽  
Survival Pathways ◽  
Pathway Activation ◽  
Signaling Inhibitors ◽  
Cancer Phenotypes

AbstractThe phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.

scholarly journals Molecular Responses in THP-1 Macrophage-Like Cells Exposed to Diverse Nanoparticles

Nanomaterials ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 687 ◽  
Author(s):  
Tana Brzicova ◽  
Eliska Javorkova ◽  
Kristyna Vrbova ◽  
Alena Zajicova ◽  
Vladimir Holan ◽  
...  
Keyword(s):  
Growth Factors ◽  
The Body ◽  
Engineered Nanoparticles ◽  
Dna Breaks ◽  
Ag Nps ◽  
Proinflammatory Response ◽  
Microscopy Imaging ◽  
Molecular Responses ◽  
Enhanced Production ◽  
Activation Of Transcription

In the body, engineered nanoparticles (NPs) may be recognized and processed by immune cells, among which macrophages play a crucial role. We evaluated the effects of selected NPs [NM-100 (TiO2), NM-110 (ZnO), NM-200 (SiO2), and NM-300 K (Ag)] on THP-1 macrophage-like cells. The cells were exposed to subcytotoxic concentrations of NPs (1–25 µg/mL) and the expression of immunologically relevant genes (VCAM1, TNFA, CXCL8, ICAM1, CD86, CD192, and IL1B) was analyzed by RT-qPCR. The expression of selected cytokines, growth factors and surface molecules was assessed by flow cytometry or ELISA. Generation of reactive oxygen species and induction of DNA breaks were also analyzed. Exposure to diverse NPs caused substantially different molecular responses. No significant effects were detected for NM-100 treatment. NM-200 induced production of IL-8, a potent attractor and activator of neutrophils, growth factors (VEGF and IGF-1) and superoxide. NM-110 triggered a proinflammatory response, characterized by the activation of transcription factor NF-κB, an enhanced production of proinflammatory cytokines (TNF-α) and chemokines (IL-8). Furthermore, the expression of cell adhesion molecules VCAM-1 and ICAM-1 and hepatocyte growth factor (HGF), as well as superoxide production and DNA breaks, were affected. NM-300 K enhanced IL-8 production and induced DNA breaks, however, it decreased the expression of chemokine receptor (CCR2) and CD86 molecule, indicating potential immunosuppressive activity. The toxicity of ZnO and Ag NPs was probably caused by their intracellular dissolution, as indicated by transmission electron microscopy imaging. The observed effects in macrophages might further influence both innate and adaptive immune responses by promoting neutrophil recruitment via IL-8 release and enhancing the adhesion and stimulation of T cells by VCAM-1 and ICAM-1 expression.

scholarly journals Roles for Growth Factors in Cancer Progression

Physiology ◽  
2010 ◽  
Vol 25 (2) ◽  
pp. 85-101 ◽  
Author(s):  
Esther Witsch ◽  
Michael Sela ◽  
Yosef Yarden
Keyword(s):  
Growth Factors ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Physiological Conditions ◽  
Downstream Signaling ◽  
Activating Mutations ◽  
Extracellular Signals ◽  
Polypeptide Growth Factors ◽  
Oncogenic Mutations

Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy.

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