scholarly journals The Saga of Endocrine FGFs

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2418
Author(s):  
Phuc Phan ◽  
Bibhuti Ballav Saikia ◽  
Shivakumar Sonnaila ◽  
Shilpi Agrawal ◽  
Zeina Alraawi ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Fibroblast Growth Factors ◽  
Therapeutic Strategies ◽  
Signaling Proteins ◽  
Future Perspectives ◽  
Active Vitamin ◽  
Downstream Signaling ◽  
Unique Protein ◽  
Metabolic Activities ◽  
Function Relationship

Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.

scholarly journals On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

2020 ◽  
Author(s):  
Rafael Deliz-Aguirre ◽  
Fakun Cao ◽  
Fenja H. U. Gerpott ◽  
Nichanok Auevechanichkul ◽  
Mariam Chupanova ◽  
...  
Keyword(s):  
Self Assembly ◽  
Intracellular Signaling ◽  
Innate Immune ◽  
Live Cells ◽  
Signaling Proteins ◽  
Protein Oligomerization ◽  
Downstream Signaling ◽  
Oligomeric Complex ◽  
Mechanistic Basis ◽  
Cell Signaling Pathways

AbstractA recurring feature of innate immune receptor signaling is the self-assembly of signaling proteins into oligomeric complexes. The Myddosome is an oligomeric complex that is required to transmit inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for how Myddosome proteins self-assemble and regulate intracellular signaling remains poorly understood. Here, we developed a novel assay to analyze the spatiotemporal dynamics of IL1R and Myddosome signaling in live cells. We found that MyD88 oligomerization is inducible and initially reversible. Moreover, the formation of larger, stable oligomers consisting of more than 4 MyD88s triggers the sequential recruitment of IRAK4 and IRAK1. Notably, genetic knockout of IRAK4 enhanced MyD88 oligomerization, indicating that IRAK4 controls MyD88 oligomer size and growth. MyD88 oligomer size thus functions as a physical threshold to trigger downstream signaling. These results provide a mechanistic basis for how protein oligomerization might function in cell signaling pathways.

scholarly journals Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins

2016 ◽  
Vol 291 (11) ◽  
pp. 5528-5540 ◽  
Author(s):  
Tom Ronan ◽  
Jennifer L. Macdonald-Obermann ◽  
Lorel Huelsmann ◽  
Nicholas J. Bessman ◽  
Kristen M. Naegle ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Signaling Proteins ◽  
Downstream Signaling ◽  
Epidermal Growth

scholarly journals Aging and plasma triglyceride metabolism

2020 ◽  
Vol 61 (8) ◽  
pp. 1161-1167 ◽  
Author(s):  
Kathryn M. Spitler ◽  
Brandon S. J. Davies
Keyword(s):  
Metabolic Disease ◽  
Metabolic Diseases ◽  
Therapeutic Strategies ◽  
Aged Rats ◽  
Older Individuals ◽  
Mechanistic Studies ◽  
Adipose Tissue Lipolysis ◽  
Ectopic Fat Deposition ◽  
Induced Changes ◽  
Made In

The risk for metabolic disease, including metabolic syndrome, insulin resistance, and diabetes, increases with age. Altered plasma TG metabolism and changes in fatty acid partitioning are also major contributors to metabolic disease. Plasma TG metabolism itself is altered by age in humans and rodents. As discussed in this review, the age-induced changes in human TG metabolism include increased plasma TG levels, reduced postprandial plasma TG clearance rates, reduced postheparin LPL activity, decreased adipose tissue lipolysis, and elevated ectopic fat deposition, all of which could potentially contribute to age-associated metabolic diseases. Similar observations have been made in aged rats. We highlight the limitations of currently available data and propose that mechanistic studies are needed to understand the extent to which age-induced alterations in TG metabolism contribute to metabolic disease. Such mechanistic insights could aid in therapeutic strategies for preventing or managing metabolic disease in older individuals.

scholarly journals Structure and Lateral Organization of Phosphatidylinositol 4,5-bisphosphate

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3885
Author(s):  
Luís Borges-Araújo ◽  
Fabio Fernandes
Keyword(s):  
Membrane Dynamics ◽  
Eukaryotic Cells ◽  
Signaling Proteins ◽  
Steady State Concentration ◽  
Biophysical Properties ◽  
Cellular Functions ◽  
Downstream Signaling ◽  
A Minor ◽  
State Concentration ◽  
Lateral Organization

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a minor but ubiquitous component of the inner leaflet of the plasma membrane of eukaryotic cells. However, due to its particular complex biophysical properties, it stands out from its neighboring lipids as one of the most important regulators of membrane-associated signaling events. Despite its very low steady-state concentration, PI(4,5)P2 is able to engage in a multitude of simultaneous cellular functions that are temporally and spatially regulated through the presence of localized transient pools of PI(4,5)P2 in the membrane. These pools are crucial for the recruitment, activation, and organization of signaling proteins and consequent regulation of downstream signaling. The present review showcases some of the most important PI(4,5)P2 molecular and biophysical properties as well as their impact on its membrane dynamics, lateral organization, and interactions with other biochemical partners.

Monoclonal Antibody Against ROR1 in Chronic Lymphocytic Leukemia Cells Induced Apoptosis Via PI3-Kinase/AKT/CREB Pathway

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1769-1769
Author(s):  
Amir Hossein Daneshmanesh ◽  
Mohammad Hojjat-Farsangi ◽  
Asa Sandin ◽  
Abdul Salam Khan ◽  
Ali Moshfegh ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Western Blot ◽  
Signaling Pathways ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Pi3 Kinase ◽  
Signaling Proteins ◽  
Downstream Signaling ◽  
Induced Apoptosis ◽  
Creb Pathway

Abstract Abstract 1769 Background: Phosphoinositide 3-kinase (PI3K)/AKT cascade regulates cell survival, proliferation and differentiation in a variety of cells. In CLL cells PI3K pathway is constitutively activated leading to AKT activation and phosphorylation of cAMP response element-binding protein (CREB). CREB is a transcription factor overexpressed and constitutively phosphorylated in a variety of cancers and seems to have a role in tumor pathobiology. There is a great need to develop novel strategies for targeted therapy in CLL. Monoclonal antibodies (mAbs) specifically targeting leukemic cells might be a rewarding approach. ROR1 is a type I transmembrane receptor tyrosine kinase belonging to one of the twenty families of receptor tyrosine kinases (RTKs). ROR1 is overexpressed on CLL cells but not in white blood cells of healthy donors. ROR1 is constitutively phosphorylated in CLL and siRNA transfection induced apoptosis. We have developed a unique anti-ROR1 mAb directed against CRD (cysteine-rich domain) of the extracellular region of ROR1 capable of inducing direct apoptosis of primary CLL cells. Our anti-CRD mAb induced dephosphorylation of the ROR1 molecule. Aims: To study the apoptotic effect of an anti-ROR1 CRD mAb and effects on downstream signaling pathways involved in CLL, specially the PI3-kinase/AKT/CREB pathway using primary CLL cells. Methods: Using a peptide-based mouse mAb generation method we produced several mAbs against the three extracellular domains of ROR1. In the current study we used one of the best anti-ROR1 antibodies, an anti-CRD mAb raised against the CRD region of ROR1 (Daneshmanesh et al., Leukemia. 2012 Jun;26(6):1348-55). Flow cytometry was used for surface staining of ROR1. Primary CLL cells were incubated with the anti-ROR1 CRD mAb and apoptosis was detected by the MTT assay and Annexin V/propidium iodide (flow cytometry) methods in a 24 h assay. Antibody untreated and treated cell lysates were prepared and subjected to Western blot analysis for identification of signaling molecules involved in apoptosis induced by the anti-ROR1 CRD mAb. We analysed total and phosphorylated levels of the following signaling proteins: AKT, p-AKT, PI3K, p-PI3K, CREB, p-CREB, ERK, p-ERK, PKC and p-PKC. Phosphoproteins were measured before incubation with the mAb and after 20 min-2 h. Results: ROR1 surface expression was detected on 80–85% of the CLL cells. The frequency of apoptotic cells induced by the anti-CRD mAb was in the range of 45–50% which is in accordance with our previous reports (see above). Time kinetics experiments using anti-ROR1 CRD mAb incubated with primary CLL cells revealed dephosphorylation of ROR1 downstream signaling molecules. We analysed the following molecules known to be involved in CLL: PKC, PI3-kinase and ERK1/2. After co-culturing CLL cells with the anti-ROR1 CRD mAb, Western blot analysis showed decreased level of phosphorylated AKT in treated compared to untreated samples. No changes in the phosphorylation levels of ERK1/2 and PKC proteins were seen. Furthermore, we analysed the PI3-kinase protein which is upstream of AKT, and noticed that in CLL cells treated with the anti-ROR1 CRD mAb, the phosphorylation intensity of PI3-kinase p85 isoform has decreased but not p55 isoforrn. Moreover, we also studied the CREB phosphorylation in treated and untreated CLL samples and detected dephosphorylation of CREB in treated as compared to untreated samples. Conclusion: Incubation of CLL cells with an anti-ROR1 CRD mAb induced apoptosis of primary CLL cells. Apoptosis was preceded by dephosphorylation within 2 h of PI3-kinase, AKT and CREB proteins indicating deactivation of these signaling proteins by the anti-ROR1 mab. In untreated CLL cells no effect on phosphorylation of these proteins was noted. Furthermore our ROR1 mAb did not dephosphorylate PKC or ERK. Our data may suggest that activation of CREB molecule might occur via the PI3K/AKT pathway and may be a survival signal in CLL cells associated with the aberrant expression of ROR1. The constitutive phosphorylation of PKC and ERK1/2 seen in CLL might not be related to the overexpression of ROR1. Further studies are warranted for a better understanding of signaling pathways associated with ROR1 and the downstream signaling effects of ROR1 targeting drugs. Disclosures: No relevant conflicts of interest to declare.

Activation of P38MAP kinase in estrogen-positive invasive breast cancers: Relation with HER2 and downstream signaling phosphorylated proteins expression.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11560-e11560
Author(s):  
Jean-Louis Merlin ◽  
Alexandre Harle ◽  
Maeva Lion ◽  
Anne-Sophie Chrétien ◽  
Carole Ramacci ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Her2 Status ◽  
Signaling Proteins ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Downstream Signaling ◽  
Phosphorylated Proteins ◽  
Significant Difference ◽  
Mitogen Activated Protein

e11560 Background: P38 kinases are members of the mitogen-activated protein kinase (MAPK) family. In breast cancers MAPK, as well as PI3 kinase-AKT pathway signaling proteins have major implication in molecular oncogenesis and are extensively investigated as putative targets for therapy. The present study reports the investigation of the expression of P38MAPK and its phosphorylated form (p-P38MAPK) in clinical specimens of invasive breast carcinomas in relation with estrogen receptor and HER2 expression, as well as MAPK and PI3K signaling phosphorylated proteins. Methods: The expression of P38MAPK and p-P38MAPK as well as p-AKT, p-GSK3β, p-S6 kinase, p-MEK1, p-ERK1/2 were semi-quantitatively assessed using multiplex bead immuno-assay. The analyses were performed retrospectively in frozen specimens from 46 invasive breast tumors classified according to estrogen receptor (ER) and HER2 status. Results: All specimens were taken at diagnosis and validated for tumor content >50%. Twenty-nine were ER+, 17 were HER2+, 10 were triple negative (TN) tumors. Analyses were performed in triplicate from total protein extracts and were achievable in all specimens. P38MAPK was found to be expressed in all tumor specimen and significantly (P=0.002) overexpressed in ER+ tumors. P38MAPK was lower in TN tumors than in all others. The median expression of phosphorylated-P38MAPK was also higher in ER+ than in ER- tumors and lower in TN tumors than in all others. HER2 status had no influence on P38MAPK and p-P38MAPK expression. No variation in the phosphorylation rate of P38MAPK was observed in relation with ER, HER2 or TN status. Significantly higher (P=0.0048) expression of p-AKT tumors was observed in HER2+ tumors. No significant difference in p-MEK1, p-GSK3β and p-S6K expression was evidenced in any other comparisons based on ER and HER2 expression subtypes. Conclusions: Investigation of the expression of multiple phosphorylated signaling proteins can be used as molecular biomarkers for personalized targeted therapy. In ER+ invasive breast cancer, the overexpression of P38MAPK could serve as biomarker for evaluation of P38MAPK inhibitors.

scholarly journals Histone Deacetylases in the Pathogenesis of Diabetic Cardiomyopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiangyu Ke ◽  
Zhirui Lin ◽  
Zebing Ye ◽  
Meifang Leng ◽  
Bo Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Diabetic Cardiomyopathy ◽  
Histone Deacetylases ◽  
Cardiac Fibrosis ◽  
Metabolic Diseases ◽  
Therapeutic Strategies ◽  
Global Burden ◽  
Comprehensive Understanding ◽  
Cellular Processes

The global burden of diabetes mellitus and its complications are currently increasing. Diabetic cardiomyopathy (DCM) is the main cause of diabetes mellitus associated morbidity and mortality; therefore, a comprehensive understanding of DCM development is required for more effective treatment. A disorder of epigenetic posttranscriptional modification of histones in chromatin has been reported to be associated with the pathology of DCM. Recent studies have implicated that histone deacetylases could regulate cardiovascular and metabolic diseases in cellular processes including cardiac fibrosis, hypertrophy, oxidative stress and inflammation. Therefore in this review, we summarized the roles of histone deacetylases in the pathogenesis of DCM, aiming to provide insights into exploring potential preventative and therapeutic strategies of DCM.

Activation of Nuclear Factor KappaB in ETV6/FLT3-Transformed Ba/F3 Cells Depends on the FLT3 Tyrosine 591.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4666-4666
Author(s):  
Hoang Anh Vu ◽  
Phan Thi Xinh ◽  
Yasuhiko Kano ◽  
Takaomi Ishida ◽  
Toshiki Watanabe ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Fusion Gene ◽  
Hematologic Malignancies ◽  
Signaling Proteins ◽  
Interleukin 3 ◽  
Downstream Signaling ◽  
Support Cell ◽  
Helix Loop Helix ◽  
Oligomerization Domain

Abstract The FLT3 gene is one of the most frequently mutated genes in hematologic malignancies. Mutated FLT3 has been found to lead to strong constitutive activation of several signaling proteins such as STAT5, CBL, VAV, SHP2, NF-kB, and AKT. Recently, we have reported that FLT3 contributed to leukemogenesis through generating a ETV6/FLT3 fusion gene in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation, which is the first report to show that FLT3 fusion gene can be involved in leukemogenesis. The ETV6/FLT3 which contained the helix-loop-helix oligomerization domain of ETV6 fused to the juxtamembrane (JM) domain plus tyrosine kinase (TK) domains of FLT3, conferred interleukin-3-independent growth on Ba/F3 cells (Vu HA, et al. LEUKEMIA20:1414–21, 2006). To assess a role of the JM domain of FLT3 in the ETV6/FLT3 protein, we generated a series of ETV6/FLT3 mutants (tyrosine to phenylalanine substitution and deletion of the JM domain or N-terminal region of the TK1 domain). Each mutant was introduced into Ba/F3 cells and downstream signaling as well as cell proliferation was investigated. We found that the wild-type ETV6/FLT3 in Ba/F3 cells was a constitutively activated tyrosine kinase that led to activation of STAT5, AKT, MAPK, and NF-kB pathways as well as up-regulation of PIM-1. Deletion of the JM domain retained compatible level of autophosphorylation of the fusion protein as well as activation of STAT5, AKT and MAPK, suggesting that the JM domain is dispensable for STAT5, MAPK and AKT activations. In contrast, deletion of the JM domain did abrogate interleukin-3-independent growth of Ba/F3 cells, PIM-1 up-regulation, and activation of NF-kB. Importantly, while substitutions of other 3 tyrosines (589, 597, and 599) had no affect on NF-kB activation, the substitution of tyrosine 591 to phenylalanine abrogated this activation. Our results suggest that the tyrosine 591 in JM domain of FLT3 in ETV6/FLT3 is critical for NF-kB activation to support cell survival and PIM-1 up-regulation.

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