Small G Proteins as Novel Therapeutic Targets in Cardiovascular Medicine

Physiology ◽  
2003 ◽  
Vol 18 (1) ◽  
pp. 18-22 ◽  
Author(s):  
Christine Barandier ◽  
Xiu-Fen Ming ◽  
Zhihong Yang
Keyword(s):  
G Proteins ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiovascular Disorders ◽  
Therapeutic Approaches ◽  
Cardiovascular Medicine ◽  
Downstream Signaling ◽  
And Migration ◽  
Function Smooth ◽  
Small G Proteins ◽  
Proliferation And Migration

Small G proteins are implicated in regulation of endothelial function, smooth muscle cell contraction, proliferation, and migration, as well as cardiomyocyte hypertrophy. Targeting small G proteins and their downstream signaling could constitute promising therapeutic approaches in cardiovascular disorders such as atherosclerosis, restenosis, hypertension, vasospasm, and cardiac hypertrophy.

scholarly journals ERK1/2-dependent activation of FCHSD2 drives cancer cell-selective regulation of clathrin-mediated endocytosis

2018 ◽  
Author(s):  
Guan-Yu Xiao ◽  
Aparna Mohanakrishnan ◽  
Sandra L. Schmid
Keyword(s):  
Cell Surface ◽  
Cancer Patient ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Patient Survival ◽  
Expression Level ◽  
Downstream Signaling ◽  
And Migration ◽  
Proliferation And Migration

AbstractClathrin-mediated endocytosis (CME) regulates the uptake of cell surface receptors, as well as their downstream signaling activities. We recently reported that signaling reciprocally regulates CME in cancer cells and that the crosstalk can contribute to cancer progression. To further explore the nature and extent of the crosstalk between signaling and CME in cancer cell biology, we analyzed a panel of oncogenic signaling kinase inhibitors for their effects on CME. Inhibition of several kinases selectively affected CME function in cancer cells. Among these, ERK1/2 inhibition selectively inhibited CME in cancer cells by decreasing the rate of CCP initiation. We identified an ERK1/2 substrate, the FCH/F-BAR and SH3 domain-containing protein, FCHSD2, as being essential for the ERK1/2-dependent effects on CME and CCP initiation. ERK1/2 phosphorylation activates FCHSD2 and regulates EGFR endocytic trafficking as well as downstream signaling activities. Loss of FCHSD2 activity in non-small-cell lung cancer cells leads to increased cell surface expression and altered signaling downstream of EGFR, resulting in enhanced cell proliferation and migration. The expression level of FCHSD2 is positively correlated with higher cancer patient survival rate, suggesting that FCHSD2 negatively affects cancer progression. These findings provide new insight into the mechanisms and consequences of the reciprocal regulation of signaling and CME in cancer cells.SignificanceClathrin-mediated endocytosis (CME) determines the internalization of receptors and their downstream signaling. We discovered that CME is differentially regulated by specific signaling kinases in cancer cells. In particular, ERK1/2-mediated phosphorylation of the FCH/F-BAR and double SH3 domains-containing protein 2 (FCHSD2) regulates CME, and the trafficking and signaling activities of EGF receptors. This reciprocal interaction negatively regulates cancer proliferation and migration. The expression level of FCHSD2 is positively correlated with higher cancer patient survival rates. This study identifies signaling pathways that impinge on the endocytic machinery and reveals a molecular nexus for crosstalk between intracellular signaling and CME. Cancer cells specifically adapt this crosstalk as a determinant for tumor progression, which has implications for novel therapeutics against cancers.

BCR-ABL Lacking the Pleckstrin Homology (PH) Domain of BCR Induces a More Aggressive Leukemia Than P210BCR-ABL in a Murine Model of CML.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2564-2564
Author(s):  
Shadmehr Demehri ◽  
Thomas O’Hare ◽  
Lisa J. Wood ◽  
Marc Loriaux ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
G Proteins ◽  
Critical Role ◽  
In Vivo Studies ◽  
Rank Test ◽  
Ph Domain ◽  
Downstream Signaling ◽  
Ph Domains ◽  
Small G Proteins ◽  
Homology Domains

Abstract Background: The two common types of BCR-ABL fusion protein, p190 and p210, are associated with Ph-positive ALL and CML, respectively. Compared to p190, p210 retains the Dbl-like, CDC24 homology and PH domains. Dbl-like and CDC24 homology domains are thought to serve as a guanidine exchange factor (GEF) for small G proteins, including Rac, CDC42 and RhoA. It has been suggested that the loss of GEF activity may be responsible for the more aggressive phenotype of p190-positive leukemia (McWhirter and Wang, Oncogene1997; 15(14):1625–34). PH domains bind phosphoinositides and have been implicated in targeting proteins to cellular membranes as well as modulating the activity of the adjacent Dbl-like GEFs. It is not known, however, if the PH domain of BCR plays a role in determining disease features. We therefore decided to study the biology of p200BCR-ABL, a naturally occurring variant identified in several CML patients that lacks the PH domain but retains the Dbl-like and CDC24 homology domains. Materials and methods: p190, p210 and p200BCR-ABL cDNAs were cloned into pSRa and MIGR1 for expression in cell lines and primary murine bone marrow (BM) cells, respectively. The activation of signaling pathways downstream of BCR-ABL was studied in Ba/F3 and 32D cells expressing the various constructs. For colony-forming assays, murine BM cells were infected with p210, p200 or p190 retroviral vectors and seeded in methylcellulose in the presence or absence of cytokines (SCF, IL3 & IL6) and colonies were counted on day 12. For in vivo studies, BM cells isolated from 5-fluorouracil treated 5-6 week-old female Balb/c mice were infected with the various retroviral constructs in the presence of cytokines (SCF, IL3 & IL6), and 4.0 x 105 cells were injected retro-orbitally into lethally irradiated recipient mice. Disease latency was determined by monitoring white blood counts at 48h intervals. Moribund animals were sacrificed and studied by FACS and histopathology. Results: As expected, p200 transformed Ba/F3 and 32D cells to IL-3 independence. Immunoblotting of whole cell lysates with a phosphotyrosine antibody revealed no significant differences in global protein phosphorylation between the three variants, but phosphorylation of BCR-ABL was consistently less sensitive to imatinib inhibition in cells expressing p190 compared to p200 and p210. Analysis of downstream signaling showed approximately 15 fold higher levels of phosphorylated STAT6 in Ba/F3 cells expressing p200 and p190 vs. p210, while STAT5 and AKT phophorylation were similar in all variants. In the absence of cytokines, BM cells from Balb/c mice transduced with p200 and p190 generated significantly more CFU-GM than cells transduced with p210 (p<0.001, Student’s t-test). The significance of these findings was tested in vivo in a murine CML model. Mice transplanted with p210-transduced cells survived 16–20 days, significantly longer than mice transplanted with p200 or p190 expressing cells (13–15 days) (p = 0.01, log-rank test). Conclusion: p200 is closely related to p190 but very distinct from p210 with respect to downstream signaling and in vivo transforming potential. These data suggest a critical role for the PH domain of BCR in attenuating the phenotype of the leukemia. We speculate that deletion of the PH domain may disrupt the ability of the Dbl-like and CDC24 homology domains to function as a GEF towards small G proteins.

scholarly journals The Effect of Photobiomodulation Therapy on the Differentiation, Proliferation, and Migration of the Mesenchymal Stem Cell: A Review

2019 ◽  
Vol 10 (5) ◽  
pp. S96-S103
Author(s):  
Behnaz Ahrabi ◽  
Mostafa Rezaei Tavirani ◽  
Maryam Sadat Khoramgah ◽  
Mohsen Noroozian ◽  
Shahram Darabi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Low Power ◽  
The Other ◽  
Therapeutic Approaches ◽  
Power Laser ◽  
Different Types ◽  
Key Factor ◽  
And Migration ◽  
Positive Effect ◽  
Proliferation And Migration

Introduction: The purpose of this study is to investigate the effect of a low-power laser on the proliferation, migration, differentiation of different types of mesenchymal stem cells (MSCs) in different studies. Methods: The relevant articles that were published from 2004 to 2019 were collected from the sources of PubMed, Scopus, and only the articles specifically examining the effect of a lowpower laser on the proliferation, differentiation, and migration of the MSCs were investigated. Results: After reviewing the literature, only 42 articles were found relevant. Generally, most of the studies demonstrated that different laser parameters increased the proliferation, migration, and differentiation of the MSCs, except the results of two studies which were contradictory. In fact, changing the parameters of a low-power laser would affect the results. On the other hand, the source of the stem cells was reported as a key factor. In addition, the combination of lasers with other therapeutic approaches was found to be more effective. Conclusion: The different parameters of lasers has been found to be effective in the proliferation, differentiation, and migration of the MSCs and in general, a low-power laser has a positive effect on the MSCs, helping to improve different disease models.

scholarly journals Insights Into Signaling in Cell-Based Therapy for Heart Disease

2017 ◽  
Vol 6 ◽  
pp. 117864341771768
Author(s):  
Angela C Rieger ◽  
Bryon A Tompkins ◽  
Monisha Banerjee ◽  
Makoto Natsumeda ◽  
Victoria Florea ◽  
...  
Keyword(s):  
Stem Cell ◽  
Heart Disease ◽  
Signaling Pathways ◽  
Cardiac Disease ◽  
Cell Contact ◽  
Downstream Signaling ◽  
Cell Based Therapy ◽  
And Migration ◽  
And Function ◽  
Proliferation And Migration

Over the past several decades, stem cell therapy for heart disease has been translated from the bench to the bedside and in clinical trials improves cardiac structure and function in both ischemic and nonischemic cardiac disease. Although the regenerative effects of stem cells in cardiac disease are mediated by both paracrine and cell-to-cell contact mechanisms, many of the downstream signaling pathways remain to be fully elucidated. This review outlines what is currently known about the main signaling pathways involved in mesenchymal stem cell and cardiac stem cell survival, proliferation, and migration and mechanisms of action to repair the damaged heart.

scholarly journals Prolidase Stimulates Proliferation and Migration through Activation of the PI3K/Akt/mTOR Signaling Pathway in Human Keratinocytes

2020 ◽  
Vol 21 (23) ◽  
pp. 9243
Author(s):  
Magdalena Misiura ◽  
Weronika Baszanowska ◽  
Ilona Ościłowska ◽  
Jerzy Pałka ◽  
Wojciech Miltyk
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Human Keratinocytes ◽  
Immunocytochemical Staining ◽  
Β1 Integrin ◽  
Collagen Biosynthesis ◽  
Downstream Signaling ◽  
And Migration ◽  
Proliferation And Migration

Recent reports have indicated prolidase (PEPD) as a ligand of the epidermal growth factor receptor (EGFR). Since this receptor is involved in the promotion of cell proliferation, growth, and migration, we aimed to investigate whether prolidase may participate in wound healing in vitro. All experiments were performed in prolidase-treated human keratinocytes assessing cell vitality, proliferation, and migration. The expression of downstream signaling proteins induced by EGFR, insulin-like growth factor 1 (IGF-1), transforming growth factor β1 (TGF-β1), and β1-integrin receptors were evaluated by Western immunoblotting and immunocytochemical staining. To determine collagen biosynthesis and prolidase activity radiometric and colorimetric methods were used, respectively. Proline content was determined by applying the liquid chromatography coupled with mass spectrometry. We found that prolidase promoted the proliferation and migration of keratinocytes through stimulation of EGFR-downstream signaling pathways in which the PI3K/Akt/mTOR axis was involved. Moreover, PEPD upregulated the expression of β1-integrin and IGF-1 receptors and their downstream proteins. Proline concentration and collagen biosynthesis were increased in HaCaT cells under prolidase treatment. Since extracellular prolidase as a ligand of EGFR induced cell growth, migration, and collagen biosynthesis in keratinocytes, it may represent a potential therapeutic approach for the treatment of skin wounds.

Role of microenvironment on proliferation and migration of an SDHB silenced murine Pheochromocytoma cell line

2017 ◽  
Author(s):  
Serena Martinelli ◽  
Vanessa D'Antongiovanni ◽  
Susan Richter ◽  
Letizia Canu ◽  
Tonino Ercolino ◽  
...  
Keyword(s):  
Cell Line ◽  
Pheochromocytoma Cell ◽  
And Migration ◽  
Proliferation And Migration

ARFGAP3 an androgen target gene promotes prostate cancer cell proliferation and migration.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Cell Biology ◽  
Adaptor Protein ◽  
Cancer Cell Proliferation ◽  
Lncap Cells ◽  
Gtpase Activating Protein ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

ADP ribosylation factor GTPase-activating protein 3 (ARFGAP3) is a GTPase-activating protein that associates with the Golgiapparatus and regulates the vesicular trafficking pathway. In the present study, we examined the contribution of ARFGAP3 toprostate cancer cell biology. We showed that ARFGAP3 expression was induced by 100 nM of dihydrotestosterone (DHT) atboth the mRNA and protein levels in androgen-sensitive LNCaP cells. We generated stable transfectants of LNCaP cells withFLAG-tagged ARFGAP3 or a control empty vector and showed that ARFGAP3 overexpression promoted cell proliferation andmigration compared with control cells. We found that ARFGAP3 interacted with paxillin, a focal adhesion adaptor protein thatis important for cell mobility and migration. Small interfering RNA (siRNA)-mediated knockdown of ARFGAP3 showed thatARFGAP3 siRNA markedly reduced LNCaP cell growth. Androgen receptor (AR)-dependent transactivation activity on prostatespecificantigen (PSA) enhancer was synergistically promoted by exogenous ARFGAP3 and paxillin expression, as shown byluciferase assay in LNCaP cells. Thus, our results suggest that ARFGAP3 is a novel androgen-regulated gene that can promoteprostate cancer cell proliferation and migration in collaboration with paxillin.

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