scholarly journals Comparable affinity of RabGDIα for GTP- and GDP-bound forms of Rab7 supports a four-state transition model for Rab7 subcellular localization

2018 ◽  
Author(s):  
Akane Kanemitsu-Fujita ◽  
So Morishita ◽  
Svend Kjaer ◽  
Mitsunori Fukuda ◽  
Giampietro Schiavo ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
State Transition ◽  
Transition Model ◽  
Late Endosomes ◽  
Cell Life ◽  
Inactive Form ◽  
State Transition Model ◽  
Almost All

AbstractEndolysosomal system is linked to almost all aspects of cell life and diseases, and Rab7 occupies a critical node in this crucial pathway. However, there have been conflicting views about the exact role of Rab7 in membrane trafficking, since some studies have reported that Rab7 regulates the trafficking from early to late endosomes, while others highlighted its role in late endosomes to lysosomes progression. In the present study, we have revisited this issue from a new viewpoint. In COS-7 cells, a GDP-bound Rab7 mutant, T22N, was located to vesicular membranes as well as in cytoplasm. Similarly, the GTPase-deficient Q67L mutant of Rab7 resided in cytoplasm as well as on membranes. Additionally, we found that RabGDI interacted with both GTP- and GDP-bound forms of Rab7 in vitro. These results have prompted us to propose a four-state transition model for Rab7. This four-state model matches with our recent findings that Rab7 was initially recruited to macropinosomes in a GDP-bound inactive form and subsequently became activated during endocytic maturation in EGF-stimulated COS-7 cells.

scholarly journals Role of the V1G1 subunit of V-ATPase in breast cancer cell migration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria De Luca ◽  
Roberta Romano ◽  
Cecilia Bucci
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Downstream Signaling ◽  
Late Endosomes ◽  
Intracellular Compartments

AbstractV-ATPase is a large multi-subunit complex that regulates acidity of intracellular compartments and of extracellular environment. V-ATPase consists of several subunits that drive specific regulatory mechanisms. The V1G1 subunit, a component of the peripheral stalk of the pump, controls localization and activation of the pump on late endosomes and lysosomes by interacting with RILP and RAB7. Deregulation of some subunits of the pump has been related to tumor invasion and metastasis formation in breast cancer. We observed a decrease of V1G1 and RAB7 in highly invasive breast cancer cells, suggesting a key role of these proteins in controlling cancer progression. Moreover, in MDA-MB-231 cells, modulation of V1G1 affected cell migration and matrix metalloproteinase activation in vitro, processes important for tumor formation and dissemination. In these cells, characterized by high expression of EGFR, we demonstrated that V1G1 modulates EGFR stability and the EGFR downstream signaling pathways that control several factors required for cell motility, among which RAC1 and cofilin. In addition, we showed a key role of V1G1 in the biogenesis of endosomes and lysosomes. Altogether, our data describe a new molecular mechanism, controlled by V1G1, required for cell motility and that promotes breast cancer tumorigenesis.

scholarly journals Exploring the Cost Effectiveness of Shared Decision Making for Choosing between Disease-Modifying Drugs for Relapsing-Remitting Multiple Sclerosis in the Netherlands: A State Transition Model

2020 ◽  
Vol 40 (8) ◽  
pp. 1003-1019
Author(s):  
Ingrid E. H. Kremer ◽  
Mickael Hiligsmann ◽  
Josh Carlson ◽  
Marita Zimmermann ◽  
Peter J. Jongen ◽  
...  
Keyword(s):  
Decision Making ◽  
Cost Effectiveness ◽  
Shared Decision Making ◽  
State Transition ◽  
Transition Model ◽  
Shared Decision ◽  
Relapsing Remitting ◽  
State Transition Model ◽  
The Cost ◽  
Relapsing Remitting Multiple Sclerosis

Background Up to 31% of patients with relapsing-remitting multiple sclerosis (RRMS) discontinue treatment with disease-modifying drug (DMD) within the first year, and of the patients who do continue, about 40% are nonadherent. Shared decision making may decrease nonadherence and discontinuation rates, but evidence in the context of RRMS is limited. Shared decision making may, however, come at additional costs. This study aimed to explore the potential cost-effectiveness of shared decision making for RRMS in comparison with usual care, from a (limited) societal perspective over a lifetime. Methods An exploratory economic evaluation was conducted by adapting a previously developed state transition model that evaluates the cost-effectiveness of a range of DMDs for RRMS in comparison with the best supportive care. Three potential effects of shared decision making were explored: 1) a change in the initial DMD chosen, 2) a decrease in the patient’s discontinuation in using the DMD, and 3) an increase in adherence to the DMD. One-way and probabilistic sensitivity analyses of a scenario that combined the 3 effects were conducted. Results Each effect separately and the 3 effects combined resulted in higher quality-adjusted life years (QALYs) and costs due to the increased utilization of DMD. A decrease in discontinuation of DMDs influenced the incremental cost-effectiveness ratio (ICER) most. The combined scenario resulted in an ICER of €17,875 per QALY gained. The ICER was sensitive to changes in several parameters. Conclusion This study suggests that shared decision making for DMDs could potentially be cost-effective, especially if shared decision making would help to decrease treatment discontinuation. Our results, however, may depend on the assumed effects on treatment choice, persistence, and adherence, which are actually largely unknown.

scholarly journals Sec1p directly stimulates SNARE-mediated membrane fusion in vitro

2004 ◽  
Vol 167 (1) ◽  
pp. 75-85 ◽  
Author(s):  
Brenton L. Scott ◽  
Jeffrey S. Van Komen ◽  
Hassan Irshad ◽  
Song Liu ◽  
Kirilee A. Wilson ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Membrane Fusion ◽  
Membrane Trafficking ◽  
Snare Complex ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Bud Neck ◽  
Precise Role

Sec1 proteins are critical players in membrane trafficking, yet their precise role remains unknown. We have examined the role of Sec1p in the regulation of post-Golgi secretion in Saccharomyces cerevisiae. Indirect immunofluorescence shows that endogenous Sec1p is found primarily at the bud neck in newly budded cells and in patches broadly distributed within the plasma membrane in unbudded cells. Recombinant Sec1p binds strongly to the t-SNARE complex (Sso1p/Sec9c) as well as to the fully assembled ternary SNARE complex (Sso1p/Sec9c;Snc2p), but also binds weakly to free Sso1p. We used recombinant Sec1p to test Sec1p function using a well-characterized SNARE-mediated membrane fusion assay. The addition of Sec1p to a traditional in vitro fusion assay moderately stimulates fusion; however, when Sec1p is allowed to bind to SNAREs before reconstitution, significantly more Sec1p binding is detected and fusion is stimulated in a concentration-dependent manner. These data strongly argue that Sec1p directly stimulates SNARE-mediated membrane fusion.

Experience with Formal Specifications Using an Extended State Transition Model

1982 ◽  
Vol 30 (12) ◽  
pp. 2506-2513 ◽  
Author(s):  
G. Bochmann ◽  
E. Cerny ◽  
M. Gagne ◽  
C. Jard ◽  
A. Leveille ◽  
...  
Keyword(s):  
State Transition ◽  
Transition Model ◽  
Formal Specifications ◽  
Extended State ◽  
State Transition Model

Protocol Analysis and Synthesis using a State Transition Model

1982 ◽  
pp. 645-669 ◽  
Author(s):  
Pitro Zafiropulo ◽  
Colin H. West ◽  
Harry Rudin ◽  
D. D. Cowan ◽  
Daniel Brand
Keyword(s):  
State Transition ◽  
Protocol Analysis ◽  
Transition Model ◽  
Analysis And Synthesis ◽  
State Transition Model
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