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Markevich Ni
Thomas Jefferson University
18Publications
8H-index
1,093Citations
Publications 18
Newest
#1Markevich NiH-Index: 8
#2Jan B. HoekH-Index: 45
The main goal of this work is to develop a computational model of reactive oxygen species (ROS) production by the mitochondrial respiratory chain and analyze the control of oxidative stress that is enhanced by acute and excessive chronic ethanol treatment, resulting in ethanol-induced injury. The computational model consists of a system of 35 ordinary differential equations and describes the oxidized and reduced states of different electron carriers and the electron flow through Complexes I, II,...
1 Citations
Abstract Grb2-associated binder 1 (GAB1) is a scaffold protein involved in numerous interactions that propagate signaling by growth factor and cytokine receptors. Here we explore in silico and validate in vivo the role of GAB1 in the control of mitogenic (Ras/MAPK) and survival (phosphatidylinositol 3-kinase (PI3K)/Akt) signaling stimulated by epidermal growth factor (EGF). We built a comprehensive mechanistic model that allows for reliable predictions of temporal patterns of cellular responses ...
133 CitationsSource
#1Nikolay M. Borisov (Thomas Jefferson University)H-Index: 14
#2Markevich Ni (Thomas Jefferson University)H-Index: 8
Last.Boris N. Kholodenko (Thomas Jefferson University)H-Index: 49
view all 4 authors...
Membrane receptors and proteins involved in signal transduction display numerous binding domains and operate as molecular scaffolds generating a variety of parallel reactions and protein complexes. The resulting combinatorial explosion of the number of feasible chemical species and, hence, different states of a network greatly impedes mechanistic modeling of signaling systems. Here we present novel general principles and identify kinetic requirements that allow us to replace a mechanistic pictur...
44 CitationsSource
#1Markevich Ni (Thomas Jefferson University)H-Index: 8
#2Mikhail A. Tsyganov (Thomas Jefferson University)H-Index: 14
Last.Boris N. Kholodenko (Thomas Jefferson University)H-Index: 49
view all 4 authors...
A hallmark of protein kinase/phosphatase cascades, including mitogen-activated protein kinase (MAPK) pathways, is the spatial separation of their components within cells. The top-level kinase, MAP3K, is phosphorylated at the cell membrane, and cytoplasmic kinases at sequential downstream levels (MAP2K and MAPK) spread the signal to distant targets. Given measured protein diffusivity and phosphatase activities, signal propagation by diffusion would result in a steep decline of MAP2K activity and ...
75 CitationsSource
#1Markevich Ni (Thomas Jefferson University)H-Index: 8
#2Oleg Yu. Pimenov (RAS: Russian Academy of Sciences)H-Index: 4
Last.Kokoz Ym (RAS: Russian Academy of Sciences)H-Index: 2
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Abstract A kinetic model of Ca 2+ -dependent inactivation (CDI) of L-type Ca 2+ channels was developed. The model is based on the hypothesis that postulates the existence of four short-lived modes with lifetimes of a few hundreds of milliseconds. Our findings suggest that the transitions between the modes is primarily determined by the binding of Ca 2+ to two intracellular allosteric sites located in different motifs of the CI region, which have greatly differing binding rates for Ca 2+ (differe...
3 CitationsSource
#1Nikolay M. Borisov (Thomas Jefferson University)H-Index: 14
#2Markevich Ni (Thomas Jefferson University)H-Index: 8
Last.Boris N. Kholodenko (Thomas Jefferson University)H-Index: 49
view all 4 authors...
After activation, many receptors and their adaptor proteins act as scaffolds displaying numerous docking sites and engaging multiple targets. The consequent assemblage of a variety of protein complexes results in a combinatorial increase in the number of feasible molecular species presenting different states of a receptor-scaffold signaling module. Tens of thousands of such microstates emerge even for the initial signal propagation events, greatly impeding a quantitative analysis of networks. He...
94 CitationsSource
#1Markevich Ni (Thomas Jefferson University)H-Index: 8
#2Gisela Moehren (Thomas Jefferson University)H-Index: 10
Last.Boris N. Kholodenko (Thomas Jefferson University)H-Index: 49
view all 6 authors...
A systems biology approach is applied to gain a quantitative understanding of the integration of signalling by the small GTPase Ras. The Ras protein acts as a critical switch in response to signals that determine the cell's fate. In unstimulated cells, Ras switching between an inactive GDP-binding and active GTP-binding state is controlled by the intrinsic catalytic activities of Ras. The calculated high sensitivity of the basal Ras-GTP fraction to changes in the rate constant of GTP-hydrolysis ...
49 CitationsSource
#1Markevich NiH-Index: 8
#2Jan B. HoekH-Index: 16
Last.Boris N. KholodenkoH-Index: 49
view all 3 authors...
Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the report...
573 CitationsSource
#1Gisela MoehrenH-Index: 10
#2Markevich NiH-Index: 8
Last.Boris N. KholodenkoH-Index: 49
view all 7 authors...
Stimulation of isolated hepatocytes with epidermal growth factor (EGF) causes rapid tyrosine phosphorylation of the EGF receptor (EGFR) and adapter/target proteins, which was monitored with 1 and 2 s resolution at 37, 20,and 4 °C. The temporal responses detected for multiple signaling proteins involve both transient and sustained phosphorylation patterns, which change dramatically at low temperatures. To account quantitatively for complex responses, we employed a mechanistic kinetic model of the...
70 CitationsSource
#1Kokoz YuMH-Index: 1
#2Grichenko AsH-Index: 3
Last.Markevich NiH-Index: 8
view all 6 authors...
The action of isoproterenol and BAY K 8644 on voltage-dependent Ca2+ currents in isolated ground squirrel cardiac myocytes was studied in two (active and hibernating) states of the animal. In cardiac myocytes of active animals the effect of both drugs was shown to depend on the holding potential. At Vh of about -50 mV both isoproterenol and BAY K 8644 increased the Ca2+ current and their action was additive. At Vh of about -20 mV, both drugs inhibited the Ca2+ current. In cardiac myocytes from h...
2 Citations
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