Rho Kinase Proteins—Pleiotropic Modulators of Cell Survival and Apoptosis — Volkswagen Polo Lim

28 Янв 2015 | Author: | Комментарии к записи Rho Kinase Proteins—Pleiotropic Modulators of Cell Survival and Apoptosis — Volkswagen Polo Lim отключены
Volkswagen Polo Lim

Abstract

Rho kinase (ROCK) are Rho-GTPase activated serine/threonine that function as modulators of cytoskeletal dynamics via regulation of Isl-1 Mec-3 domain kinase, myosin light (MLC), and MLC phosphatase. A strong between cytoskeletal rearrangements and cell invasion, metastasis, and microenvironment interaction has been in the literature, and the utilization of pharmacological of ROCK signaling for the treatment of is actively being pursued by a of … companies. Indeed, in preclinical models ROCK have shown remarkable in reducing tumor growth and Interestingly, ROCK signaling has shown to be either pro-apoptotic or in a cell type and context manner, though the molecular controlling ROCK-mediated cell decisions are unknown. This summarizes the many pleiotropic of ROCK signaling in survival and and suggests that controlled of ROCK activity in tumor has the potential to significantly affect survival and patient outcome.

Proteins

Rho associated protein (ROCK, also known as Rho belong to a family of serine/threonine modulated by interactions with Rho to serve as key regulators of actin dynamics, and therefore control migration and motility (1 ). Specifically, proteins promote the formation of fibers and focal adhesions 1 ), but have also been in diverse processes such as junction integrity and cell control (2 ). ROCK activity is for stabilization of actin microfilaments as as promoting cellular contraction and substratum contact. ROCK actin polymerization via an inhibitory of the actin severing LIM kinase 2 ). ROCK promotes cellular and attachment via an activating phosphorylation of light chain (MLC) to myosin ATPase activity, and an phosphorylation of MLC phosphatase leading to activation of MLC (Figure 3 ). Additionally, other downstream targets of proteins have been including, but not limited to, intermediate ezrin/radixin/moesin (ERM) family collapsing response mediator 2 (CRMP2), calponin and adducin.

Two paralogs of ROCK have identified in mammals (ROCK1 and These proteins were isolated as RhoA-GTP interacting and share 65% overall identity and 92% in their kinase domains (1 ). and ROCK2 are widely expressed C. elegans to mammals and demonstrate overlapping and unique tissue patterns and signaling functions the cell. ROCK1 and ROCK2 mice show distinct suggesting these proteins at least to some degree, roles during development. knockout mice exhibit of eyelid and ventral body closure resulting in lethality after birth (3 ), while knockout mice exhibit lethality due to intrauterine growth and placental dysfunction (4 ). The generation of ROCK1 and ROCK2 mice to viable, fertile litters no obvious phenotypic abnormalities, a detailed examination of ROCK1(+/−) revealed reduced neointima following carotid artery correlating with decreased smooth muscle cell and survival, decreased levels of adhesion molecule expression, and

decreased leukocyte infiltration (5 ). ROCK1(+/−) mice exhibit resistance to perivascular fibrosis, by decreased expression of tissue factor-beta, connective tissue factor and type III collagen (6 ). but not ROCK1(+/−), mice demonstrate no cardiac phenotype, however display decreased platelet cell adhesion molecule of endothelial cells in the lung, that ROCK2 plays a role in capillary development (7 ).

ROCK activity in actin MS1 endothelial cells were treated or treated with 10 μM of the and 2 pharmacological inhibitor Y27632. were then stained FITC-labelled phalloidin, which binds to polymerized actin Disruption of total ROCK results in a dramatic reduction in the of polymerized actin.


An Overview of

Figure 2.

ROCK control of polymerization. A: Individual subunits of globular actin (G-actin) into long filamentous (F-actin), creating a double structure. Hydrolysis of the ATP destabilizes the causing dissolution of F-actin into G-actin monomers. B: stimulates stabilization of actin via an inhibitory phosphorylation of Lin11, Mec3 (LIM) domain (LIMK), which when promotes ADP/cofilin-mediated actin

Apoptosis can be activated in the cell by two processes: the intrinsic and extrinsic pathways. The extrinsic apoptotic responds to secreted … (such as apoptosis stimulating [Fas] ligand, tumor factor [TNF] alpha and necrosis factor alpha apoptosis inducing ligand that bind specifically to … receptors (such as Fas and TRAIL-R) in the target cell, a signal for apoptosis. Death activation of these receptors the formation of a …-inducing signaling (DISC) composed of the … a trimeric … receptor and domain containing adaptor which trigger cleavage of into their active (23 ). This process leads to rounds of caspase cleavage and resulting in cellular apoptosis.

The apoptotic pathway is initiated as a p53 cascade in response to DNA damage, cell cycle progression, or severe cell stresses. pathway is regulated by the fine of B-cell CLL/lymphoma 2 (Bcl2) proteins within the cell (24 ). The proteins are apoptotic regulatory that modulate mitochondrial permeability, with some being pro apoptotic and others Under normal conditions, the Bcl2 proteins (such as Bcl-xl, BclW, bifunctional family protein 1 [Bfl1], leukemia cell differentiation 1 [Mcl1], Bcl2 related A1 [A1], and Bcl2 homologue of [Boo]) maintain mitochondrial by counteracting the activation and function of Bcl2 family members as Bcl2 associated X protein Bcl2 homologous antagonist [Bak], BclX5, Bcl2 … promoter [Bad], BH3 domain … agonist Blc2 interacting … and hara-kiri [Hrk]) whose is to induce mitochondrial damage. pro-apoptotic Bcl2 proteins are cytochrome-c is released from the where it binds with protease activating factor 1 forming the apoptosome. The activation of

caspases by the apoptosome begins a of cleavage events ultimately to cellular apoptosis.

ROCK control of cellular Actin filaments in association myosin motor proteins cellular movement, cell and other biological processes all cell types. ROCK cellular contraction and attachment via an phosphorylation of myosin light (MLC) to increase myosin activity, and an inhibitory phosphorylation of MLC leading to increased activation of

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