Cytoskeletal integrity

The last part of this account will be devoted to protein kinases and protein phosphatases and some recent results we have obtained for them. Protein kinases and phosphatases are signaling biomolecules that control the level of phosphorylation and dephosphorylation of tyrosine, serine or threonine residues in other proteins, and by this means regulate a variety of fundamental cellular processes including cell growth and proliferation, cell cycle and cytoskeletal integrity. 

Ras is a G protein that cycle between two conformations, an activated Ras-GTP or inactivated form Ras-GDP. Ras, attached to the cell membrane by lipidation, is a key component in many signalling cascades, which couple growth factor receptors to downstream effectors that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis and cell migration. Mutations and dysregulations of the Ras protein leading to increased invasion and metastasis, and decreased apoptosis are very common in cancers. 

Antibiotics alter the normal colonic flora, leading to loss of colonization resistance, which is the ability of the normal flora to protect against overgrowth of pathogens, especially when the anaerobic flora are depleted [15], In CDAD, the altered colonization resistance can allow for the overgrowth of C. difficile in the colon. The bacteria produces two toxins which cause disease (toxin A, an enterotoxin, and toxin B, a cytotoxin). The toxins of C. difficile inactivate Rho proteins, which results in the loss of cytoskeletal integrity in enterocytes. Cellular damage results in fluid loss, exudation and diarrhea. The most severe form of C. difficile diarrhea is pseudomembranous colitis, which can cause severe colitis, toxic colon and rarely colon perforation and death. 

Manning, B.W., Adams, D.O. Lewis, J.G. (1994) Effects of benzene metabolites on receptor-mediated phagocytosis and cytoskeletal integrity in mouse peritoneal macrophages. Toxicol, appl. Pharmacol., 126, 214-223... 

Eriksson, J.E. et al., Cytoskeletal integrity in interphase cells requires protein phosphatase activity, Proc. Natl. Acad. Sci. USA, 89, 11093, 1992. 

Holen, I., Gordon, P.B. Seglen, P.O. (1992) Biochem. J. 284, 633 36. Protein kinase-dependent effects of okadaic acid on hepatocytic autophagy and cytoskeletal integrity. 

Thus far, microtubules and actin filaments and their associated proteins have been discussed to advantage as independent cytoskeletal components. In actual fact, all of the components of the cytoskeleton (including intermediate filaments) are precisely integrated with one another (Langford, 1995), as well as with various cytoplasmic organelles, the nuclear membrane, the plasma membrane, and the extracellular matrix. In its totality the cytoskeleton subserves many coordinated and regulated functions in the cell ... 

Figure 52-4. Diagrammatic representation of the interaction of cytoskeletal proteins with each other and with certain integral proteins of the membrane of the red blood cell. (Reproduced, with permission, from Beck WS, Tepper Rl Hemolytic anemias III membrane disorders. In Hematology, 5th ed. Beck WS [editor]. The MIT Press, 1991.)...

Mechanical functions of cells require interactions between integral membrane proteins and the cytoskeleton 29 The spectrin-ankyrin network comprises a general form of membrane-organizing cytoskeleton within which a variety of membrane-cytoskeletal specializations are interspersed 29 Interaction of rafts with cytoskeleton is suggested by the results of video microscopy 29... 

Mechanical functions of cells require interactions between integral membrane proteins and the cyto-skeleton. These functions include organization of signaling cascades, formation of cell junctions and regulation of cell shape, motility, endo- and exocytosis. Several different families of membrane-associated proteins mediate specific interactions among integral membrane proteins, cytoskeletal proteins and contractile proteins. Many of these linker proteins consist largely of various combinations of conserved protein-association domains, which often occur in multiple variant copies. 

Vesicular trafficking and inclusion body formation are both dependent on the integrity of microtubules and other cytoskeletal components. Parkin has been shown to target misfolded tubulin for degradation [251] (figure 4.6B) and to interact with centrosomes upon proteasomal inhibition [252]. Whether this reflects association with specific substrates or co-localization with proteasomes in centrosomes re-... 

Neurons possess a cell body (also referred to as a soma or perikaryon), which consists of a nucleus surrounded by cytoplasm and membrane. The survival of the rest of the neuron is dependent upon the integrity of the cell body. Axons and dendrites are both processes that extend from the cell body. Also located in the cell body are the Golgi apparatus, smooth ER, rough ER, and mitochondria. Cytoskeletal elements—microtubules and neurofilaments—are also present. 

Alterations in the cytoskeleton. The cytoskeleton depends on the intracellular Ca2+ concentration, which affects actin bundles, the interactions between actin and myosin and a-tubulin polymerization. The effect of increases in Ca2+ on the cytoskeletal attachments to the plasma membrane and the role of the cytoskeleton in cellular integrity have already been mentioned (see above). If the cytoskeleton is damaged or disrupted or its function altered by an increase in Ca2+, then blebs or protrusions appear on the plasma membrane (see below). As well as an increase in Ca2+, oxidation of, or reaction with sulfydryl groups, such as alkylation or arylation, for example, may disrupt the cytoskeleton, as thiols... 

Phospholipid molecules in the plasma membrane diffuse rapidly enough to go from one end of an average-sized animal cell to the other in a few minutes. In a bacterial cell, such a trip would take only a few seconds. Integral membrane proteins move more slowly than phospholipids, as we expect in view of their greater mass. Diffusion of membrane proteins plays essential roles in many biochemical processes, including the cellular uptake of lipoproteins (chapter 18), responses of cells to hormones (chapter 24), immunological reactions (supplement 3), vision (supplement 2), and the transport of nutrients and ions. As we see in a later section, however, some membrane proteins cannot move about rapidly because they are attached to cytoskeletal scaffolds. 

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