Article

Adhesion signaling: PAK meets Rac on solid ground

The Picower Institute for Medical Research, Manhasset, NY 11030, USA. .
Current Biology (Impact Factor: 9.92). 08/2000; 10(14):R535-7. DOI: 10.1016/S0960-9822(00)00588-1
Source: PubMed

ABSTRACT Interaction of cells with the extracellular matrix influences various aspects of cellular behavior. A recent study shows that cell-substrate adhesion is necessary for effective coupling of the small GTPase Rac to its effector PAK.

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    • "Large clostridial toxins possess a glucosyltransferase activity allowing glucosylation at Threonin 35/37 of small G-proteins of the Ras superfamily by direct inhibition of effector binding (Popoff, 1987). Small GTPases include, among others, members of the Ras family (Ras, Rap and Ral) involved in signal transduction and members of the Rho family (Rho, Rac, Cdc42) implicated in actin cytoskeleton remodelling but also in a variety of cell functions such as cell cycle progression and gene transcription (Van Aelst and D'Souza- Schorey, 1997; Symons, 2000). The targets of toxins A and B from C. difficile are Rho, Rac and Cdc42, whereas LT, isolated from C. sordellii , strain IP-82, has been reported to inactivate Ras, Ral, Rap and Rac (Popoff et al ., 1996; Richard et al ., 1999). "
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    ABSTRACT: Lethal toxin (LT) from Clostridium sordellii (strain IP82) inactivates in glucosylating the small GTPases Ras, Rap, Ral and Rac. In the present study we show that LT-IP82 induces cell death via an intrinsic apoptotic pathway in the myeloid cell-line HL-60. LT-IP82 was found to disrupt mitochondrial homeostasis as characterized by a decrease in mitochondrial transmembrane potential and cardiolipin alterations, associated with the release of cytochrome c in the cytosol. Time-course studies of caspase activation revealed that caspase-9 and caspase-3 were activated before caspase-8. Moreover, although LT-IP82-induced cell death was abrogated by caspase-inhibitors, these inhibitors did not suppress mitochondrial alterations, indicating that caspase activation occurs downstream of mitochondria. Protection of mitochondria by Bcl-2 overexpression prevented mitochondrial changes as well as apoptosis induction. Furthermore, evidence is provided that LT-IP82-induced apoptosis is not a consequence of cortical actin disorganization, suggesting that Rac inactivation does not initiate the apoptotic process. Cell exposure to LT-IP82 leads to a co-localization of the toxin with a mitochondrial marker within 2 h. Therefore, we suggest that LT-IP82 could act at the mitochondrion level independently of its enzymatic effect on small GTPases.rde
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    • "The N-terminal part of TcsL cleaves UDP-glucose and transfers the glucose moiety to the Thr35/37 of target GTPases belonging to the Ras family (Ras, Rap and Ral) and Rho family (Rac, Cdc42) (Barbier et al., 2004; Boehm et al., 2006; Herrmann et al., 1998). By inhibiting the activation of these signaling proteins a variety of cellular functions including signal transduction, cytoskeleton remodeling, cell cycle progression and gene transcription are disturbed leading to characteristical cytotoxic and cytopathic effects (Petit et al., 2003; Symons, 2000; Van Aelst and D'Souza-Schorey, 1997; Voth and Ballard, 2007). As described for humans (Sinave et al., 2002), cattle and sheep (Morris et al., 2002), infection with C. sordellii leads to development of toxic shock syndrome and multiorgan failure due to TcsLinduced apoptosis of various cell types. "
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    ABSTRACT: The lethal toxin of Clostridium sordellii (TcsL) evokes severe, mostly fatal disease patterns like toxic shock syndrome in humans and animals. Since this large clostridial toxin-induced severe muscle damaging when injected intramuscularly into mice, we hypothesized that TcsL is also associated with equine atypical myopathy (EAM), a fatal myodystrophy of hitherto unknown etiology. Transmission electron microscopy revealed skeletal and heart muscles of EAM-affected horses to undergo degeneration ultrastructurally similar to the damage found in TcsL-treated mice. Performing immunohistochemistry, myofibers of EAM-affected horses specifically reacted with sera derived from horses with EAM as well as an antibody specific for the N-terminal part of TcsL, while both antibodies failed to bind to the myofibers of either healthy horses or those with other myopathies. The presence of TcsL in myofibers of horses with EAM suggests that it plays a role as trigger or even as lethal factor in this disease.
    Veterinary Microbiology 02/2010; 144(3-4):487-92. DOI:10.1016/j.vetmic.2010.01.024 · 2.73 Impact Factor
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    • "FAK also regulates adhesion-dependent Rac activation by promoting the p130-Cas/Crk complex, which stimulates the novel guanine nucleotide exchange factor DOCK180 [82 –84]. In addition to inducing actin rearrangement and cell spreading, p21-Rac stimulates the kinase PAK [85], which feeds back directly on the Ras – MAPK pathway by phosphorylating and activating both Raf and MEK [71] [74]. An additional integrin-dependent feedback from PAK to the MAPK pathway may occur through FAK. "
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    ABSTRACT: Adhesion to extracellular matrix regulates cell survival through both integrin engagement and appropriate cell spreading. Numerous signaling pathways converge to affect the levels and posttranslational modifications of Bcl-2 family proteins. Recent work has defined specific roles for different Bcl-2 proteins in the disruption of mitochondrial function that leads to cell death. Using this understanding of Bcl-2 protein function as a framework, we will consider the molecular mechanisms of apoptosis induced by integrin detachment (anoikis) and cell death stimulated by the loss of cytoskeletal architecture (amorphosis).
    Biochimica et Biophysica Acta 08/2004; 1692(2-3):145-57. DOI:10.1016/j.bbamcr.2004.02.008 · 4.66 Impact Factor
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