Phosphatidylinositol 3-Kinase-dependent Pathways Oppose Fas-induced Apoptosis and Limit Chloride Secretion in Human Intestinal Epithelial Cells

Abreu, María T.; Arnold, Elizabeth T.; Chow, Jennifer; Barrett, Kim E.

doi:10.1074/jbc.m106226200

Cited by 24 publications

(21 citation statements)

References 94 publications

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“…Recent reports have indicated that blockade of the PI 3-kinase pathway with inhibitors sensitized endothelial and epithelial cells to both Fas-and TNF␣-induced death (43,44), thus setting a precedent for the importance of the PI 3-kinase/Akt pathway in inhibiting stress-induced apoptosis. Our observations support this notion in that neutrophils incubated with the integrin-activating antibody VIM12 and the stress stimulus TNF␣ or anti-Fas IgM displayed a significant increase in apoptosis, which was shown to be directly linked to loss of Akt activity (Fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of SHIP by NADPH Oxidase-stimulated Lyn Leads to Enhanced Apoptosis in Neutrophils

Gardai

Whitlock

Helgason

et al. 2002

Journal of Biological Chemistry

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Neutrophils undergo rapid spontaneous apoptosis. Multiple antiapoptotic stimuli can inhibit this process via activation of the Akt pathway. However, despite no such effect singly, combined anti-and proapoptotic stimuli inhibit Akt activity, leaving the cells susceptible to accelerated apoptosis. The blockade of Akt activation depended on reduced phosphoinositide 3,4,5-trisphosphate levels but not decreased phosphatidylinositol 3-kinase activity, thus implicating the involvement of an inositol phosphatase. Evidence for SHIP involvement was provided by SHIP localization to membrane receptors and subsequent activation along with the observed inability of SHIP ؊/؊ neutrophils to exhibit enhanced apoptosis with the stimulus combination. Activation of SHIP was found to depend on Lyn activation, and this, in turn, required NADPH oxidase. Neutrophils from chronic granulomatous disease patients and Lyn ؊/؊ mice no longer responded to the combined stimuli. Thus, we propose a role for oxidants and Lyn in SHIP regulation and suggest a novel mechanism for regulating neutrophil apoptosis.

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Section: Discussionmentioning

confidence: 99%

Activation of SHIP by NADPH Oxidase-stimulated Lyn Leads to Enhanced Apoptosis in Neutrophils

Gardai

Whitlock

Helgason

et al. 2002

Journal of Biological Chemistry

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“…The phosphoinositide 3-kinase (PI3K)/ Akt pathway plays a pivotal role in these mechanisms. Studies that evaluated Fas-mediated apoptosis of intestinal epithelial cells showed that the inhibition of PI3K sensitizes cells to Fas-induced apoptosis, whereas the constitutive expression of Akt protects cells from apoptosis (21). CK8/ 18-free hepatocytes from CK8-null mice were shown to be more sensitive than wild-type mouse hepatocytes to Fasmediated apoptosis after stimulation with Jo2, an agonistic antibody of Fas ligand (12).…”

Section: Cell Signalingmentioning

confidence: 99%

“…Further investigation is needed to determine the consequences of altered expression of CK18 on cellular function. Investigators have explored various post-translational modifications of CK18, including site-specific phosphorylation (16,19,21), OGlcN-arylation (18,19), and acetylation (20). These modifications regulate each other and determine the solubility, filament organization, and stability of CK8/18.…”

Section: Expression and Clinical Applications Of Ck18 In Cancer Exprementioning

confidence: 99%

Biological Functions of Cytokeratin 18 in Cancer

Weng

Cui²,

Fang³

2012

Molecular Cancer Research

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The structural proteins cytokeratin 18 (CK18) and its coexpressed complementary partner CK8 are expressed in a variety of adult epithelial organs and may play a role in carcinogenesis. In this study, we focused on the biological functions of CK18, which is thought to modulate intracellular signaling and operates in conjunction with various related proteins. CK18 may affect carcinogenesis through several signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt, Wnt, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways. CK18 acts as an identical target of Akt in the PI3K/Akt pathway and of ERK1/2 in the ERK MAPK pathway, and regulation of CK18 by Wnt is involved in Akt activation. Finally, we discuss the importance of gaining a more complete understanding of the expression of CK18 during carcinogenesis, and suggest potential clinical applications of that understanding. Mol Cancer Res; 10(4); 485-93. Ó2012 AACR.

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“…Nevertheless, caspase 8 does not appear to be present in established focal adhesions, nor does caspase 8 activation occur during integrin ligation events during cell spreading. However, caspase 8 is not always activated by DR ligation and membrane recruitmentin fact, the activation of signaling molecules such as Akt (Abreu et al, 2001;Li et al, 2002;Thakkar et al, 2001) or PKC (Gomez-Angelats and Cidlowski, 2001;Miranti et al, 1999;Zhuang et al, 2001;Meng et al, 2002) suppresses activation of caspase 8 and may be involved in DR-mediated signaling to the NFκB, JNK or ERK1/2 pathways (Fig. 4).…”

Section: Do Integrins Communicate With the Ded?mentioning

confidence: 99%

Get a ligand, get a life: integrins, signaling and cell survival

Stupack

Cheresh

2002

Journal of Cell Science

530

434

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Programmed cell death is crucial for the development and maintenance of multicellular organisms. The decision to live, or to die, depends, at the cellular level, upon the cell's interaction with extracellular cues that trigger cell signaling pathways promoting survival or death. The extracellular matrix (ECM) influences the execution of the apoptotic program through the actions of adhesion receptors. Among these, integrins initiate a variety of downstream signaling events in response to ECM ligation. Integrins directly activate survival pathways via the PI 3-kinase and MAPK pathways and act as essential cofactors for their stimulation by growth factors. Conversely,elevated integrin expression in the absence of appropriate ligands, or in the presence of natural or synthetic antagonists, can promote apoptosis under otherwise permissive growth conditions. Integrins thus act in a crucial biosensory role, coordinating survival or death responses as a function of ECM composition. This dual function provides an elegant mechanism through which tissue-remodeling events may regulate cell death or survival in a temporal,ECM-governed manner.

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Phosphatidylinositol 3-Kinase-dependent Pathways Oppose Fas-induced Apoptosis and Limit Chloride Secretion in Human Intestinal Epithelial Cells

Cited by 24 publications

References 94 publications

Activation of SHIP by NADPH Oxidase-stimulated Lyn Leads to Enhanced Apoptosis in Neutrophils

Activation of SHIP by NADPH Oxidase-stimulated Lyn Leads to Enhanced Apoptosis in Neutrophils

Biological Functions of Cytokeratin 18 in Cancer

Get a ligand, get a life: integrins, signaling and cell survival

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