A transient increase in the activity of Src-family kinases induced by cell detachment delays anoikis of intestinal epithelial cells

Loza-Coll, Mariano; Perera, Sheron; Shi, Wen; Filmus, Jorge

doi:10.1038/sj.onc.1208379

Cited by 57 publications

(45 citation statements)

References 47 publications

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“…17 Detachment of intestineal epithelial cells triggers a transient c-src and c-fyn activation, antagonizing detachment-induced anoikis in these cells. 18 Loss of lck has no effect on the survival of peripheral T cells; however, deletion of both lck and fyn substantially diminishes its survival. 19 TRANCE-induced survival of osteoclasts isolated from src À/À mice is compromised relative to wild-type mice.…”

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confidence: 99%

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Tang

Feng

2006

Cell Death Differ

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Phosphatidylinositol 3-kinase enhancer-activating Akt (PIKE-A) binds Akt and upregulates its kinase activity, preventing apoptosis. PIKE-A can be potently phosphorylated on tyrosine residues 682 and 774, leading to its resistance to caspase cleavage. However, the upstream tyrosine kinases responsible for PIKE-A phosphorylation and subsequent physiological significance remain unknown. Here, we show that PIKE-A can be cleaved by the active apoptosome at both D474 and D592 residues. Employing fyn-deficient mouse embryonic fibroblast cells and tissues, we demonstrate that fyn is essential for phosphorylating PIKE-A and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with PIKE-A and phosphorylates it on both Y682 and Y774 residues. Tyrosine phosphorylation in PIKE-A is required for its association with active fyn but not for Akt. Mutation of D into A in PIKE-A protects it from caspase cleavage and promotes cell survival. Thus, this finding provides a molecular mechanism accounting for the antiapoptotic action of src-family tyrosine kinase.

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confidence: 99%

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Tang

Feng

2006

Cell Death Differ

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“…It was previously established that the survival of cells cultured without extracellular attachments is promoted by PI 3-K 2 and AKT because inhibition of these kinases increased anoikis (6,7). Moreover, the anchorage-independent survival of cancer cells that is induced by transforming oncogenes such as Ras and Src depends in part on PI 3-K and AKT (8 -10).…”

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confidence: 99%

Antianoikis Effect of Nuclear Factor-κB through Up-regulated Expression of Osteoprotegerin, BCL-2, and IAP-1

Törüner

Fernández-Zapico

Sha

et al. 2006

Journal of Biological Chemistry

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Contact with extracellular matrix provides survival signals to epithelial cells. When epithelial cells lose such contacts, a form of apoptosis results, which has been termed anoikis (1). Physiologically, anoikis is important in the regulation of cell number in the intestinal tract, where epithelial cells are shed from villus tips in the small intestine and from the intercrypt epithelium of the colon and die by anoikis (2, 3). Pathophysiologically, resistance to anoikis has been associated with metastatic spread of carcinoma cells (4, 5), which reflects the ability of malignantly transformed epithelial cells to evade apoptosis when deprived of extracellular matrix attachment during dissemination in lymph or blood. The molecular mechanisms that govern susceptibility to anoikis have not been fully characterized and could provide important insights into epithelial homeostasis and carcinogenesis.It was previously established that the survival of cells cultured without extracellular attachments is promoted by PI 3-K 2 and AKT because inhibition of these kinases increased anoikis (6, 7). Moreover, the anchorage-independent survival of cancer cells that is induced by transforming oncogenes such as Ras and Src depends in part on PI 3-K and AKT (8 -10). However, the molecular mechanisms by which cells activate PI 3-K and AKT after loss of extracellular attachments and through which this pathway blocks anoikis have not been completely characterized; nor have the molecular factors that ultimately control the susceptibility of cells to undergo anoikis been identified.NF-B constitutes a family of transcription factors defined by the presence of a Rel homology domain. When exposed to certain stresses, such as inflammation, infection, oxidative stress, or DNA double strand breaks, NF-B dissociates from inhibitory I B molecules, translocates from cytoplasm to nucleus, and binds to B sequences in the promoter regions of specific target genes, up-regulating their expression (11). Prominent among the more than 150 genes known to be regulated by NF-B proteins are a subset whose products inhibit apoptosis, including BCL-X L , BCL-2, IAP-1 and -2, c-FLICE inhibitory protein, growth arrest and DNA damage associated protein 45␤, and tumor necrosis factor (TNF) receptor-associated proteins 1 and 2 (12). NF-B activation is strongly associated with resistance to apoptosis induced by TNF-␣ (13), ionizing radiation (14), and cancer chemotherapeutic drugs (15). An important role for NF-B in carcinogenesis has been proposed, based on the oncogenicity of v-rel (16), the effect of NF-B in promoting chemotherapy and radiotherapy resistance of cancer cells (17), and the functional requirement for NF-B in tumorigenesis in the colon, breast, and liver (18 -20). Because of the importance of NF-B in apoptosis resistance and carcinogenesis, we suspected that this factor might regulate anoikis.To address this possibility, we evaluated a functional role for NF-B in the regulation of anoikis susceptibility, using a suspension culture model of intestinal e...

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“…Recent studies indicate that detachment of nonmalignant intestinal and breast epithelial cells triggers not only pro-but also antiapoptotic signals, and it is the balance between these signals that is primarily responsible for the regulation of anoikis (Gilmore et al, 2000;Wang et al, 2003;Loza-Coll et al, 2005;Yan et al, 2005). It is now thought that the role of detachmenttriggered antiapoptotic mechanisms in the control of anoikis is to delay the onset of this process and thus establish the timing of detachment-induced apoptosis (Loza-Coll et al, 2005;Yan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…It is now thought that the role of detachmenttriggered antiapoptotic mechanisms in the control of anoikis is to delay the onset of this process and thus establish the timing of detachment-induced apoptosis (Loza-Coll et al, 2005;Yan et al, 2005). These antiapoptotic events allow the cells to survive if the cells are given a chance to re-establish contacts with the ECM relatively soon after detachment.…”

Section: Introductionmentioning

confidence: 99%

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Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Liu

et al. 2006

Oncogene

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Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro-and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachmentdependent activation of the transcription factor nuclear factor-jB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.

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A transient increase in the activity of Src-family kinases induced by cell detachment delays anoikis of intestinal epithelial cells

Cited by 57 publications

References 47 publications

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Antianoikis Effect of Nuclear Factor-κB through Up-regulated Expression of Osteoprotegerin, BCL-2, and IAP-1

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

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