Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: Role in absorption and differentiation

Li, Xshang; Leu, Sharon; Cheong, Alice; Zhang, Huiping; Baibakov, Boris; Shih, Chris; Birnbaum, Morris J.; Donowitz, Mark

doi:10.1053/j.gastro.2003.10.061

Cited by 66 publications

(57 citation statements)

References 40 publications

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“…SDS-PAGE immunoblots suggested that Akt2 is the predominant isoform expressed in these cells (Fig. 6A), consistent with the pattern of expression in rabbit ileal villus enterocyte brush border membranes (42). Akt1 was detected only faintly using isoform-specific antibodies, and Akt3 was not detected at all.…”

Section: Akt Inhibition Prevents Ezrin Phosphorylation After Initiatisupporting

confidence: 80%

“…This PI3-kinase-dependent increase in Akt activity correlated with translocation of NHE3 to the brush border (50). Separate studies have shown that a significant fraction of brush border NHE3 is found in detergent-insoluble lipid rafts (50) that also contain Akt2 (42) and ezrin (51,52). Until now, however, a functional relationship between ezrin and Akt2 has not been proposed.…”

Section: Fig 8 Akt2 Expression Is Required For Nhe3 Translocation Amentioning

confidence: 98%

“…a direct interaction mediated by a putative ezrin-binding site at the C-terminal of NHE3 (21)) may be involved. Although Akt has been previously associated with translocation of NHE3 (24,26,42), the mechanisms of this regulation are incompletely defined. For example, EGF-mediated stimulation of PI3-kinase results in increased Akt activity within early endosome and brush border plasma membrane fractions that correlates with increased total and phosphorylated Akt2 at those sites.…”

Section: Fig 8 Akt2 Expression Is Required For Nhe3 Translocation Amentioning

confidence: 99%

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Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Shiue

Musch

Wang

et al. 2005

Journal of Biological Chemistry

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Initiation of Na؉ -glucose cotransport in intestinal absorptive epithelia causes NHE3 to be translocated to the apical plasma membrane, leading to cytoplasmic alkalinization. We reported recently that this NHE3 translocation requires ezrin phosphorylation. However, the kinase that phosphorylates ezrin in this process has not been identified. Because Akt has also been implicated in NHE3 translocation, we investigated the hypothesis that Akt phosphorylates ezrin. After initiation of Na ؉ -glucose cotransport, Akt is activated with kinetics that parallel those of ezrin phosphorylation. Inhibition of p38 MAP kinase, which blocks ezrin phosphorylation, also prevents Akt activation. Purified Akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an ATP-dependent manner. This in vitro phosphorylation can be prevented by Akt inhibitors. In intact cells, inhibition of either phosphoinositide 3-kinase, an upstream regulator of Akt, or inhibition of Akt itself using inhibitors validated in vitro prevents ezrin phosphorylation after initiation of Na ؉ -glucose cotransport. Specific small interfering RNA knockdown of Akt2 prevented ezrin phosphorylation in intact cells. Pharmacological Akt inhibition or Akt2 knockdown also prevented NHE3 translocation and activation after initiation of Na ؉ -glucose cotransport, confirming the functional role of Akt2. These studies therefore identify Akt2 as a critical kinase that regulates ezrin phosphorylation and activation. This Akt2-dependent ezrin phosphorylation leads to NHE3 translocation and activation.

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Section: Akt Inhibition Prevents Ezrin Phosphorylation After Initiatisupporting

confidence: 80%

Section: Fig 8 Akt2 Expression Is Required For Nhe3 Translocation Amentioning

confidence: 98%

Section: Fig 8 Akt2 Expression Is Required For Nhe3 Translocation Amentioning

confidence: 99%

See 1 more Smart Citation

Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Shiue

Musch

Wang

et al. 2005

Journal of Biological Chemistry

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“…It is believed that SopB is involved in the delay of apoptosis, although the role of apoptosis in gastroenteritis is still unclear (32). Although the role of the prosurvival molecule Akt in infectious colitis has not yet been explored, Akt2 has been shown to play a role in enterocyte differentiation (35). In the present study, we used a Salmonella-induced intestinal inflammation model to examine the role of Akt2 in host defense against Salmonella infection.…”

mentioning

confidence: 97%

“…Akt1 also induces protein synthesis and is critical to growth and development (9,47). Akt2 has been shown to be present in intestinal cells (35), although it is expressed mainly in insulin-responsive organs, including liver, skeletal muscle, and adipose tissue, and functions primarily in insulin signaling (8,11,18,23). Akt3 is expressed abundantly in the brain and testis, and mice lacking Akt3 have smaller brains (19,57).…”

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confidence: 99%

Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

Kum

2011

Infect Immun

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The Salmonella effector protein SopB has previously been shown to induce activation of Akt and protect epithelial cells from apoptosis in vitro. To characterize the role of Akt2 in host defense against Salmonella enterica serovar Typhimurium infection, wild-type (WT) mice and mice lacking Akt2 (Akt2 knockout [KO] mice) were infected using a Salmonella acute gastroenteritis model. Infected Akt2 KO mice showed a more pronounced morbidity and mortality associated with higher bacterial loads in the intestines and elevated levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), and MCP-1, in the colons at 1 day postinfection compared to those shown in WT mice. Histopathological assessment and immunohistochemical analysis of cecal sections at 1 day postinfection revealed more severe inflammation and higher levels of neutrophil infiltration in the ceca of Akt2 KO mice. Flow cytometry analysis further confirmed an increase in the recruitment of Gr-1 ؉ CD11b ؉ neutrophils and F4/80 ؉ CD11b ؉ macrophages in the intestines of infected Akt2 KO mice. Additionally, enhanced levels of annexin V ؉ and terminal transferase dUTP nick end labeling-positive (TUNEL ؉ ) apoptotic cells in the intestines of infected Akt2 KO mice were also observed, indicating that Akt2 plays an essential role in protection against apoptosis. Finally, the differences in bacterial loads and cecal inflammation in WT and Akt2 KO mice infected with WT Salmonella were abolished when these mice were infected with the sopB deletion mutant, indicating that SopB may play a role in protecting the mice from Salmonella infection through the activation of Akt2. These data demonstrate a definitive phenotypic abnormality in the innate response in mice lacking Akt2, underscoring the important protective role of Akt2 in Salmonella infection.

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Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells

et al. 2009

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Loud sound exposure is a significant cause of hearing loss worldwide. We asked whether a lack of vezatin, an ubiquitous adherens junction protein, could result in noise-induced hearing loss. Conditional mutant mice bearing non-functional vezatin alleles only in the sensory cells of the inner ear (hair cells) indeed exhibited irreversible hearing loss after only one minute exposure to a 105 dB broadband sound. In addition, mutant mice spontaneously underwent late onset progressive hearing loss and vestibular dysfunction related to substantial hair cell death. We establish that vezatin is an integral membrane protein with two adjacent transmembrane domains, and cytoplasmic N- and C-terminal regions. Late recruitment of vezatin at junctions between MDCKII cells indicates that the protein does not play a role in the formation of junctions, but rather participates in their stability. Moreover, we show that vezatin directly interacts with radixin in its actin-binding conformation. Accordingly, we provide evidence that vezatin associates with actin filaments at cell–cell junctions. Our results emphasize the overlooked role of the junctions between hair cells and their supporting cells in the auditory epithelium resilience to sound trauma.

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Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: Role in absorption and differentiation

Cited by 66 publications

References 40 publications

Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation

Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells

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