PI3-K and GSK-3: Akt-ing together with microtubules

Buttrick, Graham J.; Wakefield, James G.

doi:10.4161/cc.7.17.6514

Cited by 80 publications

(55 citation statements)

References 43 publications

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“…A major downstream effector of PI3K is Akt, a serine-threonine kinase that regulates the activity of many other target molecules (45). We further found that Akt1/2 inhibitor (an inhibitor for Akt1 and Akt2) caused the decrease of Ca0438 invasion in a dose-dependent manner (Fig.…”

Section: Adhesion Of K Pneumoniae To Human Intestinal Epithelial Cellsmentioning

confidence: 52%

Klebsiella pneumoniae Translocates across the Intestinal Epithelium via Rho GTPase- and Phosphatidylinositol 3-Kinase/Akt-Dependent Cell Invasion

et al. 2015

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bKlebsiella pneumoniae is an important pathogen that causes hospital-acquired septicemia and is associated with the recent emergence of community-acquired pyogenic liver abscess (PLA). Clinical typing suggests that K. pneumoniae infections originate from the gastrointestinal reservoir. However, the underlying mechanism remains unknown. Here, we have sought to determine how K. pneumoniae penetrates the intestinal barrier. We identified that bacteremia and PLA clinical isolates adhered to and invaded intestinal epithelial cells. Internalization of K. pneumoniae in three different human colonic cell lines was visualized by confocal microscopy and three-dimensional (3D) imaging. Using a Transwell system, we demonstrated that these K. pneumoniae isolates translocated across a polarized Caco-2 monolayer. No disruptions of transepithelial electrical resistance and altered distribution of tight junction protein ZO-1 or occludin were observed. Therefore, K. pneumoniae appeared to penetrate the intestinal epithelium via a transcellular pathway. Using specific inhibitors, we characterized the host signaling pathways involved. Inhibition by cytochalasin D and nocodazole suggested that actin and microtubule cytoskeleton were both important for K. pneumoniae invasion. A Rho inhibitor, ML141, LY294002, and an Akt1/2 inhibitor diminished K. pneumoniae invasion in a dose-dependent manner, indicating that Rho family GTPases and phosphatidylinositol 3-kinase (PI3K)/Akt signaling were required. By a mouse model of gastrointestinal colonization, in vivo invasion of K. pneumoniae into colonic epithelial cells was demonstrated. Our results present evidence to describe a possible mechanism of gastrointestinal translocation for K. pneumoniae. Cell invasion by manipulating host machinery provides a pathway for gut-colonized K. pneumoniae cells to penetrate the intestinal barrier and access extraintestinal locations to cause disease.

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Section: Adhesion Of K Pneumoniae To Human Intestinal Epithelial Cellsmentioning

confidence: 52%

Klebsiella pneumoniae Translocates across the Intestinal Epithelium via Rho GTPase- and Phosphatidylinositol 3-Kinase/Akt-Dependent Cell Invasion

et al. 2015

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“…This suggests that the inhibition of the PI3K/Akt pathway may impact aspects of orthopoxvirus biology other than the control of survival and/or apoptosis. Indeed, the PI3K/Akt pathway regulates a variety of biological processes that are potentially important for viral replication, including actin remodeling, cell migration (3,29,47,59,64), and microtubule stabilization (10,23,54). Previous research demonstrated that usurping these pathways would benefit orthopoxviruses in several ways: (i) transportation of the virus through the microtubules to the cell periphery, followed by a switch from microtubule-to actinbased motility (reviewed in reference 53); (ii) transcription and translation of viral mRNAs (32,46); (iii) alteration of cytoskeletal organization and translocation of translation factors to viral factories (32,53,68,85); (iv) bleb formation and apoptotic mimicry to penetrate the cell (49); and (v) phosphorylation of Akt(S473) by mTORC2, which regulates the actin cytoskeleton (9,37,72).…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological disruption of the PI3K/Akt pathway with the specific PI3K inhibitor LY294002 (2-morpholino-8-phenyl-4H-1-benzopyran-4-one) (82) has been reported to not only increase the cleavage of downstream molecules associated with proapoptotic activity [e.g., poly(ADP-ribose) polymerase (PARP) and the executioner caspase-3] (38, 41) but also promote microtubule stabilization, actin filament remodeling/cell migration, and bleb formation/viral infectivity (10,35,49,54,59).…”

mentioning

confidence: 99%

Activation of the PI3K/Akt Pathway Early during Vaccinia and Cowpox Virus Infections Is Required for both Host Survival and Viral Replication

Soares¹,

Leite²,

Andrade³

et al. 2009

J Virol

116

103

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The family Poxviridae is a family of large, linear, doublestranded DNA viruses that carry out their entire life cycle within the cytoplasmic compartment of infected cells. Vaccinia virus (VACV) is a prototypical member of the genus Orthopoxvirus, which also includes the closely related cowpox virus (CPXV) (12, 52). The genomes of these viruses are approximately 200 kbp in length, with a coding capacity of approximately 200 genes. The genes involved in virus-host interactions are situated at both ends of the genome and are associated with the evasion of host immune defenses (1). These evasion mechanisms operate mainly extracellularly. For example, the secretion of soluble cytokine and chemokine receptor homologues blocks the receptor recognition by intercepting the cognate cytokine/chemokine in the extracellular environment.This mechanism facilitates viral attachment and entry into cells (1, 70). Therefore, decoy receptors for alpha interferon (IFN-␣), IFN-␤, IFN-␥, and tumor necrosis factor alpha play an important immunomodulatory role by affecting both the host antiviral and apoptotic responses.To counteract the host proapoptotic response, poxviruses have developed a number of antiapoptotic strategies, including the inhibition of apoptotic signals triggered by the extrinsic pathway (those mediated by death receptors such as tumor necrosis factor and Fas ligand) or the intrinsic pathway (mediated by the mitochondria and triggered upon viral infection) (1,25,70,74). Many studies previously identified viral inhibitors that block specific steps of the intrinsic pathway. These include the VACV-encoded E3L, F1L, and N1L genes and the myxoma virus (MYXV)-encoded M11L gene, which block cytochrome c release (14,20,34,39,45,75,90), and the CPXVencoded cytokine response modifier gene (CrmA) as well as the VACV-encoded SPI-2 gene, which inhibits both caspase-1 and caspase-8 (25,58,61,74).An emerging body of evidence has also highlighted the pivotal role played by intracellular signaling pathways in Orthopoxvirus biology (18,48,92). We and others have shown that poxvirus manipulation of signaling pathways can be virus specific. For example, while both VACV and CPXV stimulate the

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“…In mammalian cells, Akt regulates the activity of the ankyrin-repeat domain-containing protein Kank, a central protein involved in RhoA-dependent formation of actin stress fibers and cell migration (41). Recently, it was shown that Akt directly downregulates glycogen synthase kinase-3 (GSK-3) and thus acts on microtubule cytoskeleton during early mitosis (42). Our findings support the concept, which we believe to be novel, that the PI3K/Akt pathway is a key actor in the cytokinesis process, which, like cell polarization and migration, requires specific regulation of cytoskeleton networks.…”

Section: Figurementioning

confidence: 99%

The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents

Celton-Morizur¹,

Merlen²,

Couton³

et al. 2009

J. Clin. Invest.

117

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The formation of polyploid cells is part of the developmental program of several tissues. During postnatal development, binucleated tetraploid cells arise in the liver, caused by failure in cytokinesis. In this report, we have shown that the initiation of cytokinesis failure events and the subsequent appearance of binucleated tetraploid cells are strictly controlled by the suckling-to-weaning transition in rodents. We found that daily light/dark rhythms and carbohydrate intake did not affect liver tetraploidy. In contrast, impairment of insulin signaling drastically reduced the formation of binucleated tetraploid cells, whereas repeated insulin injections promoted the generation of these liver cells. Furthermore, inhibition of Akt activity decreased the number of cytokinesis failure events, possibly through the mammalian target of rapamycin signaling complex 2 (mTORC2), which indicates that the PI3K/Akt pathway lies downstream of the insulin signal to regulate the tetraploidization process. To our knowledge, these results are the first demonstration in a physiological context that insulin signaling through Akt controls a specific cell division program and leads to the physiologic generation of binucleated tetraploid liver cells.

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PI3-K and GSK-3: Akt-ing together with microtubules

Cited by 80 publications

References 43 publications

Klebsiella pneumoniae Translocates across the Intestinal Epithelium via Rho GTPase- and Phosphatidylinositol 3-Kinase/Akt-Dependent Cell Invasion

Klebsiella pneumoniae Translocates across the Intestinal Epithelium via Rho GTPase- and Phosphatidylinositol 3-Kinase/Akt-Dependent Cell Invasion

Activation of the PI3K/Akt Pathway Early during Vaccinia and Cowpox Virus Infections Is Required for both Host Survival and Viral Replication

The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents

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