RACK1 mediates activation of JNK by protein kinase C

Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Molecular Cell (Impact Factor: 14.02). 09/2005; 19(3):309-20. DOI: 10.1016/j.molcel.2005.06.025
Source: PubMed


Activation of the Jun-N-terminal kinase (JNK) signaling cascade by phorbol esters (TPA) or protein kinase C (PKC) is well documented, although the underlying mechanism is not known. Here, we demonstrate that the receptor for activated C kinase 1 (RACK1) serves as an adaptor for PKC-mediated JNK activation. Phosphorylation of JNK by PKC occurs on Ser129 and requires the presence of RACK1. Ser129 phosphorylation augments JNK phosphorylation by MKK4 and/or MKK7 and is required for JNK activation by TPA, TNFalpha, UV irradiation, and PKC, but not by anisomycin or MEKK1. Inhibition of RACK1 expression by siRNA attenuates JNK activation, sensitizes melanoma cells to UV-induced apoptosis, and reduces their tumorigenicity in nude mice. In finding the role of RACK1 in activation of JNK by PKC, our study also highlights the nature of crosstalk between these two signal-transduction pathways.

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Available from: Ze’ev Ronai, Mar 07, 2015
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    • "Through Src-dependent phosphorylation of the Rac1 GEF, Vav2, [36] or through the PI3K/Akt signaling pathway [37] RACK1 may address Rac1. It also interacts with MKK7 and enhances MKK7/JNK activity [38] and can even directly interact with JNK and promote its activation through phosphorylation by PKC [39]. Even more intriguingly, E1A reportedly interacts with RACK1 through the E1A N-terminus [40]. "
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    ABSTRACT: The adenoviral oncoprotein E1A influences cellular regulation by interacting with a number of cellular proteins. In collaboration with complementary oncogenes, E1A fully transforms primary cells. As part of this action, E1A inhibits transcription of c-Jun:Fos target genes while promoting that of c-Jun:ATF2-dependent genes including jun. Both c-Jun and ATF2 are hyperphosphorylated in response to E1A. In the current study, E1A was fused with the ligand binding domain of the estrogen receptor (E1A-ER) to monitor the immediate effect of E1A activation. With this approach we now show that E1A activates c-Jun N-terminal kinase (JNK), the upstream kinases MKK4 and MKK7, as well as the small GTPase Rac1. Activation of the JNK pathway requires the N-terminal domain of E1A, and, importantly, is independent of transcription. In addition, it requires the presence of ERM proteins. Downregulation of signaling components upstream of JNK inhibits E1A-dependent JNK/c-Jun activation. Taking these findings together, we show that E1A activates the JNK/c-Jun signaling pathway upstream of Rac1 in a transcription-independent manner, demonstrating a novel mechanism of E1A action.
    Oncotarget 03/2014; 5(8). DOI:10.18632/oncotarget.1860 · 6.36 Impact Factor
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    • "Combined with other factors, such as HIV/AIDS-caused reduction of immune response to HSV, this may increase the risk of subsequent development of HSV-associated diseases. Topical inhibitors of HIV tat- and gp120-activated MAPK signaling [21], [22], [23], [24], [25], [26], [128], [129], [130], [131], [132], [133], [134], [135], which plays a key role in disruption of epithelial junctions and exposure of nectin-1 in HIV-infected individuals, may be useful for reducing HSV-1 spread within the oral and genital epithelium. "
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    ABSTRACT: Herpes simplex virus (HSV) types 1 and 2 are the most common opportunistic infections in HIV/AIDS. In these immunocompromised individuals, HSV-1 reactivates and replicates in oral epithelium, leading to oral disorders such as ulcers, gingivitis, and necrotic lesions. Although the increased risk of HSV infection may be mediated in part by HIV-induced immune dysfunction, direct or indirect interactions of HIV and HSV at the molecular level may also play a role. In this report we show that prolonged interaction of the HIV proteins tat and gp120 and cell-free HIV virions with polarized oral epithelial cells leads to disruption of tight and adherens junctions of epithelial cells through the mitogen-activated protein kinase signaling pathway. HIV-induced disruption of oral epithelial junctions facilitates HSV-1 paracellular spread between the epithelial cells. Furthermore, HIV-associated disruption of adherens junctions exposes sequestered nectin-1, an adhesion protein and critical receptor for HSV envelope glycoprotein D (gD). Exposure of nectin-1 facilitates binding of HSV-1 gD, which substantially increases HSV-1 infection of epithelial cells with disrupted junctions over that of cells with intact junctions. Exposed nectin-1 from disrupted adherens junctions also increases the cell-to-cell spread of HSV-1 from infected to uninfected oral epithelial cells. Antibodies to nectin-1 and HSV-1 gD substantially reduce HSV-1 infection and cell-to-cell spread, indicating that HIV-promoted HSV infection and spread are mediated by the interaction of HSV gD with HIV-exposed nectin-1. Our data suggest that HIV-associated disruption of oral epithelial junctions may potentiate HSV-1 infection and its paracellular and cell-to-cell spread within the oral mucosal epithelium. This could be one of the possible mechanisms of rapid development of HSV-associated oral lesions in HIV-infected individuals.
    PLoS ONE 02/2014; 9(2):e88803. DOI:10.1371/journal.pone.0088803 · 3.23 Impact Factor
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    • "Combined with other factors such as attenuated immune response to HPV antigen, this may increase the risk of subsequent development of HPV-associated neoplasia. Topical inhibitors of HIV tat-and gp120-activated signaling molecules including MAPK, PI3K/AKT and JNK (Ali et al., 2009; Andras et al., 2005; Bai et al., 2008; Cai et al., 1997; Kawakami et al., 2004; Lopez-Bergami et al., 2005; Marshall, 1996; Preiss et al., 2007; Pu et al., 2005; Song et al., 2007; Toschi et al., 2006; Wang et al., 2004; Zhong et al., 2008; Zhou et al., 2003) that contribute to TJ disruption in HIV-infected individuals may be useful for improving mucosal epithelial integrity and reducing the risk of exposure to HPV and potentially other infectious agents in the environment. "
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    ABSTRACT: The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral, cervical and anal epithelial cells, and oral tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration in to the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia.
    Virology 11/2013; 446(1-2):378-88. DOI:10.1016/j.virol.2013.08.018 · 3.32 Impact Factor
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