CDC42 and Rac1 are implicated in the activation of the Nef-associated kinase and replication of HIV-1

Lü, Xiaobin; Wu, Xiaoning; Plemenitaš, Ana; Yu, Haiqin; Sawai, Earl T.; Abo, Arie; Peterlin, B. Matija

doi:10.1016/s0960-9822(02)70792-6

Cited by 129 publications

(133 citation statements)

References 42 publications

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“…As viruses can manipulate or make use of the cytoskeletal network of actin filaments during their life cycles, (virus-induced) Rac1 activity has been linked to viral infection or protein trafficking processes as well as the spread of several viruses causing severe human diseases, for example, HIV (Lu et al, 1996), Ebola (Saeed et al, 2008), HSV-1 (Hoppe et al, 2006), HBV (Gros et al, 2008) and paramyxoviruses, for example, Hendra virus (Schowalter et al, 2006). From rodent experiments Rac1 is known to have oncogenic activity and to be involved in tumorigenesis (Kissil et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

et al. 2010

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Oncolytic Newcastle disease virus (NDV) replicates selectively in most human tumor cells but not in normal cells. The relationship between tumorigenesis and the selective susceptibility of most tumor cells to oncolytic NDV replication is poorly understood. A multistage skin carcinogenesis model derived from non-tumorigenic HaCaT cells was used to systematically investigate the molecular mechanisms involved in the oncolytic NDVsensitivity associated with tumorigenic transformation. No significant differences in interferon signaling were observed between the virus-sensitive tumor cells and the virus-resistant non-tumorigenic parental cells. Oncogenic H-Ras, which had been used for tumorigenic transformation, was shown to be necessary for virus replication but was not sufficient to render cells susceptible to NDV replication. By using an siRNA screening approach to search for virus-sensitizing genes in the tumorigenic cells, we could identify the small GTPase Rac1 as an oncogenic protein that is essential for NDV replication and anchorage-independent growth in tumorigenic cells. Furthermore, Rac1 expression was sufficient to render non-tumorigenic cells susceptible to NDV replication and to oncolytic cytotoxicity. This study establishes Rac1 as a link between tumorigenesis and oncolytic virus sensitivity in the HaCaT multistage skin carcinogenesis model.

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Section: Discussionmentioning

confidence: 99%

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

et al. 2010

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“…In addition to its essential roles in both clathrin-mediated and clathrin-independent endocytic events, Dyn2 has been implicated in the regulation of actin dynamics (48,49), in signaling (50), and in centrosome cohesion (51). In particular, Dyn2 controls cytoskeletal remodeling by Rac (52), a small GTPase that has been implicated in the function of Nef (12,53). However, the modulation of Rac function by Dyn2 appears unrelated to clathrin-mediated endocytosis (52), whereas our results imply that Dyn2 and clathrin are both required for the enhancement of infectivity by Nef, suggesting that this activity of Nef depends on the function of Dyn2 in the budding of clathrin-coated vesicles.…”

Section: Discussionmentioning

confidence: 99%

Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef

Pizzato

Helander

Попова

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

150

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Nef is a virulence factor of HIV-1 and other primate lentiviruses that is crucial for rapid progression to AIDS. In cell culture, Nef increases the infectivity of HIV-1 progeny virions by an unknown mechanism. We now show that dynamin 2 (Dyn2), a key regulator of vesicular trafficking, is a binding partner of Nef that is required for its ability to increase viral infectivity. Dominant-negative Dyn2 or the depletion of Dyn2 by small interfering RNA potently inhibited the effect of Nef on HIV-1 infectivity. Furthermore, in Dyn2-depleted cells, this function of Nef could be rescued by ectopically expressed Dyn2 but not by Dyn1, a closely related isoform that does not bind Nef. The infectivity enhancement by Nef also depended on clathrin, because it was diminished in clathrin-depleted cells and profoundly inhibited in cells expressing the clathrin-binding domain of AP180, which blocks clathrin-coated pit formation but not clathrin-independent endocytosis. Together, these findings imply that the infectivity enhancement activity of Nef depends on Dyn2-and clathrin-mediated membrane invagination events.HIV accessory protein ͉ host factor ͉ virion infectivity

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“…In lymphocytes infected in vitro by HIV or SIV, a Pak-like kinase has been shown to associate with and be activated by the HIV regulatory protein Nef (Lu et al, 1996;Nunn and Marsh, 1996;. There is also evidence that the association and activation of this Pak-like kinase is dependent on Cdc42 and Rac1, and activation of the Pak-like kinase leads to the activation of the serum response pathway (Lu et al, 1996).…”

mentioning

confidence: 99%

“…There is also evidence that the association and activation of this Pak-like kinase is dependent on Cdc42 and Rac1, and activation of the Pak-like kinase leads to the activation of the serum response pathway (Lu et al, 1996). Moreover, the Nef-mediated activation of a Pak-related kinase correlates with the induction of high virus loads and the development of AIDS in the infected host .…”

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confidence: 99%

Mechanism of activation of Pak1 kinase by membrane localization

Mayer

1999

Oncogene

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Pak kinases are a family of serine/threonine protein kinases homologous to Ste20p of yeast. Paks can be activated in vivo and in vitro by binding to GTP-bound Cdc42 and Rac1, members of the Rho family of small GTPases implicated in regulating the organization of the actin cytoskeleton. We have previously reported that the SH2/SH3-containing adaptor protein Nck binds Pak kinase through its second SH3 domain. Pak1 can be targeted to the membrane by Nck in response to tyrosine phosphorylation, and membrane association of Pak1 is su cient to increase its speci®c activity. The mechanism whereby Pak is activated by membrane localization, however, is unknown. We show here that expression of three proteins that inhibit Rho-family GTPases by di erent mechanisms (RhoGDI, Bcr and D57Y Cdc42) all block the activation of Pak by a membrane-targeted Nck SH3 domain, demonstrating that the in vivo activation of Pak1 induced by membrane localization is dependent on Rho-family GTPases. This implies that Pak activity can be regulated in cells both by the level of GTP loading of various Rho-family GTPases and the local concentration of Pak relative to these GTPases. Our data also suggest the existence of Rho-family GTPases in addition to Cdc42 and Rac1 that can activate Pak on membranes.

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CDC42 and Rac1 are implicated in the activation of the Nef-associated kinase and replication of HIV-1

Cited by 129 publications

References 42 publications

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef

Mechanism of activation of Pak1 kinase by membrane localization

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