Role of the p21-activated kinases (PAKs) in influenza A virus replication

Pascua, Philippe Noriel Q.; Lee, Jun-Han; Song, Min‐Suk; Park, Soo‐Jin; Baek, Yun Hee; Ann, Byung-Hoon; Shin, Eun‐Young; Kim, Eung‐Gook; Choi, Young‐Ki

doi:10.1016/j.bbrc.2011.09.119

Cited by 18 publications

(21 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…114 In recent years, PAK1 was reported to contribute to ERK phosphorylation and thereby enhance influenza virus production, although the mechanism involved remained elusive. 115,116 Another publication also reported ERK activation upon influenza infection, but showed that this was mediated by RhoA. Irrespective of the contributing triggers, further downstream, MLC phosphorylation appears to be at the crossroad of different signaling pathways induced by influenza infection, and is critically involved in virus replication.…”

Section: Virus Assembly and Egressmentioning

confidence: 99%

“…In support of this notion, the identification of downstream effectors of Rho GTPase signaling revealed that MHC phosphorylation is at the crossroad of different signaling pathways induced by influenza A infection, making it a very interesting target in a strategy to reduce viral replication. 115,116 Such a strategy to attempt to identify common signaling nodes may be of particular importance in the context of transforming viruses. Since Rho GTPase signaling is involved in the tumorigenic properties of all major oncogenic viruses, it will be particularly interesting to investigate potential signaling similarities.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

See 1 more Smart Citation

Rho’ing in and out of cells

2014

View full text Add to dashboard Cite

These authors contributed equally to this work Keywords: Rho GTPase, actin, egress, entry, gene expression, immune system, transformation, virus Rho GTPases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. in this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.©2014 Landes Bioscience. Do not distribute. e28318-2Small GTPases volume 5effector of ROCK, which phosphorylates and inhibits cofilin.14 Cofilin is an F-actin-severing protein. Mainly depending on the local availability of G-actin monomers, cofilin activity may lead to net actin depolymerization or increased actin polymerization and branching. Other RhoA effectors include members of the ezrin/radixin/moesin (ERM) proteins 15 . Rac1 is thought to release WAVE from an inhibited complex, thereby activating the actin-polymerizing complex Arp2/3. 16,17 Active Arp2/3 mediates branching and elongation of existing actin filaments, generating a meshwork. Cdc42 also activates Arp2/3 through a direct interaction with the Arp2/3 activators Wiskott-Aldrich syndrome protein (WASP) or N-WASP.18 Both Rac1 and Cdc42 also activate group I serine/threonine p21 activating kinases (PAK). These different signalization branches are interconnected. In general, RhoA pathway signaling counteracts the Rac1 and Cdc42 signaling axes and vice versa.Because Rho GTPase signaling is involved in a plethora of cellular processes, it is perhaps not surprising that several viral gene products have evolved to interfere with and modulate these signaling axes. Indeed, several viruses interfere with the actin cytoskeleton and Rho GTPase signaling during many steps of their replication cycle. During entry and egress, these interactions may allow or facilitate viral particle passage across the cortical actin barrier and to rearrange actin to conformations that promote virus infection and spread, while other viral processes, such as intracellular movement, gene expression and latency, but also interaction with the immune system or oncogenesis may also depend to some extent on Rho GTPase signaling and associated actin rearrangements. In this review, the current kno...

show abstract

Section: Virus Assembly and Egressmentioning

confidence: 99%

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Rho’ing in and out of cells

2014

View full text Add to dashboard Cite

show abstract

“…Human immunodeficiency virus (HIV) encodes and secretes negative factor (Nef) protein that contributes to pathogenesis, 47 and both PAK1 and PAK2 associate with and can be activated by Nef as part of the virus life cycle. 48,49 PAK1 activity is also stimulated by influenza A virus replication, and while PAK1-specific siRNA knockdown decreased viral titers by 10-to 100-fold, 50 in vivo data confirming the requirement of PAKs for robust replication of this pathogen are still required. In summary, the involvement of PAKs in promoting pathogen survival and proliferation may offer new avenues for therapeutic approaches to mitigate infectious diseases in the future.…”

Section: ■ Role Of Paks In Nononcology Indicationsmentioning

confidence: 89%

“…A key to the high cell potency of this series is likely its off-target activity against kinases involved in the cell-cycle mechanism such as CDK7 (IC 50 = 7 nM). 69 HCT116 cells treated with 100 nM compound exhibited cell-cycle arrest and apoptosis after 48 h. 66 5 also showed activity against other cell types, including p53-containing cell lines (IC 50 Unfortunately, clinical investigation of 5 revealed major liabilities. First, very low oral bioavailability (∼1%) was observed upon dosing in patients (n = 33).…”

Section: ■ Atp Competitive Pak Inhibitorsmentioning

confidence: 97%

“…In a subsequent filing, Genentech reported on related compounds, this time with aza-bicyclic heterocycles at the pyrimidine 2-position. 77 Again, no further data beyond PAK1 IC 50 and pMEK were provided. The aminopyrazole substituent was almost exclusively cyclopropyl or fluorocyclopropyl, suggesting that this is important for binding affinity.…”

Section: ■ Atp Competitive Pak Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitors of p21-Activated Kinases (PAKs)

Rudolph¹,

Crawford²,

et al. 2014

View full text Add to dashboard Cite

The p21-activated kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular morphogenesis, and survival, and members of this family have been implicated in many diseases including cancer, infectious diseases, and neurological disorders. Owing to their large and flexible ATP binding cleft, PAKs, particularly group I PAKs (PAK1, -2, and -3), are difficult to drug; hence, few PAK inhibitors with satisfactory kinase selectivity and druglike properties have been reported to date. Examples are a recently discovered group II PAK (PAK4, -5, -6) selective inhibitor series based on a benzimidazole core, a group I PAK selective series based on a pyrido[2,3-d]pyrimidine-7-one core, and an allosteric dibenzodiazepine PAK1 inhibitor series. Only one compound, an aminopyrazole based pan-PAK inhibitor, entered clinical trials but did not progress beyond phase I trials. Clinical proof of concept for pan-group I, pan-group II, or PAK isoform selective inhibition has yet to be demonstrated.

show abstract

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

137

151

View full text Add to dashboard Cite

Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

show abstract

Role of the p21-activated kinases (PAKs) in influenza A virus replication

Cited by 18 publications

References 28 publications

Rho’ing in and out of cells

Rho’ing in and out of cells

Inhibitors of p21-Activated Kinases (PAKs)

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Contact Info

Product

Resources

About