Targeting PAK1

Semenova, Galina; Chernoff, Jonathan

doi:10.1042/bst20160134

Cited by 74 publications

(58 citation statements)

References 69 publications

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Section: Introductionmentioning

confidence: 99%

“…Group I PAKs can be targeted by multiple inhibitors (Semenova and Chernoff, 2017). These are two different types of PAK inhibitors, such as ATP-competitive (non-covalent) and non-ATP-competitive (allosteric) PAK1 inhibitors (Semenova and Chernoff, 2017). Among the ATP-competitive (noncovalent) ones are the FRAX Aminopyrimidine-based series that are PAK-inhibiting compounds based on a pyrido[2,3d]pyrimidine-7-one core, such as FRAX597 which potently inhibits PAK1 (IC50 = 7.7 nM), while it displays moderate selectivity against other kinases, such as receptor tyrosine kinases (Licciulli et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…These inhibitors possess a greater selectivity across the kinome compared to ATPcompetitive inhibitors, since they interact with less conserved regions of group I PAKs. However, this kind of inhibitors are less potent than ATP-competitive inhibitors, since their targeted protein binding pockets are not so deep and contain not multiple binding sites (Semenova and Chernoff, 2017). The sulfhydrylcontaining compound IPA3 (an allosteric inhibitor p21-activated kinase-3) binds covalent to the N-terminal regulatory domain of group I PAKs (Deacon et al, 2008), which prevents the GTPase binding and subsequently the conversion toward a catalytically active state (Viaud and Peterson, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Effect of PAK Inhibition on Cell Mechanics Depends on Rac1

Mierke

Puder

Aermes

et al. 2020

Front. Cell Dev. Biol.

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Besides biochemical and molecular regulation, the migration and invasion of cells is controlled by the environmental mechanics and cellular mechanics. Hence, the mechanical phenotype of cells, such as fibroblasts, seems to be crucial for the migratory capacity in confined 3D extracellular matrices. Recently, we have shown that the migratory and invasive capacity of mouse embryonic fibroblasts depends on the expression of the Rho-GTPase Rac1, similarly it has been demonstrated that the Rho-GTPase Cdc42 affects cell motility. The p21-activated kinase (PAK) is an effector down-stream target of both Rho-GTPases Rac1 and Cdc42, and it can activate via the LIM kinase-1 its down-stream target cofilin and subsequently support the cell migration and invasion through the polymerization of actin filaments. Since Rac1 deficient cells become mechanically softer than controls, we investigated the effect of group I PAKs and PAK1 inhibition on cell mechanics in the presence and absence of Rac1. Therefore, we determined whether mouse embryonic fibroblasts, in which Rac1 was knockedout, and control cells, displayed cell mechanical alterations after treatment with group I PAKs or PAK1 inhibitors using a magnetic tweezer (adhesive cell state) and an optical cell stretcher (non-adhesive cell state). In fact, we found that group I PAKs and Pak1 inhibition decreased the stiffness and the Young's modulus of fibroblasts in the presence of Rac1 independent of their adhesive state. However, in the absence of Rac1 the effect was abolished in the adhesive cell state for both inhibitors and in their nonadhesive state, the effect was abolished for the FRAX597 inhibitor, but not for the IPA3 inhibitor. The migration and invasion were additionally reduced by both PAK inhibitors in the presence of Rac1. In the absence of Rac1, only FRAX597 inhibitor reduced their invasiveness, whereas IPA3 had no effect. These findings indicate that group I PAKs and PAK1 inhibition is solely possible in the presence of Rac1 highlighting Rac1/PAK I (PAK1, 2, and 3) as major players in cell mechanics.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of PAK Inhibition on Cell Mechanics Depends on Rac1

Mierke

Puder

Aermes

et al. 2020

Front. Cell Dev. Biol.

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“…We also discovered p21-activated kinase 1 (PAK1) as a novel downstream effector of cytoplasmic p27-mediated cell motility that may represent a therapeutic target in OS and other cancers that harbor p27 mislocalization. PAK inhibitors are under active development, and some of the inhibitors are being used in ongoing clinical trials (Semenova and Chernoff, 2017), suggesting that the results of this study may have a near-term impact on the treatment of OS.…”

Section: Introductionmentioning

confidence: 97%

Mislocalized cytoplasmic p27 activates PAK1‐mediated metastasis and is a prognostic factor in osteosarcoma

Chen

Cates

et al. 2020

Molecular Oncology

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The development of pulmonary metastasis is the leading cause of death in osteosarcoma (OS), which is the most common malignant bone tumor in children. We have previously reported that the tumor suppressor p27 (KIP1, CDKN1B) is frequently mislocalized to the cytoplasm of OS. However, its prognostic significance and metastatic mechanism are still elusive. Here, we show that cytoplasmic p27 significantly correlated with a higher metastatic status and poorer survival of OS patients (n = 136, P < 0.05), highlighting the clinical significance of p27 mislocalization in OS. Mechanistically, cytoplasmic p27 is co‐immunoprecipitated with p21‐activated kinase 1 (PAK1), which resulted in higher PAK1 phosphorylations, actin polymerization, and cell motility in p27‐mislocalized OS cells. Silencing PAK1 expression in different p27‐mislocalized OS cell lines decreased the migratory and adhesion abilities in vitro, as well as the development of pulmonary metastases in vivo. Similar PAK1‐dependent motility was also observed in other p27‐mislocalized cancer cell lines. In summary, our study suggests that cytoplasmic p27‐mediated PAK1 activation is crucial for OS metastasis. A biomarker‐guided targeted therapeutic approach for metastatic OS and other cancers harboring p27 mislocalization can be developed, where cytoplasmic p27 is used for risk stratification and PAK1 can be exploited as a potential therapeutic target.

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“…Given their role in tumor-related processes, PAK were proposed as possible targets in anticancer treatment (34)(35)(36)(37)(38). However, with regard to specific functions of different family members, it will be necessary to search for more specific PAK inhibitors or to inhibit specific downstream effectors.…”

Section: Introductionmentioning

confidence: 99%

PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions

Grebeňová

Holoubek

RoÌˆselova

et al. 2019

Preprint

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P21-activated kinases (PAK) are key effectors of the small GTPases Rac1 and Cdc42, as well as of Src family kinases. In particular, PAK1 has several well-documented roles, both kinase-dependent and kinase-independent, in cancer-related processes, such as cell proliferation, adhesion, and migration. However, PAK1 properties and functions have not been attributed to individual PAK1 isoforms: besides the full-length kinase (PAK1-full), a splicing variant lacking the exon 15 (PAK1∆15) is annotated in protein databases. In addition, it is not clear if PAK1 and PAK2 are functionally overlapping. Using fluorescently tagged forms of human PAK1-full, PAK1∆15, and PAK2, we analyzed their intracellular localization and mutual interactions. Effects of PAK inhibition or depletion on cell-surface adhesion were monitored by real-time microimpedance measurement. We show that PAK1∆15 is in many aspects similar to PAK2, rather than to PAK1-full. Both PAK1∆15 and PAK2, but not PAK1-full, were enriched in focal adhesions, indicating that the C-terminus might be important for PAK intracellular localization. Using immunoprecipitation, we documented direct interactions among the studied PAK group I members: PAK1 and PAK2 form homodimers, but all possible heterodimers were also detected. Our results indicate that PAK1 and PAK2 have distinct roles in cell adhesion and mutually affect their function. PAK1full is required for formation of membrane protrusions, whereas PAK2 is involved in focal adhesion assembly. We have also noted that PAK inhibition was associated with a large reduction of the cell glycolytic rate. Altogether, our data suggest a complex interplay among different PAK group I members, which have largely non-redundant functions.PAK (p21-activated kinases) are a group of serine-threonine kinases originally identified as downstream effectors of p21 proteins, specifically of the Ras-related GTPases Rac1 and Cdc42 (1, 2). The initial phase of PAK research focused on their role as small GTPase effectors in the context of dynamic remodelling of the cytoskeleton and of cell adhesion structures (3). Later on, PAK were found to be involved in many cancer-related processes in different tumor types (4, 5). In parallel, the discovery of PAK1 nuclear localization (6) prompted the analysis of PAK functions in the cell nucleus.The human PAK family is divided into the group I (PAK1 to PAK3) and group II (PAK4 to PAK6). In general, these kinases regulate the cytoskeleton dynamics, intracellular signaling, and gene expression (7). The current knowledge about PAK group I is derived mostly from adherent cell models, where PAK activity usually correlates with increased cell motility. In this area, the research was mainly focused to PAK1, although some important differences between PAK1 and PAK2 have been reported (8). In addition, PAK are known regulators of a wide range of cellular processes, including the dynamics of actin structures and microtubules, cell division, apoptosis, and adhesion to the extracellular matrix.Despite considerable seque...

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Targeting PAK1

Cited by 74 publications

References 69 publications

Effect of PAK Inhibition on Cell Mechanics Depends on Rac1

Effect of PAK Inhibition on Cell Mechanics Depends on Rac1

Mislocalized cytoplasmic p27 activates PAK1‐mediated metastasis and is a prognostic factor in osteosarcoma

PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions

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