PAK1 and PAK2 in cell metabolism regulation

Koranova, T.; Dvoracek, L.; Grebeňová, Dana; Röselová, Pavla; Obr, Adam; Kuželová, Kateřina

doi:10.1002/jcb.30175

Cited by 11 publications

(5 citation statements)

References 32 publications

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“…4D and fig. S17), which was found to be among the most highly expressed genes in the 3q29Del interval in nearly all mouse and human cell types and was recently shown to be involved in cellular energy metabolism ( 22 ). We found that P21 (RAC1) Activated Kinase 2 (PAK2) is one of the seven 3q29-encoded proteins identified in a proximity labeling protein-protein interaction mitochondria map ( 23 ).…”

Section: Resultsmentioning

confidence: 99%

Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Purcell,

Sefik,

Werner

et al. 2023

Sci. Adv.

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The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.

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Section: Resultsmentioning

confidence: 99%

Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Purcell,

Sefik,

Werner

et al. 2023

Sci. Adv.

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“…P21-activated kinase (PAK) plays a crucial role in regulating a wide range of processes associated with cytoskeletal rearrangement, including cell migration, apoptosis, and cell division (34). P21activated kinase 2 belongs to the PAK family of serine/threonine kinases and functions as a downstream substrate of Rho family GTPases, including Rac and CDC42 (35).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of pancreatic cancer liver metastasis: the role of PAK2

Yang,

Li,

Zhu

et al. 2024

Front. Immunol.

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BackgroundPancreatic cancer remains an extremely malignant digestive tract tumor, posing a significant global public health burden. Patients with pancreatic cancer, once metastasis occurs, lose all hope of cure, and prognosis is extremely poor. It is important to investigate liver metastasis of Pancreatic cancer in depth, not just because it is the most common form of metastasis in pancreatic cancer, but also because it is crucial for treatment planning and prognosis assessment. This study aims to delve into the mechanisms of pancreatic cancer liver metastasis, with the goal of providing crucial scientific groundwork for the development of future treatment methods and drugs.MethodsWe explored the mechanisms of pancreatic cancer liver metastasis using single-cell sequencing data (GSE155698 and GSE154778) and bulk data (GSE71729, GSE19279, TCGA-PAAD). Initially, Seurat package was employed for single-cell data processing to obtain expression matrices for primary pancreatic cancer lesions and liver metastatic lesions. Subsequently, high-dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify genes associated with liver metastasis. Machine learning algorithms and COX regression models were employed to further screen genes related to patient prognosis. Informed by both biological understanding and the outcomes of algorithms, we meticulously identified the ultimate set of liver metastasis-related gene (LRG). In the study of LRG genes, various databases were utilized to validate their association with pancreatic cancer liver metastasis. In order to analyze the effects of these agents on tumor microenvironment, we conducted an in-depth analysis, including changes in signaling pathways (GSVA), cell differentiation (pseudo-temporal analysis), cell communication networks (cell communication analysis), and downstream transcription factors (transcription factor activity prediction). Additionally, drug sensitivity analysis and metabolic analysis were performed to reveal the effects of LRG on gemcitabine resistance and metabolic pathways. Finally, functional experiments were conducted by silencing the expression of LRG in PANC-1 and Bx-PC-3 cells to validate its influence to proliferation and invasiveness on PANC-1 and Bx-PC-3 cells.ResultsThrough a series of algorithmic filters, we identified PAK2 as a key gene promoting pancreatic cancer liver metastasis. GSVA analysis elucidated the activation of the TGF-beta signaling pathway by PAK2 to promote the occurrence of liver metastasis. Pseudo-temporal analysis revealed a significant correlation between PAK2 expression and the lower differentiation status of pancreatic cancer cells. Cell communication analysis revealed that overexpression of PAK2 promotes communication between cancer cells and the tumor microenvironment. Transcription factor activity prediction displayed the transcription factor network regulated by PAK2. Drug sensitivity analysis and metabolic analysis revealed the impact of PAK2 on gemcitabine resistance and metabolic pathways. CCK8 experiments showed that silencing PAK2 led to a decrease in the proliferative capacity of pancreatic cancer cells and scratch experiments demonstrated that low expression of PAK2 decreased invasion capability in pancreatic cancer cells. Flow cytometry reveals that PAK2 significantly inhibited apoptosis in pancreatic cancer cell lines. Molecules related to the TGF-beta pathway decreased with the inhibition of PAK2, and there were corresponding significant changes in molecules associated with EMT.ConclusionPAK2 facilitated the angiogenic potential of cancer cells and promotes the epithelial-mesenchymal transition process by activating the TGF-beta signaling pathway. Simultaneously, it decreased the differentiation level of cancer cells, consequently enhancing their malignancy. Additionally, PAK2 fostered communication between cancer cells and the tumor microenvironment, augments cancer cell chemoresistance, and modulates energy metabolism pathways. In summary, PAK2 emerged as a pivotal gene orchestrating pancreatic cancer liver metastasis. Intervening in the expression of PAK2 may offer a promising therapeutic strategy for preventing liver metastasis of pancreatic cancer and improving its prognosis.

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“…For example, it was found that PAK1-deficient β-cells had decreased mitochondrial copy number, mitochondrial respiration, disrupted redox balance, elevated ROS, diminished levels of the mitochondrial electron transport chain complex proteins and increased apoptosis [ 6 ]. In addition, PAK inhibition by IPA3 in leukemia cell lines significantly lowered OCR, revealing roles for PAK1 and PAK2 in the metabolic regulation of both mitochondrial respiration and aerobic glycolysis [ 40 ]. Moreover, a recent report indicated that PAK2 stimulates the activity of the cancer-specific isoform of pyruvate kinase which directs the cell metabolism to aerobic glycolysis [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Toward Ameliorating Insulin Resistance: Targeting a Novel PAK1 Signaling Pathway Required for Skeletal Muscle Mitochondrial Function

Balakrishnan,

Garcia,

Veluthakal

et al. 2023

Antioxidants

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The p21-activated kinase 1 (PAK1) is required for insulin-stimulated glucose uptake in skeletal muscle cells. However, whether PAK1 regulates skeletal muscle mitochondrial function, which is a central determinant of insulin sensitivity, is unknown. Here, the effect of modulating PAK1 levels (knockdown via siRNA, overexpression via adenoviral transduction, and/or inhibition of activation via IPA3) on mitochondrial function was assessed in normal and/or insulin-resistant rat L6.GLUT4myc and human muscle (LHCN-M2) myotubes. Human type 2 diabetes (T2D) and non-diabetic (ND) skeletal muscle samples were also used for validation of the identified signaling elements. PAK1 depletion in myotubes decreased mitochondrial copy number, respiration, altered mitochondrial structure, downregulated PGC1α (a core regulator of mitochondrial biogenesis and oxidative metabolism) and PGC1α activators, p38 mitogen-activated protein kinase (p38MAPK) and activating transcription factor 2 (ATF2). PAK1 enrichment in insulin-resistant myotubes improved mitochondrial function and rescued PGC1α expression levels. Activated PAK1 was localized to the cytoplasm, and PAK1 enrichment concurrent with p38MAPK inhibition did not increase PGC1α levels. PAK1 inhibition and enrichment also modified nuclear phosphorylated-ATF2 levels. T2D human samples showed a deficit for PGC1α, and PAK1 depletion in LHCN-M2 cells led to reduced mitochondrial respiration. Overall, the results suggest that PAK1 regulates muscle mitochondrial function upstream of the p38MAPK/ATF2/PGC1α-axis pathway.

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PAK1 and PAK2 in cell metabolism regulation

Cited by 11 publications

References 32 publications

Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Molecular mechanisms of pancreatic cancer liver metastasis: the role of PAK2

Toward Ameliorating Insulin Resistance: Targeting a Novel PAK1 Signaling Pathway Required for Skeletal Muscle Mitochondrial Function

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