High expression of P21-activated kinase 5 protein is associated with poor survival in gastric cancer

Aburatani, Tomoki; Inokuchi, Mikito; Takagi, Yoko; Ishikawa, Toshiaki; Okuno, Keisuke; Gokita, Kentaro; Tomii, Chiharu; Tanioka, Toshiro; Murase, Hideaki; Otsuki, Sho; Uetake, Hiroyuki; Kojima, Kazuyuki; Kawano, Tatsuyuki

doi:10.3892/ol.2017.6115

Cited by 14 publications

(10 citation statements)

References 24 publications

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“…Studies indicate that p21‐activated kinase 5 (PAK5), the most recently identified member of the PAK family, plays an indispensable role in regulation of the cytoskeleton, microtubule stability and cell survival . Increasing lines of evidence suggest that PAK5 is an oncogenic protein that is commonly overexpressed in many cancer tissues and contributes to the progression of diverse cancers . Likewise, in human breast cancer, PAK5 has been shown to activate a PAK5–early growth response protein 1 (Egr1)–matrix metalloproteinase 2 (MMP2) pathway to control cell migration and invasion .…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Increasing lines of evidence suggest that PAK5 is an oncogenic protein that is commonly overexpressed in many cancer tissues and contributes to the progression of diverse cancers. [7][8][9][10][11] Likewise, in human breast cancer, PAK5 has been shown to activate a PAK5-early growth response protein 1 (Egr1)-matrix metalloproteinase 2 (MMP2) pathway to control cell migration and invasion. 12 PAK5-directed GATA1 phosphorylation has been reported to induce epithelialmesenchymal transition in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

Geng

Zhang

et al. 2019

Intl Journal of Cancer

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Although clinically associated with the progression of multiple cancers, the biological function of p21‐activated kinase 5 (PAK5) in breast cancer remains largely unknown. Here, we reveal that the PAK5–aspartyl aminopeptidase (DNPEP)–ubiquitin‐specific protease 4 (USP4) axis is involved in breast cancer progression. We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. Functionally, we demonstrate that DNPEP overexpression suppresses breast cancer cell proliferation and invasion and restricts breast cancer growth and metastasis in mice. Furthermore, we identify USP4 as a downstream target of the PAK5–DNPEP pathway; DNPEP mediates USP4 downregulation. Importantly, we verify that DNPEP expression is frequently downregulated in breast cancer tissues and is negatively correlated with PAK5 and USP4 expression. PAK5 decreases DNPEP abundance via the ubiquitin–proteasome pathway. Consistently, analyses of clinical breast cancer specimens revealed significantly increased PAK5 and USP4 levels and an association between higher PAK5 and USP4 expression and worse breast cancer patient survival. These findings suggest a pivotal role for PAK5‐elicited signaling in breast cancer progression.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

Geng

Zhang

et al. 2019

Intl Journal of Cancer

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“…Although the six PAKs in mammals are divided into two groups, each member in Group 1 (PAK1-3) shares >90% homology in its kinase domain, while Group 2 members (PAK4-6) share 50% homology in the kinase domain, suggesting that there may be some overlapping functions between PAKs ( 25 ). However, PAKs also present significant differences in their tissue distribution and subcellular localization, which may partly explain the organ-specific effects of these molecules ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

PAK6 promotes cervical cancer progression through activation of the Wnt/β‑catenin signaling pathway

et al. 2020

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p21-activated kinase 6 (PAK6), a member of the serine/threonine kinase family, has been reported to be involved in numerous types of cancers. The present study aimed to investigate the role of PAK6 in cervical cancer. In the present study, PAK6 expression was evaluated in tissue microarrays and cell lines by using immunohistochemistry and western blotting. The mRNA level of PAK6 was evaluated by reverse transcription quantitative PCR. The Wnt/β-catenin signaling-related protein expression was detected by western blotting following short hairpin (sh)RNA-mediated PAK6 knockdown or PAK6 overexpression. Cell proliferation was determined using Cell Countink Kit-8. Migration, invasion and colony formation were further assessed following PAK6 knockdown or overexpression. Co-immunoprecipitation (Co-IP) and fluorescence colocalization microscopy were used to detect the interaction between PAK6 and GSK3β. The results from tissue microarray revealed that the expression levels of PAK6 in cervical cancer tissues were upregulated. The downregulation of PAK6 expression levels using shRNA not only decreased cell growth and proliferation, but it also inhibited the migration and invasion of HeLa cells. Conversely, the overexpression of PAK6 promoted the proliferation, migration and invasion of HeLa cells. In addition, the expression levels of proteins involved in the Wnt/β-catenin signaling pathway were modified in the PAK6 knockdown group, including downregulation of GSK3β phosphorylation and Cyclin D1 protein, and upregulation of β-catenin phosphorylation and E-cadherin. In contrast, following the overexpression of PAK6, the Wnt/β-catenin signaling pathway was activated. Further investigation using fluorescence microscopy and Co-IP assays indicated that PAK6 may interact with GSK3β. In conclusion, the findings of the present study suggested that PAK6 may serve a role in promoting cervical cancer through activating the Wnt/β-catenin signaling pathway.

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“…PAK7 was originally found in brain in which promotes the formation of filopodia in nerve cells 9 . However, recent studies have found that the expression level of PAK7 significantly increased in colorectal cancer 10 , 11 , ovarian cancer 12 , gastric cancer 13 - 15 , Neuroglioma 16 , 17 , Hepatocellular carcinoma 18 , 19 , Pancreatic cancer 20 , 21 , Osteosarcoma 22 , and breast cancer 23 - 25 , leading to increased proliferation and migration of tumor cells and inhibition of apoptosis. More importantly, PAK7 expression was positively correlated with the malignancy of colorectal cancer and ovarian cancer, suggesting that PAK7 indeed played an important role in tumor progression.…”

Section: Introductionmentioning

confidence: 99%

P21-activated kinase 7 (PAK7) interacts with and activates Wnt/β-catenin signaling pathway in breast cancer

Li¹,

Xu²,

He³

et al. 2018

J. Cancer

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Background: Breast cancer is the highest incidence of tumor in women, which seriously threaten women's health. The occurrence and progression of breast cancer is linked to inactivation or downregulation of tumor suppressors, and activation or upregulation of oncogenes. However, the mechanism of PAK7 involving in the occurrence and progression of breast cancer is not yet fully understood.Methods: PAK7 expression was analyzed by RT-qPCR and immunohistochemistry and correlated with clinicopatholgical parameters in breast cancer tissue microarray. The effects of PAK7 on breast cancer cells were detected by CCK-8 assay, colon formation assay, wound healing and transwell assays, and flow cytometry. The relationship between PAK7 and Wnt/β-catenin signaling pathway was determined by western blotting, TOP/FOP flash, co-Immunoprecipitation and co-localization assays.Results: PAK7 expression was significantly increased in breast cancer tissues and positively correlated with pathological differentiation and TNM stage of breast cancer. Overexpression of PAK7 could significantly promote proliferation and migration of breast cancer cells, and inhibit apoptosis. In contrast, PAK7 knockdown significantly inhibited the proliferation and migration of breast cancer cells and promoted apoptosis. In addition, PAK7 could activate Wnt/β-catenin signaling pathway in breast cancer cells. Further study found that PAK7 could directly bind to GSK3β and β-catenin, and regulate β-catenin degradation by phosphorylating GSK3β.Conclusions: Our study demonstrated that PAK7, as an oncogene, involved in breast cancer progression by activating the Wnt/β-catenin signaling pathway, suggesting that the potential applicability of PAK7 as a target for breast cancer treatment.

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High expression of P21-activated kinase 5 protein is associated with poor survival in gastric cancer

Cited by 14 publications

References 24 publications

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

PAK6 promotes cervical cancer progression through activation of the Wnt/β‑catenin signaling pathway

P21-activated kinase 7 (PAK7) interacts with and activates Wnt/β-catenin signaling pathway in breast cancer

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