Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Hong He
 -- 2630 2023-03-10 00:35:43 |
2 Reference format revised.
Lindsay Dong
 -1 word(s) 2629 2023-03-10 06:45:33 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Qiu, X.; Xu, H.; Wang, K.; Gao, F.; Xu, X.; He, H. P-21 Activated Kinases in Liver Disorders. Encyclopedia. Available online: https://encyclopedia.pub/entry/42052 (accessed on 21 December 2024).
Qiu X, Xu H, Wang K, Gao F, Xu X, He H. P-21 Activated Kinases in Liver Disorders. Encyclopedia. Available at: https://encyclopedia.pub/entry/42052. Accessed December 21, 2024.
Qiu, Xun, Hanzhi Xu, Kai Wang, Fengqiang Gao, Xiao Xu, Hong He. "P-21 Activated Kinases in Liver Disorders" Encyclopedia, https://encyclopedia.pub/entry/42052 (accessed December 21, 2024).
Qiu, X., Xu, H., Wang, K., Gao, F., Xu, X., & He, H. (2023, March 10). P-21 Activated Kinases in Liver Disorders. In Encyclopedia. https://encyclopedia.pub/entry/42052
Qiu, Xun, et al. "P-21 Activated Kinases in Liver Disorders." Encyclopedia. Web. 10 March, 2023.
P-21 Activated Kinases in Liver Disorders
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers15020551

The p21 Activated Kinases (PAKs) are serine threonine kinases and play important roles in many biological processes, including cell growth, survival, cytoskeletal organization, migration, and morphology. PAKs have emerged in the process of liver disorders, including liver cancer, hepatic ischemia-reperfusion injury, hepatitis, and liver fibrosis, owing to their effects in multiple signaling pathways in various cell types. Activation of PAKs promotes liver cancer growth and metastasis and contributes to the resistance of liver cancer to radiotherapy and chemotherapy, leading to poor survival of patients. PAKs also play important roles in the development and progression of hepatitis and other pathological processes of the liver such as fibrosis and ischemia-reperfusion injury.

p21 Activated Kinase liver cancer hepatitis liver fibrosis

1. Introduction

The p21 Activated Kinases (PAKs) are serine-threonine kinases containing six members, and play important roles in a variety of biological processes such as cell growth, survival, cytoskeletal organization, migration, and morphology [1]. These kinases act downstream of the Ras-related Rho GTPases cell division control protein 42 (CDC42) and RAC, and are involved in multiple signaling pathways such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin pathways [2][3]. PAKs can be divided into two groups based on structural and biological properties. Group I PAKs include PAK1-3, and group II PAKs contain PAK4-6. PAKs have been involved in many physiological and pathological processes. Their roles in cancer have been extensively investigated. Increasing evidence implicates PAK effects in liver disorders including liver cancer, hepatitis, liver fibrosis, and hepatic ischemia-reperfusion injury (IRI) [4][5][6][7].

2. Structure and Activation of PAKs Family

PAK proteins contain a kinase domain at the C-terminal, and an autoinhibitory domain (AID) and a GTPase-binding domain (GBD) at the N-terminus [8]. The AID of Group I PAKs overlaps with the GBD and binds in trans to the kinase domain of another PAK molecule to form a dimer, preventing the formation of an activation loop. The binding of Rho GTPases or other proteins to the GBD dissociates the binding of AID with the kinase domain and causes a conformational change, which in turn triggers autophosphorylation of Ser 144 and Thr 423 and activation of the kinase. Group II PAKs function as monomers and they have AID-like domains different from the AID in group I PAKs [9]. There are two proposed models to explain the activation of group II PAKs. One model is the AID-like domain, which binds to the kinase domain in cis, forming an inactive conformation. When CDC42 or RAC binds to GBD, this conformation will change and release the kinase domain from auto-inhibition [10]. The other model contains two phases for activation. In addition to the binding of Rho GTPases, it also requires the involvement of proteins that contain SH3 domains, which interact with the AID-like domains [11] (Figure 1).
/media/item_content/202303/640ac2d80c0aacancers-15-00551-g002.png
Figure 1. The structure and activation of PAKs. (A) Two-dimensional diagram of PAKs structure. (B) Different activation mechanisms of Group I PAKs and Group II PAKs.
PAKs act in multiple signaling pathways that are crucial for physiological and pathological processes. Particularly, overexpression of PAKs in many types of cancers is correlated with cancer progression and therapeutical resistance. Both PAK1 and PAK4 can activate the PI3K/AKT pathway, one of the key pathways for cell growth and survival. PAKs promote chemoresistance of cancer cells through activating the PI3K/AKT pathway [12]. PAK1 stimulates cell migration by activation of AKT [13]. PAK4 bind to p85, the regulatory subunit of PI3K, which in turn increases the activity of PI3K and phosphorylation of AKT, thereby promoting the migration of cancer cells [14]. On the other hand, PI3K/AKT can also regulate the activation of PAKs. It has been suggested that a positive feedback loop may exist between PAKs and PI3K/AKT in the progression of cancers [15][16][17]. RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular-regulated kinase (ERK) axis is a well-known pathway contributing to the growth, survival, and metabolism of cancer cells. PAKs can phosphorylate MEK and RAF at Ser298 and at Ser338, respectively, promoting the activation of RAS-mediated RAF/MEK/ERK signaling [18]. In IκB/nuclear factor-κB (NF-κB) signaling, PAK1 promoted the phosphorylation and degradation of IκB, leading to the activation and nuclear translocation of NF-κB [19]. Blockading PAK1-activated NF-κB inhibited the growth of HCC and alleviated the inflammatory response in acute pancreatitis [20][21]. PAKs can activate β-catenin signaling and stabilize the activation of β-catenin, contributing to the chemotherapy resistance of cancer [22][23][24]. PAKs can form a complex with β-catenin in the nucleus, which can further stabilize β-catenin. PAK4 can phosphorylate β-catenin at Ser 675, preventing the ubiquitination and degradation of β-catenin [25][26]. PAKs regulate the activation of Lin-11/Isl-1/Mec-3 kinase and matrix metalloproteinases, which are associated with cancer cell metastasis [27][28]. 

3. PAKs in Liver Cancers

Liver cancer is the sixth most common cancer worldwide and the second most common cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer [29][30]. The major risk factors for liver cancer are chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) [30][31][32]. PAKs have been reported to be upregulated in many cancers including breast cancer, glioblastoma, pancreatic cancer, and HCC, promoting tumor growth and metastasis [7][33][34]. Increased PAKs expression endowed tumors with chemoresistance, and thus PAKs become attractive therapeutical targets for cancer treatment and biomarkers to predict prognosis [35][36][37]. The roles of PAKs in liver cancer, especially HCC, are discussed below (Figure 2).
/media/item_content/202303/640ac3c13fa16cancers-15-00551-g003.png
Figure 2. The pathways affected by PAKs in liver cancer. PAKs modulate multiple signaling pathways (e.g., RAF/MEK/ERK, β-catenin) to promote the proliferation, invasion/migration, angiogenesis, and therapy resistance of cancer cells while inhibiting apoptosis.

3.1. Roles of Group I PAKs in Liver Cancer

PAK1 has been the most investigated among the I PAKs group. Overexpression of PAK1 was most frequently observed in HCC and associated with the growth and metastasis of HCC. PAK1 affects HCC progression via multiple pathways, PAK1 stimulated proliferation and inhibited apoptosis of HCC cells by activation of β-catenin signaling, and facilitated migration and invasion by upregulation of Snail [38]. Genetic inhibition of PAK1 suppressed xenograft tumor growth through Snail-, β-catenin-, and p53/p21-mediated pathways [38][39]. Treatment of phorbol ester increased PAK1, which in turn promoted HCC metastasis by activation of paxillin and c-Jun N-terminal kinase (JNK) [40]. PAK1 also promoted HCC metastasis by regulating the formation and degradation of actin stress fibers [41]. PAK1 enhanced vasculogenic mimicry in HCC through the stabilization of hypoxia-inducible factor-1α and phosphorylation of Vimentin [42]. Activation of PAK1-mediated epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways inhibited anoikis, a form of programmed cell death, contributing to the anoikis resistance of HCC cells [43][44].
A natural product, resveratrol, inhibited HCC cell proliferation and survival by downregulation of PAK1, cyclin D1, mitogen-activated protein kinase (MAPK), and AKT [45]. In a liver carcinogenesis animal model, diethylnitrosamine-induced HCC progression was correlated with increased levels of PAK1, cyclin D1, MAPK, and AKT [31]. Myricetin induces apoptosis of HCC cells by abrogating RAS-activated PAK1 and inhibiting MAPK/ERK and PI3K/AKT signaling [46]. KRAS or BRAF mutations have been shown to promote hepatic vascular cavernomas [47]. Although PAK1 has been reported to affect the activation level of RAS/MEK/ERK signaling [48][49], the role of PAK1 in hepatic vascular cavernomas is unknown.
MicroRNAs (miRNAs) are small, non-coding RNAs that bind to specific mRNA targets to regulate gene expression post-transcriptionally. Altered expression of miRNAs is associated with liver metabolic dysfunction and tumor development. LINC00460, a long intergenic non-protein coding RNA, promoted HCC progression by stimulation of PAK1 through suppressing miR-485-5p [50]. 
PAK2 played a critical role in HCC metastasis. MiR-26a inhibited metastasis of HCC through downregulation of PAK2 [51]. Sato et al. reported that PAK2 phosphorylation was associated with AKT activation in transforming growth factor-β (TGF-β)-induced migration of HCC cells [52]. PAK3 is mainly expressed in the central nervous system for regulation of neuronal plasticity and spinogenesis [53]. However, Gao and colleagues recently found that PAK3 was upregulated in HCC and stimulated the epithelial mesenchymal transition (EMT) of tumor cells through activating the TGF-β/Smad pathway [54].

3.2. Roles of Group II PAKs in Liver Cancer

PAK4 enhanced HCC cell survival by modulating caspase-8 and NF-κB pathways [55]. In an HCC transgenic mouse model, miR-199-3p inhibited HCC growth by targeting the PAK4/RAF/MEK/ERK pathway [56][57]. On the contrary, an increased cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 3 in HCC accelerated tumor metastasis bound to and activated PAK4 [58]. PAK4 promoted migration and invasion of HCC cells through direct phosphorylation of p53 at S215 [59]. MiR-1271 suppressed HCC growth and metastasis through downregulation of RAF/MEK/ERK signaling, achieved by inhibiting Zic2/PAK4. PAK4 was overexpressed in metastatic tumor tissues compared with primary tumor and normal tissues, and PAK4 expression was correlated with worse survival of HCC patients. The results from multivariate analyses of 615 HCC patients showed that PAK4 was an independent indicator of poor prognosis [60]. MiR-433 was reduced in HCC tissues. MiR-433 repressed the viability of HCC cells through directly binding to the sequence at 3’-UTR of PAK4 mRNA, which in turn inhibited PAK4 expression [61]. MiRNAs are key upstream regulators that directly modulate the translation of multiple oncogenic proteins including PAK4. A miRNA cocktail therapy targeting PAK4, mechanistic target of rapamycin (mTOR), and RAS homolog gene family member C (RHOC), showed remarkable anti-HCC effects in patient-derived xenografts [62].

4. PAKs in Hepatic Ischemia/Reperfusion Injury

Hepatic IRI commonly occurs in the process of hemorrhagic shock, liver surgery, and liver transplantation [63][64]. The underlying mechanisms of hepatic IRI relate to the elevated oxidative stress and activation of immune-metabolic responses, which are harmful to normal cellular structures and functions, and result in liver damage [65]. PAKs participate in the modulation of immune responses and inflammation [66][67], and PAKs have been reported to play a critical role in hepatic IRI [6][68].
Neuregulin-1/PAK1 axis was found to decrease IRI of liver grafts with or without steatosis through increasing vascular endothelial growth factor-α and insulin growth factor-1 levels, respectively [68]. PAK4 was upregulated in hepatic IRI in mice and humans to promote hepatic hypoxia-reoxygenation-induced damage through phosphorylating nuclear factor erythroid 2-related factor 2 and suppressing its transcriptional activity [6]. Genetic knockout or pharmacological inhibition of PAK4 reduced the inflammation and necrosis of hepatocytes [6]. These results suggest that PAK4 inhibition may protect the liver from IRI-induced damage.

5. PAKs in Hepatitis

Hepatitis is defined as inflammation of the liver, and its etiologies include virus infection, parasitic invasion, alcohol abuse, autoimmunity imbalance, and metabolic disorder. The main characteristic of hepatitis is represented by the infiltration of inflammatory cells, which induces apoptosis and necrosis of hepatocytes leading to liver damage and dysfunctions [69][70][71][72].

In hepatitis B, phosphorylation of PAK1 induced the translocation of RAF-1 to mitochondrial, which in turn facilitated the anti-apoptotic effect of HBV X protein in hepatocyte [73]. In fact, HBV X protein can activate PAK1, which protected HCC from anoikis and promoted the metastasis of HCC [74]. Results from the PCR showed that the PAK3 gene was the preferential integration site of HBV DNA and the integration potentially changed the expression of PAK3 [5]. 

Different from the promoting role of PAK1 in HBV, PAK1 had potentially inhibited HCV replication, and its antiviral effects were independent of interferon regulatory factor 3 but dependent on the mTOR-activated PI3K/AKT and ERK [75]. HCV protected the infected hepatocytes from cell death by suppressing apoptosis and inflammatory reaction partially through the upregulation of PAK2 [76]. 

In a mouse model infected with Schistosoma japonicum, PAK1 in Kupffer cells was elevated and facilitated the differentiation of CD4+ T cells to T helper 17 cells via the NF-κB/interferon regulatory factor 1/interleukin-6 pathway, leading to aggravated hepatic inflammation [77]. Increased PAK1 expression in Kupffer cells was also noticed in patients with autoimmune hepatitis, and the PAK1 expression was found to be associated with disease progression [78]. The increased expression of PAK6 found in alcoholic hepatitis may contribute to tumorigenesis [79].

6. PAKs in Liver Fibrosis

Liver fibrosis is implicated in the interaction between injured hepatocytes, inflammatory cells, and hepatic myofibroblasts. In response to injury, hepatocytes will express more profibrogenic miRNAs and proteins such as TGFβ and Notch, thus initiating fibrosis [80]. The transformation from hepatic stellate cells to myofibroblasts that produce extracellular matrix (ECM) provides a protection to liver tissue from injury, and there is a balance between ECM production and degradation. However, the excessive accumulation of ECM produced by consistently activated myofibroblasts will impair the normal physiological structure and function of the liver, resulting in the occurrence of liver fibrosis [81].
PAK1 and PAK3 were upregulated in activated hepatic myofibroblasts and promoted fibrotic effects by enhancing the expression of integrin β-1, which is essential for myofibroblasts activation and ECM production [82].

7. Therapeutic Effects of PAK Inhibitors in Liver Disorders

The main strategy for treating HBV or HCV-related liver diseases is long-term administration of antiviral drugs such as entecavir, disoproxil, and IFN-α. Different from HCV, HBV has the characteristic of escaping innate immunity, thus immune therapy is also a vital treatment for HBV [83][84]. For metabolism-related liver diseases, limiting alcohol consumption, changing eating patterns and diet composition, and reducing insulin resistance and improving lipid metabolism are effective regimens [85][86].
Liver resection and transplantation are considered as curative treatments for HCC. However, only a small proportion of patients can have these surgical operations at the diagnosis stage and the recurrence after surgery is high. Most HCC patients are diagnosed at advanced stages of the disease and can only have non-surgical treatments, including chemo-, radio-, and immune-therapies. The first-line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors, such as sorafenib and lenvatinib, and combinational therapies of immunotherapy and anti-angiogenesis therapy [87].
PAKs play key roles in liver disorders and thus are considered useful targets for the treatment of liver diseases. PAK inhibitors have been developed and can be divided into two categories depending on the binding sites within PAK molecules, ATP-competitive inhibitors, and allosteric PAK inhibitors [88]. ATP-competitive PAK inhibitors block PAK phosphorylation by targeting the ATP-binding pocket within the kinase domain. This type of PAK inhibitors is further classified into aminopyrazole-based inhibitors, aminopyrimidine-based inhibitors, indolocarbazole-based inhibitors, 2-amino pyrido[2,3-d] pyrimidine-7(8H)-one-based inhibitors, and other ATP-competitive inhibitors. Compared with ATP-competitive PAK inhibitors, allosteric PAK inhibitors have the potential to be more selective and display discriminative inhibitory activity among PAK family proteins [89][90].
The studies of the effects of PAK inhibitors in liver disorders are limited (Figure 3). PAK4 was upregulated and played a critical role in the process of hepatic IRI. Application of an ATP-competitive PAK4 inhibitor ND201651 reduced hepatic IRI [6]. Another novel specific PAK4 inhibitor, SPA7012, a pyrazolo [3,4-d] pyrimidine derivative, also showed an anti-inflammatory effect on the liver during hepatic IRI [91]. More experimental evidence is necessary for its clinical application.
/media/item_content/202303/640ac3118480acancers-15-00551-g004.png
Figure 3. PAK inhibitors applied in liver disorders. Abbreviations: HCC, hepatocellular carcinoma; IRI, ischemia-reperfusion injury; PAK, p21 Activated Kinase; ROS, reactive oxygen species.
IPA-3 is a non-ATP-competitive allosteric inhibitor targeting PAK1 phosphorylation. Since group I PAKs share the same inhibitory domain in the N-terminal sequence, IPA-3 also suppresses the activation of PAK2 and PAK3 [92]. Administration of IPA-3 remarkably improved the bile duct ligation and CCl4-induced fibrosis in mice without hepatotoxicity [82]. IPA-3 suppressed HCC growth by inhibition of PAK1-mediated JNK phosphorylation and NF-κB intranuclear localization [21].

8. Conclusions

PAKs play pivotal roles in the progression of liver disorders including liver cancer, hepatic IRI, hepatitis, and liver fibrosis. Elevated PAKs expression in liver cancer stimulates tumor growth and metastasis, contributes to therapeutical resistance, and is associated with the poor prognosis of patients. The studies of the effects of PAK1 and PAK4 in hepatic IRI have provided a useful guide for the potential application of PAK inhibitors in clinical settings. PAK1, the most extensively studied PAKs, plays important roles in the occurrence of hepatitis and liver fibrosis through affecting hepatocytes, immune cells, and myofibroblasts. It is worth noting that PAK1 promotes the development of HBV, hepatitis E virus, parasite, and autoimmune-related hepatitis while inhibiting HCV-induced hepatitis. With the increased occurrence of metabolism-related liver disease such as NAFLD, it is becoming important to explore the association between PAKs and liver metabolism and mechanisms involved.

References

  1. Rane, C.K.; Minden, A. P21 activated kinase signaling in cancer. Semin. Cancer Biol. 2019, 54, 40–49.
  2. Fruman, D.A.; Chiu, H.; Hopkins, B.D.; Bagrodia, S.; Cantley, L.C.; Abraham, R.T. The PI3K Pathway in Human Disease. Cell 2017, 170, 605–635.
  3. Li, Q.; Sun, M.; Wang, M.; Feng, M.; Yang, F.; Li, L.; Zhao, J.; Chang, C.; Dong, H.; Xie, T.; et al. Dysregulation of Wnt/β-catenin signaling by protein kinases in hepatocellular carcinoma and its therapeutic application. Cancer Sci. 2021, 112, 1695–1706.
  4. Zhou, Q.; Gu, T.; Zhang, Y.; Li, H.; Zhuansun, X.; Xu, S.; Kuang, Y. Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Hepatic Stellate Cell Activation and Liver Fibrosis by Upregulating MicroRNA-455-3p through Suppression of p21-Activated Kinase-2. BioMed Res. Int. 2021, 2021, 6685605.
  5. Ruan, P.; Dai, X.; Sun, J.; He, C.; Huang, C.; Zhou, R.; Chemin, I. Integration of hepatitis B virus DNA into p21-activated kinase 3 (PAK3) gene in HepG2.2.15 cells. Virus Genes 2020, 56, 168–173.
  6. Mao, Y.; Han, C.Y.; Hao, L.; Lee, Y.; Son, J.B.; Choi, H.; Lee, M.R.; Yang, J.D.; Hong, S.K.; Suh, K.S.; et al. p21-activated kinase 4 inhibition protects against liver ischemia/reperfusion injury: Role of nuclear factor erythroid 2-related factor 2 phosphorylation. Hepatology 2022, 76, 345–356.
  7. Tse, E.Y.; Ching, Y.P. The role of p21-activated kinases in hepatocellular carcinoma metastasis. J. Mol. Signal. 2014, 9, 7.
  8. Rane, C.K.; Minden, A. P21 activated kinases: Structure, regulation, and functions. Small GTPases 2014, 5, e28003.
  9. Liu, H.; Liu, K.; Dong, Z. The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading? Front. Cell Dev. Biol. 2021, 9, 41381.
  10. Baskaran, Y.; Ng, Y.; Selamat, W.; Ling, F.T.P.; Manser, E. Group I and II mammalian PAKs have different modes of activation by Cdc42. EMBO Rep. 2012, 13, 653–659.
  11. Ha, B.H.; Davis, M.J.; Chen, C.; Lou, H.J.; Gao, J.; Zhang, R.; Krauthammer, M.; Halaban, R.; Schlessinger, J.; Turk, B.E.; et al. Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate. Proc. Natl. Acad. Sci. USA 2012, 109, 16107–16112.
  12. Chan, C.H.; Chiou, L.W.; Lee, T.Y.; Liu, Y.R.; Hsieh, T.H.; Yang, C.Y.; Jeng, Y.M. PAK and PI3K pathway activation confers resistance to KRAS(G12C) inhibitor sotorasib. Br. J. Cancer 2023, 128, 148–159.
  13. Higuchi, M.; Onishi, K.; Kikuchi, C.; Gotoh, Y. Scaffolding function of PAK in the PDK1–Akt pathway. Nature 2008, 10, 1356–1364.
  14. King, H.; Thillai, K.; Whale, A.; Arumugam, P.; Eldaly, H.; Kocher, H.M.; Wells, C.M. PAK4 interacts with p85 alpha: Implications for pancreatic cancer cell migration. Sci. Rep. 2017, 7, 2575.
  15. Park, S.Y.; An, J.M.; Seo, J.T.; Seo, S.R. Y-27632 Induces Neurite Outgrowth by Activating the NOX1-Mediated AKT and PAK1 Phosphorylation Cascades in PC12 Cells. Int. J. Mol. Sci. 2020, 21, 7679.
  16. Fu, X.; Feng, J.; Zeng, D.; Ding, Y.; Yu, C.; Yang, B. PAK4 confers cisplatin resistance in gastric cancer cells via PI3K/Akt- and MEK/ERK-dependent pathways. Biosci. Rep. 2014, 34, e00094.
  17. Huang, N.; Li, S.; Xie, Y.; Han, Q.; Xu, X.M.; Sheng, Z.H. Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia. Curr. Biol. 2021, 31, 3098–3114.
  18. Beeser, A.; Jaffer, Z.M.; Hofmann, C.; Chernoff, J. Role of Group A p21-activated Kinases in Activation of Extracellular-regulated Kinase by Growth Factors. J. Biol. Chem. 2005, 280, 36609–36615.
  19. Frost, J.A.; Swantek, J.L.; Stippec, S.; Yin, M.J.; Gaynor, R.; Cobb, M.H. Stimulation of NFkappa B activity by multiple signaling pathways requires PAK1. J. Biol. Chem. 2000, 275, 19693–19699.
  20. Zhu, M.; Xu, Y.; Zhang, W.; Gu, T.; Wang, D. Inhibition of PAK1 alleviates cerulein-induced acute pancreatitis via p38 and NF-κB pathways. Biosci. Rep. 2019, 39, BSR20182221.
  21. Wong, L.L.; Lam, I.P.; Wong, T.Y.; Lai, W.L.; Liu, H.F.; Yeung, L.L.; Ching, Y.P. IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation. PLoS ONE 2013, 8, e68843.
  22. Liu, J.; Ren, G.; Li, K.; Liu, Z.; Wang, Y.; Chen, T.; Mu, W.; Yang, X.; Li, X.; Shi, A.; et al. The Smad4-MYO18A-PP1A complex regulates β-catenin phosphorylation and pemigatinib resistance by inhibiting PAK1 in cholangiocarcinoma. Cell Death Differ. 2022, 29, 818–831.
  23. Yi, Y.; Li, P.; Huang, Y.; Chen, D.; Fan, S.; Wang, J.; Yang, M.; Zeng, S.; Deng, J.; Lv, X.; et al. P21-activated kinase 2-mediated β-catenin signaling promotes cancer stemness and osimertinib resistance in EGFR-mutant non-small-cell lung cancer. Oncogene 2022, 41, 4318–4329.
  24. Li, T.T.; Mou, J.; Pan, Y.J.; Huo, F.C.; Du, W.Q.; Liang, J.; Wang, Y.; Zhang, L.S.; Pei, D.S. MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway. J. Biomed. Sci. 2021, 28, 56.
  25. Li, Y.; Shao, Y.; Tong, Y.; Shen, T.; Zhang, J.; Li, Y.; Gu, H.; Li, F. Nucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling. Biochim. Biophys. Acta (BBA)—Mol. Cell Res. 2012, 1823, 465–475.
  26. Vershinin, Z.; Feldman, M.; Chen, A.; Levy, D. PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway. J. Biol. Chem. 2016, 291, 6786–6795.
  27. Bastea, L.I.; Döppler, H.; Pearce, S.E.; Durand, N.; Spratley, S.J.; Storz, P. Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4. Biochem. J. 2013, 455, 251–260.
  28. Wang, J.; Hirose, H.; Du, G.; Chong, K.; Kiyohara, E.; Witz, I.P.; Hoon, D.S.B. P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway. Cancer Lett. 2017, 407, 6–75.
  29. El-Serag, H.B.; Rudolph, K.L. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007, 132, 2557–2576.
  30. McGlynn, K.A.; London, W.T. The global epidemiology of hepatocellular carcinoma: Present and future. Clin. Liver Dis. 2011, 15, 223–243.
  31. Parekh, P.; Rao, K.V. Overexpression of cyclin D1 is associated with elevated levels of MAP kinases, Akt and Pak1 during diethylnitrosamine-induced progressive liver carcinogenesis. Cell Biol. Int. 2007, 31, 35–43.
  32. Razavi, H.; Waked, I.; Sarrazin, C.; Myers, R.P.; Idilman, R.; Calinas, F.; Vogel, W.; Mendes Correa, M.C.; Hézode, C.; Lázaro, P.; et al. The present and future disease burden of hepatitis C virus (HCV) infection with today’s treatment paradigm. J. Viral Hepat. 2014, 21 (Suppl. 1), 4–59.
  33. Best, M.; Gale, M.E.; Wells, C.M. PAK-dependent regulation of actin dynamics in breast cancer cells. Int. J. Biochem. Cell Biol. 2022, 146, 06207.
  34. Wang, M.; Zhang, C.; Zheng, Q.; Ma, Z.; Qi, M.; Di, G.; Ling, S.; Xu, H.; Qi, B.; Yao, C.; et al. RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways. Int. J. Biol. Sci. 2022, 18, 942–955.
  35. Lei, K.; Luo, M.; Tu, Z.; Lv, S.; Liu, J.; Gong, C.; Ye, M.; Wu, M.; Sheng, Y.; Long, X.; et al. Comprehensive analysis of the prognostic implications and functional exploration of PAK gene family in human cancer. Cancer Cell Int. 2022, 22, 275.
  36. Yu, X.; Huang, C.; Liu, J.; Shi, X.; Li, X. The significance of PAK4 in signaling and clinicopathology: A review. Open Life Sci. 2022, 17, 586–598.
  37. Kumar, R.; Li, D.Q. PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Adv. Cancer Res. 2016, 130, 37–209.
  38. Cao, F.; Yin, L.X. PAK1 promotes proliferation, migration and invasion of hepatocellular carcinoma by facilitating EMT via directly up-regulating Snail. Genomics 2020, 112, 694–702.
  39. Zhang, Z.-L.; Liu, G.-C.; Peng, L.; Zhang, C.; Jia, Y.-M.; Yang, W.-H.; Mao, L. Effect of PAK1 gene silencing on proliferation and apoptosis in hepatocellular carcinoma cell lines MHCC97-H and HepG2 and cells in xenograft tumor. Gene Ther. 2018, 25, 284–296.
  40. Ching, Y.P.; Leong, V.Y.; Lee, M.F.; Xu, H.T.; Jin, D.Y.; Ng, I.O. P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation. Cancer Res. 2007, 67, 3601–3608.
  41. Gujdár, A.; Sipeki, S.; Bander, E.; Buday, L.; Faragó, A. Phorbol ester-induced migration of HepG2 cells is accompanied by intensive stress fibre formation, enhanced integrin expression and transient down-regulation of p21-activated kinase 1. Cell. Signal. 2003, 15, 307–318.
  42. Zhang, J.G.; Zhou, H.M.; Zhang, X.; Mu, W.; Hu, J.N.; Liu, G.L.; Li, Q. Hypoxic induction of vasculogenic mimicry in hepatocellular carcinoma: Role of HIF-1 α, RhoA/ROCK and Rac1/PAK signaling. BMC Cancer 2020, 20, 32.
  43. Chen, L.; Liu, H.; Liu, J.; Zhu, Y.; Xu, L.; He, H.; Zhang, H.; Wang, S.; Wu, Q.; Liu, W.; et al. Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma. PLoS ONE 2013, 8, e58413.
  44. Liu, J.; Liu, H.; Zhang, W.; Wu, Q.; Liu, W.; Liu, Y.; Pan, D.; Xu, J.; Gu, J. N-acetylglucosaminyltransferase V confers hepatoma cells with resistance to anoikis through EGFR/PAK1 activation. Glycobiology 2013, 23, 1097–1109.
  45. Parekh, P.; Motiwale, L.; Naik, N.; Rao, K.V. Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells. Exp. Toxicol. Pathol. 2011, 63, 67–173.
  46. Iyer, S.C.; Gopal, A.; Halagowder, D. Myricetin induces apoptosis by inhibiting P21 activated kinase 1 (PAK1) signaling cascade in hepatocellular carcinoma. Mol. Cell. Biochem. 2015, 407, 223–237.
  47. Janardhan, H.P.; Meng, X.; Dresser, K.; Hutchinson, L.; Trivedi, C.M. KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K-MAPK1 inhibition. J. Exp. Med. 2020, 217, e20192205.
  48. Chen, L.; Bi, S.; Hou, J.; Zhao, Z.; Wang, C.; Xie, S. Targeting p21-activated kinase 1 inhibits growth and metastasis via Raf1/MEK1/ERK signaling in esophageal squamous cell carcinoma cells. Cell Commun. Signal. 2019, 17, 31.
  49. Cheng, C.; Kong, X.; Wang, H.; Gan, H.; Hao, Y.; Zou, W.; Wu, J.; Chi, Y.; Yang, J.; Hong, Y.; et al. Trihydrophobin 1 Interacts with PAK1 and Regulates ERK/MAPK Activation and Cell Migration. J. Biol. Chem. 2009, 284, 8786–8796.
  50. Tu, J.; Zhao, Z.; Xu, M.; Chen, M.; Weng, Q.; Ji, J. LINC00460 promotes hepatocellular carcinoma development through sponging miR-485-5p to up-regulate PAK1. Biomed. Pharmacother. 2019, 118, 109213.
  51. Zhang, X.; Zhang, X.; Wang, T.; Wang, L.; Tan, Z.; Wei, W.; Yan, B.; Zhao, J.; Wu, K.; Yang, A.; et al. MicroRNA-26a is a key regulon that inhibits progression and metastasis of c-Myc/EZH2 double high advanced hepatocellular carcinoma. Cancer Lett. 2018, 426, 8–108.
  52. Sato, M.; Matsuda, Y.; Wakai, T.; Kubota, M.; Osawa, M.; Fujimaki, S.; Sanpei, A.; Takamura, M.; Yamagiwa, S.; Aoyagi, Y. p21-activated kinase-2 is a critical mediator of transforming growth factor-β-induced hepatoma cell migration. J. Gastroenterol. Hepatol. 2013, 28, 1047–1055.
  53. Koth, A.P.; Oliveira, B.R.; Parfitt, G.M.; Buonocore Jde, Q.; Barros, D.M. Participation of group I p21-activated kinases in neuroplasticity. J. Physiol. 2014, 108, 70–277.
  54. Gao, Z.; Zhong, M.; Ye, Z.; Wu, Z.; Xiong, Y.; Ma, J.; Chen, H.; Zhu, Y.; Yang, Y.; Zhao, Y.; et al. PAK3 promotes the metastasis of hepatocellular carcinoma by regulating EMT process. J. Cancer 2022, 13, 153–161.
  55. Li, Q.; Zhang, X.; Wei, N.; Liu, S.; Ling, Y.; Wang, H. p21-activated kinase 4 as a switch between caspase-8 apoptosis and NF-κB survival signals in response to TNF-α in hepatocarcinoma cells. Biochem. Biophys. Res. Commun. 2018, 503, 3003–3010.
  56. Callegari, E.; D’Abundo, L.; Guerriero, P.; Simioni, C.; Elamin, B.K.; Russo, M.; Cani, A.; Bassi, C.; Zagatti, B.; Giacomelli, L.; et al. miR-199a-3p Modulates MTOR and PAK4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model. Mol. Ther. Nucleic Acids 2018, 11, 85–493.
  57. Hou, J.; Lin, L.; Zhou, W.; Wang, Z.; Ding, G.; Dong, Q.; Qin, L.; Wu, X.; Zheng, Y.; Yang, Y.; et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 2011, 19, 232–243.
  58. Mak, G.W.; Chan, M.M.; Leong, V.Y.; Lee, J.M.; Yau, T.O.; Ng, I.O.; Ching, Y.P. Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis. Cancer Res. 2011, 71, 2949–2958.
  59. Xu, H.T.; Lai, W.L.; Liu, H.F.; Wong, L.L.; Ng, I.O.; Ching, Y.P. PAK4 Phosphorylates p53 at Serine 215 to Promote Liver Cancer Metastasis. Cancer Res. 2016, 76, 5732–5742.
  60. Lu, S.X.; Zhang, C.Z.; Luo, R.Z.; Wang, C.H.; Liu, L.L.; Fu, J.; Zhang, L.; Wang, H.; Xie, D.; Yun, J.P. Zic2 promotes tumor growth and metastasis via PAK4 in hepatocellular carcinoma. Cancer Lett. 2017, 402, 1–80.
  61. Xue, J.; Chen, L.Z.; Li, Z.Z.; Hu, Y.Y.; Yan, S.P.; Liu, L.Y. MicroRNA-433 inhibits cell proliferation in hepatocellular carcinoma by targeting p21 activated kinase (PAK4). Mol. Cell. Biochem. 2015, 399, 7–86.
  62. Shao, S.; Hu, Q.; Wu, W.; Wang, M.; Huang, J.; Zhao, X.; Tang, G.; Liang, T. Tumor-triggered personalized microRNA cocktail therapy for hepatocellular carcinoma. Biomater. Sci. 2020, 8, 6579–6591.
  63. Wang, M.; Zhang, J.; Gong, N. Role of the PI3K/Akt signaling pathway in liver ischemia reperfusion injury: A narrative review. Ann. Palliat. Med. 2022, 11, 806–817.
  64. Dery, K.J.; Kupiec-Weglinski, J.W. New insights into ischemia-reperfusion injury signaling pathways in organ transplantation. Curr. Opin. Organ Transplant. 2022, 27, 424–433.
  65. Gao, F.; Qiu, X.; Wang, K.; Shao, C.; Jin, W.; Zhang, Z.; Xu, X. Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments. Aging Dis. 2022, 13, 1196–1214.
  66. Ma, Y.; Nikfarjam, M.; He, H. The trilogy of P21 activated kinase, autophagy and immune evasion in pancreatic ductal adenocarcinoma. Cancer Lett. 2022, 24, 215868.
  67. Wang, K.; Zhan, Y.; Huynh, N.; Dumesny, C.; Wang, X.; Asadi, K.; Herrmann, D.; Timpson, P.; Yang, Y.; Walsh, K.; et al. Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1. Cancer Lett. 2020, 472, 8–18.
  68. Micó-Carnero, M.; Casillas-Ramírez, A.; Sánchez-González, A.; Rojano-Alfonso, C.; Peralta, C. The Role of Neuregulin-1 in Steatotic and Non-Steatotic Liver Transplantation from Brain-Dead Donors. Biomedicines 2022, 10, 978.
  69. Castaneda, D.; Gonzalez, A.J.; Alomari, M.; Tandon, K.; Zervos, X.B. From hepatitis A to E: A critical review of viral hepatitis. World J. Gastroenterol. 2021, 27, 1691–1715.
  70. Hosseini, N.; Shor, J.; Szabo, G. Alcoholic Hepatitis: A Review. Alcohol Alcohol. 2019, 54, 408–416.
  71. Sucher, E.; Sucher, R.; Gradistanac, T.; Brandacher, G.; Schneeberger, S.; Berg, T. Autoimmune Hepatitis—Immunologically Triggered Liver Pathogenesis—Diagnostic and Therapeutic Strategies. J. Immunol. Res. 2019, 2019, 9437043.
  72. Targher, G.; Tilg, H.; Byrne, C.D. Non-alcoholic fatty liver disease: A multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol. Hepatol. 2021, 6, 578–588.
  73. Chen, J.; Siddiqui, A. Hepatitis B Virus X Protein Stimulates the Mitochondrial Translocation of Raf-1 via Oxidative Stress. J. Virol. 2007, 81, 6757–6760.
  74. Xu, J.; Liu, H.; Chen, L.; Wang, S.; Zhou, L.; Yun, X.; Sun, L.; Wen, Y.; Gu, J. Hepatitis B Virus X Protein Confers Resistance of Hepatoma Cells to Anoikis by Up-regulating and Activating p21-Activated Kinase 1. Gastroenterology 2012, 143, 199–212.e4.
  75. Ishida, H.; Li, K.; Yi, M.; Lemon, S.M. p21-activated kinase 1 is activated through the mammalian target of rapamycin/p70 S6 kinase pathway and regulates the replication of hepatitis C virus in human hepatoma cells. J. Biol. Chem. 2007, 282, 11836–11848.
  76. Nguyen, H.; Sankaran, S.; Dandekar, S. Hepatitis C virus core protein induces expression of genes regulating immune evasion and anti-apoptosis in hepatocytes. Virology 2006, 354, 58–68.
  77. Chang, H.; He, K.Y.; Li, C.; Ni, Y.Y.; Li, M.N.; Chen, L.; Hou, M.; Zhou, Z.; Xu, Z.P.; Ji, M.J. P21 activated kinase-1 (PAK1) in macrophages is required for promotion of Th17 cell response during helminth infection. J. Cell. Mol. Med. 2020, 24, 14325–14338.
  78. Lin, R.; Zhang, J.; Zhou, L.; Wang, B. Altered function of monocytes/macrophages in patients with autoimmune hepatitis. Mol. Med. Rep. 2016, 13, 3874–3880.
  79. Afifiyan, N.; Tillman, B.; French, B.A.; Sweeny, O.; Masouminia, M.; Samadzadeh, S.; French, S.W. The role of Tec kinase signaling pathways in the development of Mallory Denk Bodies in balloon cells in alcoholic hepatitis. Exp. Mol. Pathol. 2017, 103, 191–199.
  80. Kisseleva, T.; Brenner, D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol. 2020, 18, 151–166.
  81. Roehlen, N.; Crouchet, E.; Baumert, T.F. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells 2020, 9, 875.
  82. Martin, K.; Pritchett, J.; Llewellyn, J.; Mullan, A.F.; Athwal, V.S.; Dobie, R.; Harvey, E.; Zeef, L.; Farrow, S.; Streuli, C.; et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat. Commun. 2016, 7, 2502.
  83. Odenwald, M.A.; Paul, S. Viral hepatitis: Past, present, and future. World J. Gastroenterol. 2022, 28, 1405–1429.
  84. Fanning, G.C.; Zoulim, F.; Hou, J.; Bertoletti, A. Therapeutic strategies for hepatitis B virus infection: Towards a cure. Nat. Rev. Drug Discov. 2019, 18, 827–844.
  85. Powell, E.E.; Wong, V.W.; Rinella, M. Non-alcoholic fatty liver disease. Lancet 2021, 397, 2212–2224.
  86. Ganne-Carrié, N.; Nahon, P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J. Hepatol. 2019, 70, 284–293.
  87. Fan, Y.; Xue, H.; Zheng, H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J. Hepatocell. Carcinoma 2022, 9, 233–263.
  88. Yao, D.; Li, C.; Rajoka, M.S.R.; He, Z.; Huang, J.; Wang, J.; Zhang, J. P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer. Theranostics 2020, 10, 9741–9766.
  89. Rudolph, J.; Crawford, J.J.; Hoeflich, K.P.; Chernoff, J. p21-activated kinase inhibitors. Enzymes 2013, 34, 57–180.
  90. Amirthalingam, M.; Palanisamy, S.; Tawata, S. p21-Activated kinase 1 (PAK1) in aging and longevity: An overview. Ageing Res. Rev. 2021, 71, 101443.
  91. Mao, Y.; Lee, E.; Yang, X.; Bae, E.J.; Jeon, R.; Park, B.H. Targeting p21-activated kinase 4 (PAK4) with pyrazolopyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice. J. Enzyme Inhib. Med. Chem. 2022, 37, 2133–2146.
  92. Deacon, S.W.; Beeser, A.; Fukui, J.A.; Rennefahrt, U.E.; Myers, C.; Chernoff, J.; Peterson, J.R. An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem. Biol. 2008, 15, 322–331.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Xun Qiu
,
Hanzhi Xu
,
Kai Wang
,
Fengqiang Gao
,
Xiao Xu
,
Hong He
View Times: 530
Revisions: 2 times (View History)
Update Date: 10 Mar 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback