Ask about this productRelated genes to: PAK4 protein
- Gene:
- PAK4 NIH gene
- Name:
- p21 (RAC1) activated kinase 4
- Previous symbol:
- -
- Synonyms:
- -
- Chromosome:
- 19q13.2
- Locus Type:
- gene with protein product
- Date approved:
- 2001-07-12
- Date modifiied:
- 2016-05-03
Related products to: PAK4 protein
Related articles to: PAK4 protein
- The phosphorylation dependent regulation of transcription factors, transcriptional co-regulators and chromatin remodelling factors influences transcription. Aberrant transcriptional regulations driven by chromatin-associated oncogenic factors are a feature of various cancers; however, their phosphorylation-dependent regulation remains poorly characterised. ATPase family AAA domain-containing protein 2 (ATAD2) is a chromatin-associated factor implicated in oncogenic transcriptions. Here, we present a comprehensive phosphosite-centric analysis of ATAD2 by integrating data from multiple phosphoproteomic studies, encompassing 859 profiling and 285 differential datasets. From the class 1 differentially regulated phosphosites, four predominant phosphosites-S327, S337, S342, and T1152, emerged as consistently regulated and were frequently detected in diverse tumour datasets. The co-differentially phosphorylated proteins, including their interactors and potential upstream kinases (HASPIN, STK10, CDK12, PRP4K, CDK13, PAK4), were involved in cell cycle, chromatin remodelling, transcription, and DNA repair. Several phosphosites in transcription factors were found to be coregulated along with ATAD2 phosphosites. Phosphorylation at S327 and S342 was broadly upregulated and positively associated with transcriptional activators, suggesting a role in promoting transcription. In contrast, phosphorylation at S337 and T1152 correlated with proteins involved in transcriptional repression, indicating its involvement in inhibitory function. Collectively, these findings indicate the involvement of the ATAD2 phosphoregulatory network in transcriptional regulation and provide insights into the regulatory landscape of ATAD2, laying the groundwork for its potential therapeutic targeting in cancers. - Source: PubMed
Publication date: 2026/04/11
Fahma AmalLubaba FathimathulMohan AswinSekhar Pathiyil SajiniGopalakrishnan Athira PerunellyRaju Rajesh - Rhotekin (RTKN), a Rho GTPase effector, promotes the development of malignancies, including breast, gastric, and colon cancers, by enhancing cell proliferation and migration while inhibiting apoptosis. Despite its oncogenic role, the phosphoregulatory network of RTKN remains largely unexplored, with no experimental evidence on its upstream kinases and functional phosphosites. To characterize RTKN-associated phosphorylation dynamics, PubMed-indexed studies were systematically retrieved using predefined MeSH terms to compile large-scale cellular phosphoproteomics datasets. Analysis of 618 quantitative profiling and 179 differential abundance datasets identified 27 Class-I phosphosites in RTKN. Among these, five sites-Ser106, Ser220, Ser520, Ser529, and Ser543 were consistently observed across multiple datasets, suggesting them as predominant sites with potential functional significance. Structural mapping of predominant sites onto the AlphaFold2-predicted model indicated that these sites are located in accessible regions, highlighting their potential susceptibility to kinase-mediated regulation. As these sites represent understudied phosphosites, a robust strategy was employed to identify their functional role by assessing co-regulated phosphosites on other proteins (PsOPs). ACIN1_Ser243, CTNNA1_Ser641, and SHROOM2_Ser1036 were among the top positively co-regulated PsOPs, whereas MICALL1_Ser644, PRP4K_Ser366, and MYO18A_Ser1970 were negatively co-regulated. PsOPs were mainly involved in apoptosis, cell growth, motility, and cytoskeletal reorganization, suggesting potential functional convergence with RTKN. Additionally, phosphorylation at RTKN Ser520 and Ser543 co-occurred across multiple datasets. Moreover, TRPM7 and PAK4 were identified as predicted upstream kinases phosphorylating RTKN at Ser220 and Ser520. Pathway analysis showed involvement of co-regulated proteins in cancer-associated signaling pathways. These findings provide a foundation for future research to elucidate the phosphosite-specific role of RTKN in cancer. - Source: PubMed
Publication date: 2026/04/10
Palollathil AkhinaMahin AlthafGopalakrishnan Athira PerunellySambreena AlimathUmmar SamseeraShivamurthy Prathik BasthikoppaGanesan RVijayakumar ManavalanRaju Rajesh - Endometriosis is a benign yet invasive disease characterized by ectopic endometrial growth and immune remodeling. While emerging evidence implicates cellular senescence in disease progression, the underlying mechanisms remain largely undefined. In this study, we identified marked heterogeneity in senescence across ectopic lesions and observed that P21-activated kinase 4 (PAK4) was consistently upregulated in senescent cells. Mechanistically, senescence induced PAK4 expression, which in turn interacted with AKT and enhanced its phosphorylation, thereby activating the PI3K/AKT signaling pathway and further amplifying the senescence phenotype. This senescence-PAK4-AKT positive feedback loop ultimately promoted lesion aggressiveness and M2 macrophage polarization. Silencing PAK4 alleviated cellular senescence, attenuated lesion invasiveness, and suppressed immune remodeling. Notably, stigmasterol, a natural phytosterol, effectively downregulated PAK4 expression, disrupted the senescence-AKT feedback loop, and consequently inhibited senescence, invasion, and M2 polarization both in vitro and in vivo. Together, our findings establish a senescence-driven PAK4/AKT signaling circuit that fosters an aggressive, immunomodulatory endometriosis subtype and identify stigmasterol as a promising senescence-targeted therapeutic agent. - Source: PubMed
Liu JingchunHan WuyueTang JianmingWan HuanzhiWang HaoyuPeng JiaxinMa WenjingHu MinHong Li - Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that represents a significant therapeutic challenge because of its immunosuppressive tumor microenvironment (TME). GBM employs multiple sophisticated mechanisms for immune evasion, including proinflammatory cytokine secretion and immune cell effector function impairment. Due to these complex immune evasion strategies, immunotherapies are effective in only a minority of GBM patients. Herein, we identified P21-activated kinase 4 (PAK4) as a critical immunosuppressive gene that is highly expressed in GBM and actively promotes tumor progression. Mechanistically, PAK4 mediates transforming growth factor-beta 1 (TGF-β1) release from GBM cells, triggering PI3K/AKT/NF-κB signalling pathway activation in CD8 + T cells, which consequently upregulates phospholipase A2 group IVA (PLA2G4A) expression. PLA2G4A activation triggers phosphatidylcholine (PC) depletion in CD8 + T cells, damages mitochondrial and lysosomal functions, inducing subsequent mitophagic flux suppression, which culminates in the functional exhaustion of CD8 + T cells. Furthermore, PLA2G4A inhibitor treatment effectively reduces CD8 + T cell exhaustion while enhancing T cell cytotoxic capacity. Finally, combined PAK4 inhibitor and anti-PD-L1 therapy increases the CD8 + T cell cytotoxic function and suppresses tumor growth. Overall, our study results suggest that targeting PAK4 could be a potential strategy for GBM immunotherapy. - Source: PubMed
Publication date: 2026/03/23
Yao LinGao HeyangSu ZuopengZhao GuozhengTang LiyanFeng ShuoMa YutingZhang XiaoFeng MingQian JialiangLi YanyanSun TingLiu JiangangWang HaoZhou Youxin - Subretinal fibrosis underlies the end-stage pathogenesis of retinal diseases including age-related macular degeneration (AMD). It can disrupt retinal structure and eventually lead to legal blindness by generating contractile force, fibrotic scarring, subretinal hemorrhage, and retinal detachment. Myofibroblasts are the predominant cells critically involved in subretinal fibrosis, however, the cellular contribution to myofibroblasts remains unclear. Here we demonstrate that multiple cell lineages, including macrophages, endothelial cells (EC), retinal pigment epithelial (RPE) cells and pericytes, significantly contribute to myofibroblasts in a laser-induced subretinal fibrosis model. We found microRNA is significantly downregulated in the plasma of wet AMD patients. Overexpression of represses epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndMT), and the resulting fibrosis by regulating TGF-β/SMAD3 and PAK4/LIMK2/MRTF pathways. Consistently, a combination of SMAD3 and MRTF inhibitors show superior efficacy to individual inhibitors in repressing fibrosis and laser-induced subretinal fibrosis . Together, these suggest the contribution of multiple cell-types in myofibroblast transformation in subretinal fibrosis, and repression of -regulated TGF-β/SMAD3 and PAK4/LIMK2/MRTF pathways in multiple cell types holds therapeutic potential for treating subretinal fibrosis in AMD and other fibrotic disorders. - Source: PubMed
Publication date: 2026/03/04
Wu YingaTong YaoByrnes Katherine GZhou QiDong ChunminBenjamin ChaseParker EmmaBao DuranRen ZhaoyangAnderson Chastain AUfret-Vincenty Rafael LHe Yu-GuangZhang ZeHinkle DavidMa JingWang Shusheng