PAK6 (P21 (RAC1) Activated Kinase 6)

Mechanistically, K176la strengthened the binding of HNRNPC with poly-U motifs in p21-activated kinase 6 (PAK6) pre-mRNA, facilitating the expression of the oncogenic isoform PAK6S. Therefore, our study identifies a number of cancer-specific Kla sites spanned on alternative splicing (AS)-related proteins and unravels the significance of HNRNPC K176la in RNA splicing and PC development.

These findings highlight LNN as a critical prognostic factor in NPC and suggest that PAK6 could be a promising therapeutic target for improving treatment outcomes in NPC patients.

Our study underscores the significance of PAK6 as a diagnostic and prognostic biomarker in CRC, with the potential to inform targeted therapeutic strategies and enhance patient outcomes. Future research should focus on validating these findings in larger cohorts and exploring PAK6-targeted interventions to improve immunotherapeutic responses in CRC patients.

Increased serum PAK6 expression correlated with shorter PFS (HR = 2.02 [1.33-3.07], P = 0.001). Serum PAK6 holds significant clinical value for the diagnosis, treatment monitoring, and prognosis evaluation of SCLC and may serve as a potential therapeutic target for the disease.

This study demonstrates that PUM1 enhances the RNA stability of PAK6, thereby contributing to ferroptosis resistance in LUAD cells.

In this study, we specifically targeted PAK6 in imatinib (IM)-resistant cells and CD34+ stem/progenitor cells from IM-nonresponders using a lentiviral-mediated PAK6 knockdown strategy...Mechanically, we identified a PAK6-mediated MDM2-p21 axis that regulates cell cycle arrest and senescence. Thus, PAK6 plays a critical role in determining alternative cell fates in leukemic cells, and targeting PAK6 may offer a therapeutic strategy to selectively eradicate TKI-resistant cells.

In subsequent combination screenings, cladribine, venetoclax, and azacytidine emerged as most effective combination partners of STAT3/STAT5 degraders, even in low-responding T-PLL samples, all synergistically reducing STAT5 phosphorylation. These findings highlight dual STAT3/STAT5 inhibition, particularly in combination with hypomethylating and BCL2-targeting agents, as a promising interventional approach in T-PLL, warranting further investigation.

Notably, a positive correlation between METTL3 and PAK6 expression is observed in clinical specimens of CC. Collectively, our findings highlight the critical role of METTL3/PAK6 axis in driving CC progression, offering potential therapeutic targets for patients with CC.

miR-3191 promotes the proliferation and metastasis of HCC cells via targeting PAK6 and may serve as a prognostic biomarker and potential therapeutic target.

Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.

Further validation experiments confirmed that VAS significantly reduced the mRNA and protein expression of PAK6, which led to the abolition of cell viability and colony formation. These findings demonstrated that VAS reduced cell viability, suppressed colony formation and induced autophagy and revealed PAK6 and other DEGs as potential therapeutic targets for GBM treatment.

Our work points to an important PAK6-IQGAP3-RhoA pathway that drives the cellular contractility of breast cancer cells promoting both cell migration and adhesive invasion of these cells. As this phenotype is relevant to the process of metastasis and re-seeding of metastasis, the pharmacological targeting of PAK6 could lead to clinical benefit in TNBC patients.